ZOLIDRATE

Tablets, USP contains Zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class.

Tablets, USP is available in 5 mg and 10 mg strength tablets for oral administration.

Chemically, Zolpidem is N, N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1).

It has the following structure

Zolpidem Tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol.

It has a molecular weight of 764.88.

Tablet, USP includes the following inactive ingredients: lactose anhydrous, sodium starch glycolate, colloidal silicon dioxide, microcrystalline cellulose, magnesium stearate.

The 10 mg tablets also contain Opadry II (white) and the 5 mg tablets contain Opadry II (pink).

II (white) contains hypromellose, polyeth ylene glycol, polydextrose, titanium dioxide, and triacetin.

II (pink) contains hypromellose, FD&C Red no. 40 aluminum lake, FD&C Blue no. 2 aluminum lake, FD&C Yellow no. 6 aluminum lake, polyeth ylene glycol, polydextrose, titanium dioxide, and triacetin.

Test 3.

Tablets is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.

Tablets has been shown to decrease sleep latency for up to 35 days in controlled clinical studies.

The clinical trials performed in support of efficacy were 4–5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

Tablets, a gamma-aminobutyric acid (GABA) A receptor positive modulator, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.

Alcoholism History of alcoholism History of psychiatric illness History of drug abuse Depression State of dependency, history Female likely to be pregnant Pregnancy Mild to moderate hepatic impairment Respiratory impairment Newborn exposed in utero to the medicine High dose treated patient Elderly Subject debility Subject under 18 Congenital long QT syndrome Trend in drug abuse Extended treatment.

Mechanism of Action Zolpidem is a GABA A receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of α1 subunit containing GABA A receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation. 12.2 Pharmacodynamics Zolpidem binds to GABA A receptors with greater affinity for α1 subunit relative to α2 and α3 subunit containing receptors.

Zolpidem has no appreciable binding affinity for α5 subunit containing GABA A receptors.

This binding profile may explain the relative absence of myorelaxant effects in animal studies.

Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT2, adrenergic, histaminergic or muscarinic receptors. 12.3 Pharmacokinetics The pharmacokinetic profile of Zolpidem Tartrate Tablets is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life (T 1/2 ) in healthy subjects.

In a single-dose crossover study in 45 healthy subjects administered and 10 mg Zolpidem Tartrate Tablets, the mean peak concentrations (C max ) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (T max ) of 1.6 hours for both.

The mean Zolpidem Tartrate

Tablets elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the and 10 mg tablets, respectively.

Tablets is converted to inactive metabolites that are eliminated primarily by renal excretion.

Tablets demonstrated linear kinetics in the dose range of to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 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 Tablets 10 mg when administered while fasting or 20 minutes after a meal.

Results demonstrated that with food, mean AUC and C max were decreased by 15% and 25%, respectively, while mean T max 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 Tablets should not be administered with or immediately after a meal.

In the elderly, the dose for Zolpidem Tartrate Tablets should be 5 mg.

This recommendation is based on several studies in which the mean C max, T 1/2, and AUC were significantly increased when compared to results in young adults.

In one study of eight elderly subjects (>70 years), the means for C max, T 1/2, 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.

Tablets did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

Hepatic impairment The pharmacokinetics of Zolpidem Tartrate Tablets in eight patients with chronic hepatic insufficiency was compared to results in healthy subjects.

Following a single 20 mg oral ZOLPIDEM Tartrate dose, mean C max 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.

T max 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) .

Renal impairment The pharmacokinetics of Zolpidem

Tartrate was studied in 11 patients with end-stage renal failure (mean Cl Cr = 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 C max, T max, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made.

Zolpidem was not hemodialyzable.

No accumulation of unchanged drug appeared after 14 or 21 days.

Zolpidem pharmacokinetics was not significantly different in renally impaired patients.

No dosage adjustment is necessary in patients with compromised renal function.

Drug Interactions CNS-depressants Coadministration of

Zolpidem with other CNS depressants increases the risk of CNS depression.

Tartrate was evaluated in healthy volunteers 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 the absence of an effect following chronic administration.

An additive adverse effect on psychomotor performance between alcohol and oral Zolpidem was demonstrated.

Following five consecutive nightly doses at bedtime of oral Zolpidem Tartrate 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), Zolpidem C max was significantly higher (43%) and T max was significantly decreased (-53%).

Pharmacokinetics of sertraline and

N-desmethylsertraline were unaffected by Zolpidem.

A single-dose interaction study with Zolpidem

Tartrate 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 were given at steady state and the concentrations evaluated in healthy females, an increase in the Zolpidem half-life (17%) was observed.

There was no evidence of an additive effect in psychomotor performance.

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 on the pharmacokinetics of Zolpidem is unknown.

Tartrate 10 mg and itraconazole 200 mg at steady.

• state levels in male volunteers resulted in a 34% increase in AUC 0-∞ of Zolpidem tartrate.

There were no pharmacodynamic effects of

Zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.

Tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects showed significant reductions of the AUC (-73%), C max (-58%), and T 1/2 (-36 %) of Zolpidem together with significant reductions in the pharmacodynamic effects of Zolpidem tartrate.

Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of Zolpidem.

John's wort, a CYP3A4 inducer, may also decrease the blood levels of Zolpidem.

Tartrate 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased C max of Zolpidem (30%) and the total AUC of Zolpidem (70%) compared to Zolpidem alone and prolonged the elimination half-life (30 %) along with an increase in the pharmacodynamic effects of Zolpidem.

Additionally, fluvoxamine (a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2C9) and ciprofloxacin (a strong inhibitor of CYP1A2 and a moderate inhibitor of CYP3A4) are also likely to inhibit Zolpidem's metabolic pathways, potentially leading to an increase in Zolpidem exposure.

Other drugs with no interactions with Zolpidem A study involving cimetidine/Zolpidem Tartrate and ranitidine/Zolpidem Tartrate combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of Zolpidem.

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

Mechanism of action

Zolpidem is a hypnotic benzodiazepine-related imidazopyridine and has a pharmacodynamic activity qualitatively similar to that of other compounds in this class: myorelaxant, anxiolytic, sedative, hypnotic, anticonvulsive and amnesian.

Experimental studies have shown a sedative effect at doses below the doses necessary to obtain anticonvulsant, myorelaxant or anxiolytic effects.

These effects are linked to a specific agonistic action on a central receptor forming part of the GABA-OMEGA macromolecular receptor complex, also known as BZ1 and BZ2 and modulating the opening of the chlorine channel.

Zolpidem preferentially binds to the omega 1 subtype (or BZ1).

• Liver enzymes (increase) (Uncommon)
• Skin reaction (Uncommon)
• Rash (Uncommon)
• Pruritus (Uncommon)
• Urticaria (Rare)
• Asthenia (Common)
• Fatigue (Common)
• Recrudescence of symptoms Fall
• Cholestatic liver damage (Rare)
• Cholestatic hepatitis (Rare)
• Mixed hepatitis (Rare)
• Oedema of Quincke Appetizer disorder (Uncommon)
• Blurty vision (Uncommon)
• Diplopia (Uncommon)
• Visual acuity (decrease) (Rare)
• Vertigo (Common)
• Irritability (Uncommon)
• Attention disorder (Uncommon)
• Nervousness (Uncommon)
• Insomnia (Common)
• Behavioural disorder (Uncommon)
• Cognitive disorder (Common)
• Psychosis (Uncommon)
• Euphoria (Uncommon)
• Depression (Common)
• Nightmare (Common)
• Emotional Detachment (Common)
• Complex Sleep Behaviour (Uncommon)
• Mental confusion (Uncommon)
• Aggressiveness (Uncommon)
• Hallucination (Common)
• Agitation (Common)
• Delicious (Very rare)
• Libido disorder (Rare)
• Psychic dependence (Very rare)
• Physical dependence (Very rare)
• Bounce phenomenon
• Behavioural disorder Libido (decrease)
• Substance abuse Anger Abdominal pain (Common)
• Digestive disorder (Uncommon)
• Nausea (Common)
• Vomiting (Common)
• Diarrhoea (Common)
• Hepatocellular lesion (Rare)
• Muscle hypotonia (Uncommon)
• Joint pain (Uncommon)
• Muscle weakness (Common)
• Muscle pain (Uncommon)
• Muscle spasm (Uncommon)
• Headache (Common)
• Watchfulness disorder (Common)
• Speech Disorder (Uncommon)
• Somnambulism (Uncommon)
• Trembling (Uncommon)
• Paraesthesia (Uncommon)
• Alteration of consciousness (Rare)
• Balance disorder (Rare)
• Somnolence Ataxia Anterograde amnesia
• Upper respiratory tract infection (Common)
• Lower respiratory tract infection (Common)
• Respiratory depression (Very rare)
• Weaning syndrome.

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. 10.2 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.

Tablets is contraindicated in patients who have experienced complex sleep behaviors after taking Zolpidem Tartrate Tablets with known hypersensitivity to zolpidem.

Observed reactions include anaphylaxis and angioedema Patients who have experienced complex sleep behaviors after taking Zolpidem Tartrate Tablets Known hypersensitivity to Zolpidem.

Use the lowest dose effective for the patient and must not exceed a total of 10 mg daily Treatment should be as short as possible Recommended initial dose is a single dose of 5 mg for women and a single dose of 5 or 10 mg for men, immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening Geriatric patients and patients with mild to moderate hepatic impairment: Recommended dose is 5 mg for men and women Lower doses of CNS depressants may be necessary when taken concomitantly with Zolpidem Tartrate Tablets The effect of Zolpidem Tartrate Tablets may be slowed if taken with or immediately after a meal 2.1 Dosage in Adults Use the lowest effective dose for the patient.

The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening.

If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next-day impairment of driving and other activities that require full alertness.

The total dose of Zolpidem Tartrate

Tablets should not exceed 10 mg once daily immediately before bedtime.

Tablets should be taken as a single dose and should not be readministered during the same night.

The recommended initial doses for women and men are different because Zolpidem clearance is lower in women.

Long-term use of Zolpidem Tartrate

Tablets is not recommended.

Treatment should be as short as possible.

Extended treatment should not take place without re-evaluation of the patient's status because the risk of abuse and dependence increase with the duration of treatment 2.2 Special Populations Elderly or debilitated patients may be especially sensitive to the effects of Zolpidem tartrate.

The recommended dose of Zolpidem Tartrate

Tablets in these patients is 5 mg once daily immediately before bedtime.

Patients with mild to moderate hepatic impairment do not clear the drug as rapidly as normal subjects.

Tablets use in patients with severe hepatic impairment as it may contribute to encephalopathy. 2.3 Use with CNS Depressants Dosage adjustment may be necessary when Zolpidem Tartrate Tablets is combined with other CNS-depressant drugs because of the potentially additive effects. 2.4 Administration The effect of Zolpidem Tartrate Tablets may be slowed by ingestion with or immediately after a meal.

Tablets, USP 5 mg is pink film coated, round biconvex tab lets, debossed "IT 117" on one side, other side is plain and supplied as: NDC Number Size 71093-155-04 bottle of 100 71093-155-06 bottle of 1000 Zolpidem Tartrate Tablets, USP 10 mg is white film coated, round biconvex tab lets, debossed "IT 118" on one side, other side is plain and supplied as: NDC Number Size 71093-156-04 bottle of 100 71093-156-06 bottle of 1000 Store at controlled room temperature 20°C-25°C (68°F-77°F).

Risk Summary Neonates born to mothers using Zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation.

Published data on the use of

Zolpidem during pregnancy have not reported a clear association with Zolpidem and major birth defects.

Oral administration of

Zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Fetal/neonatal adverse reactions Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates.

Monitor neonates exposed to Zolpidem Tartrate

Tablets during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly.

Data Human data

Published data from observational studies, birth registries, and case reports on the use of Zolpidem during pregnancy do not report a clear association with Zolpidem and major birth defects.

There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken Zolpidem during pregnancy.

These cases required artificial ventilation or intratracheal intubation.

The majority of neonates recovered within hours to a few weeks after birth once treated.

Zolpidem has been shown to cross the placenta.

Animal data Oral administration of

Zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg Zolpidem base) based on mg/m 2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses and 120 times the MRHD based on mg/m 2 body surface area.

Zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2.5, 10, and 40 times the MRHD of 10 mg/day (8 mg Zolpidem base) based on mg/m 2 body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 40 times the MRHD based on mg/m 2 body surface area.

Zolpidem to pregnant rats from day of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10 mg/day (8 mg Zolpidem base) based on mg/m 2 body surface area, delayed offspring growth and decreased survival at doses and 120 times, respectively, the MRHD based on mg/m 2 body surface area.

Tablets is not recommended for use in children.

Safety and effectiveness of

Zolpidem in pediatric patients below the age of 18 years have not been established.

In an 8-week study, in pediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD) an oral solution of Zolpidem Tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo.

Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with Zolpidem versus placebo and included dizziness (23.5% vs 1.5%), headache (12.5% vs 9.2%), and hallucinations were reported in 7% of the pediatric patients who received Zolpidem; none of the pediatric patients who received placebo reported hallucinations.

Ten patients on

Zolpidem (7.4%) discontinued treatment due to an adverse reaction.

A total of 154 patients in U.S. controlled clinical trials and 897 patients in non-U.S. clinical trials who received Zolpidem were ≥60 years of age.

For a pool of

U.S. patients receiving Zolpidem at doses of ≤10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for Zolpidem and for which the Zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug related).

Dizziness 3% 0% Drowsiness 5% 2% Diarrhea 3% 1% A total of 30/1,959 (1.5%) non-U.S. patients receiving Zolpidem reported falls, including 28/30 (93%) who were ≥70 years of age.

Of these 28 patients, 23 (82%) were receiving Zolpidem doses >10 mg. A total of 24/1,959 (1.2%) non-U.S. patients receiving Zolpidem reported confusion, including 18/24 (75%) who were ≥70 years of age.

Of these 18 patients, 14 (78%) were receiving Zolpidem doses >10 mg. The dose of Zolpidem Tartrate Tablets in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs.