Zolpidem

Zolpidem is a Sedative and hypnotic agent belonging to Non-benzodiazepine Benzodiazepine Receptor Agonist class.

Zolpidem is a sedative hypnotic used for the short-term treatment of insomnia to improve sleep latency.

Zolpidem is Rapidly absorbed from GI tract. It is having Absolute bioavailability: of Approximately 70%. Time taken to reach peak plasma concentration for Immediate release is 1.6 hours and for extended release it is 1.5 hours. Zolpidem is having Volume of distribution of approximately 0.54 kg/L. It is Approximately 92% bound to Plasma protein. Zolpidem is metabolized to three pharmacologically by various hepatic cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, but also CYP1A2 and CYP2C9, primarily by CYP3A4 isoenzyme and it is excreted Via urine (48-67%) and about faeces (29-42%) as inactive metabolites.

Zolpidem shows side effects like Drowsiness, tiredness, headache, dizziness, light-headedness, unsteady walking, difficulty keeping balance, nausea, constipation, diarrhea, gas, heartburn, stomach pain, etc.

Zolpidem is available in the form of an Oral Tablet, Oral capsule.

Zolpidem is available in India, UK, Canada, US, Philippines, Australia, Germany, Singapore and Mexico.

Zolpidem belongs to Nonbenzodiazepine Benzodiazepine Receptor Agonis to the class acts as Sedative and hypnotic agent.

Zolpidem, an imidazopyridine hypnotic that is structurally dissimilar to benzodiazepines, enhances the activity of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA), via selective agonism at the benzodiazepine-1 (BZ₁) receptor; the result is increased chloride conductance, neuronal hyperpolarization, inhibition of the action potential, and a decrease in neuronal excitability leading to sedative and hypnotic effects. Because of its selectivity for the BZ₁ receptor site over the BZ₂ receptor site, zolpidem exhibits minimal anxiolytic, myorelaxant, and antiseizure properties (effects largely attributed to agonism at the BZ₂ receptor site).

The Onset and duration of action of Zolpidem is approximately 30 minutes and 6-8 hours respectively.

The Time to peak plasma concentration of Zolpidem approximately 1.6 hours.

Zolpidem is available in the form of an Oral Tablet, Oral capsule.

Zolpidem Tablet and capsule taken orally, immediately before bedtime due to rapid onset of action.

Zolpidem is a hypnotic and sedative which is used in severe sleep disorders.

Zolpidem is a Sedative and hypnotic agent belonging to Nonbenzodiazepine Benzodiazepine Receptor Agonist class.

Zolpidem is approved for use in the following clinical indications

• Insomnia

Zolpidem is a sedative hypnotic used for the short-term treatment of insomnia to improve sleep latency.

• Insomnia

Oral: Reduce by the smallest available dosage form every week or every other week; ER tablets and IR capsules cannot be split.

For patients taking higher doses of zolpidem (eg, 10 to 12.5 mg/day) for an extended period, tapering zolpidem even more slowly in conjunction with cognitive behavioral therapy for insomnia is encouraged. Because the ER tablets and IR capsules cannot be split, the taper is generally done with IR tablets.

Zolpidem is available in various strengths as 5 mg; 10 mg; 6.25 mg; 12.5 mg; 5 mg/spray; 3.5 mg; 1.75 mg; 7.5 mg.

Zolpidem is available in the form of an Oral Tablet, Oral capsule.

• Dosage Adjustment in Kidney Patient

No dosage adjustment is necessary for any degree of kidney dysfunction.

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate impairment: 5 mg or 6.25 mg immediately before bedtime.

Severe impairment: Avoid use.

Zolpidem is contraindicated in patients with

• Zolpidem 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.

• Depression

Use with caution in patients with depression, particularly if suicidal risk may be present.

• Drug misuse

Use with caution in patients with a history of substance use disorder. Risk of misuse is increased in patients with a history of or family history of alcohol or substance use disorder or mental illness.

• Hepatic impairment

GABA agonists, including zolpidem, have been associated with precipitation of hepatic encephalopathy in patients with hepatic impairment. Patients with hepatic impairment do not clear zolpidem as rapidly as patients with normal hepatic function. Use with caution in patients with mild to moderate hepatic impairment; dose adjustment recommended. Avoid use of IR capsules and tablets and ER tablets in patients with severe hepatic impairment; may result in encephalopathy.

• Myasthenia gravis

Use with caution in patients with myasthenia gravis.

• Respiratory disease

Use with caution in patients with respiratory compromise, COPD, or sleep apnea.

Consumption of alcohol with Zolpidem is not recommended as it increases the risk of side effects like dizziness and difficulty in concentration.

The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Zolpidem is administered to a nursing mother.

There are no adequate and well-controlled studies in pregnant women. Zolpidem should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

• Common

Abnormal gait, abnormality in thinking, aggressive behavior, altered sense of smell, apathy, delusion, dementia, drug dependence, dysphasia, hypotonia, hysteria, manic reaction, myasthenia, neuralgia, neuritis, neuropathy, neurosis, numbness of tongue, pain, panic disorder, paresis, personality disorder, restless leg syndrome, rigors, sciatica, strange feeling, yawning, Hypokinesia, osteoarthritis, tendinopathy, tetany, Abnormal lacrimation, accommodation disturbance, conjunctivitis, corneal ulcer, glaucoma, periorbital edema, photopsia, Otitis externa, otitis media, Acute kidney injury, polyuria, pyelonephritis, renal pain, Bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia, pulmonary edema, respiratory depression.

• Rare

Cholestatic hepatitis, hepatocellular hepatitis, Anaphylaxis, angioedema, Complex sleep-related disorder, delirium, somnambulism, suicidal ideation, suicidal tendencies, withdrawal syndrome, Bone fracture, femoral neck fracture Accidental injury.

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if co-administering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be co-administered with blonanserin.

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labelling states that an appropriately reduced dose should be used if such a combination must be used.

Ciprofloxacin (Systemic): May increase the serum concentration of Zolpidem. Management: Consider avoiding the combination of ciprofloxacin and zolpidem if possible. If combined, monitor for signs of zolpidem toxicity (eg, somnolence, dizziness, lethargy).

CNS Depressants: May enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol.

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended.

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available.

Hydroxyzine: May enhance the CNS depressant effect of CNS Depressants.

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary.

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression.

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania).

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended.

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide.

Valerian: May enhance the CNS depressant effect of CNS Depressants.

The common side effects of Zolpidem include the following

• Common side effects

Drowsiness, tiredness, headache, dizziness, lightheadedness, unsteady walking, difficulty keeping balance, nausea, constipation, diarrhea, gas, heartburn, stomach pain or tenderness, changes in appetite, uncontrollable shaking of a part of the body, pain, burning, numbness, or tingling in the hands, arms, feet, or legs, unusual dreams, redness, burning, or tingling of the tongue (with sublingual tablets), dry mouth or throat, ringing, pain, or itching in the ears, eye redness, muscle aches or cramps, joint, back, or neck pain, heavy menstrual bleeding.

• Rare side effects

Rash, hives, itching, swelling of the eyes, face, lips, tongue, or throat, feeling that the throat is closing, difficulty breathing or swallowing, hoarseness, shortness of breath, yellow eyes or skin, light-coloured stools, nausea, vomiting, pounding heartbeat, chest pain.

• Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Zolpidem should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

• Nursing Mothers

The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Zolpidem is administered to a nursing mother.

• Pediatric Use

Safety and effectiveness of zolpidem have not been established in pediatric patients.

Symptoms: Drowsiness, impairment of consciousness from somnolence to coma, compromised CV and respiratory function.

Management:

• Treatment is largely symptomatic and supportive.
• IV fluids should be administered as needed.
• Activated charcoal may be given if presented within 1 hour of ingestion of >1 mg/kg zolpidem in adults or children.
• Gastric lavage may be considered if presented within 1 hour of ingestion of >100 mg zolpidem and monitor for at least 12 hr.
• Flumazenil may be used if there is severe CNS depression, but generally not needed. Haemodialysis is unlikely to be useful.

• Pharmacodynamic

Zolpidem is an imidazopyridine derivative that acts by binding to the benzodiazepine (BZD) receptors of the GABA receptor complex resulting in neuronal hyperpolarisation, action potential inhibition, increased in chloride conductance and decreased in neuronal excitability. It has strong sedative action but only minimal anxiolytic, myorelaxant and anticonvulsant properties due to its selectivity for the BZ₁-receptor over the BZ₂-receptor. Zolpidem has a rapid onset but short duration of hypnotic action.

• Pharmacokinetics

Absorption

Zolpidem is Rapidly absorbed from GI tract. It is having Absolute bioavailability: of Approximately 70%. Time taken to reach peak plasma concentration for Immediate release is 1.6 hours and for extended release it is 1.5 hours.

Distribution

Zolpidem is having Volume of distribution of approximately 0.54 kg/L. It is Approximately 92% bound to Plasma protein.

Metabolism and Excretion

Zolpidem is metabolized to three pharmacologically by various hepatic cytochrome P450 (CYP) isoenzymes, mainly CYP3A4, but also CYP1A2 and CYP2C9, primarily by CYP3A4 isoenzyme and it is excreted Via urine (48-67%) and about faeces (29-42%) as inactive metabolites.

• https://www.uptodate.com/contents/zolpidem-drug-information#F236139
• https://go.drugbank.com/drugs/DB00425
• https://www.rxlist.com/ambien-drug.htm#indications
• https://medlineplus.gov/druginfo/meds/a693025.html
• https://reference.medscape.com/drug/ambien-cr-zolpidem-342931
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019908s027lbl.pdf
• https://www.drugs.com/zolpidem.html