Brands, Medical Use, Clinical Data
Drug Category
- Hypnotics and Sedatives
- Anticonvulsants
- Anxiolytics sedatives and hypnotics
Dosage Forms
Brands / Synonyms
Dea No. 2781; Sonata; Zalaplon; Zaleplon [Usan:Inn]
Indications
For the treatment of short-term treatment of insomnia in adults
Pharmacology
Zaleplon is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zaleplon is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABABZ) receptor complex. Subunit modulation of the GABABZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zaleplon binds selectively to the brain alpha subunit of the GABA A omega-1 receptor.
Mechanism of Action
Zaleplon exerts its action through subunit modulation of the GABABZ receptor chloride channel macromolecular complex.Zaleplon binds selectively to the brain alomega-1 receptor situated on the alpha subunit of the GABA-A/chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding.
Absorption
Absorption Zaleplon is rapidly and almost completely absorbed following oral administration.
Toxicity
Side effects include abdominal pain, amnesia, dizziness, drowsiness, eye pain, headache, memory loss, menstrual pain, nausea, sleepiness, tingling, weakness
Biotrnasformation / Drug Metabolism
Zaleplon is primarily metabolized by aldehyde oxidase
Contraindications
Hypersensitivity to zaleplon or any excipients in the formulation .
Drug Interactions
As with all drugs, the potential exists for interaction with other drugs by a variety of
mechanisms.
CNS-Active Drugs
Ethanol: Sonata 10 mg potentiated the CNS-impairing effects of ethanol 0.75 g/kg on balance
testing and reaction time for 1 hour after ethanol administration and on the digit symbol substitution test (DSST),
symbol copying test, and the variability component of the divided attention test for 2.5 hours after ethanol
administration. The potentiation resulted from a CNS pharmacodynamic interaction; zaleplon did not affect the
pharmacokinetics of ethanol.
Imipramine: Coadministration of single doses of Sonata 20 mg and imipramine 75 mg produced
additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug.
Paroxetine: Coadministration of a single dose of Sonata 20 mg and paroxetine 20 mg daily for 7
days did not produce any interaction on psychomotor performance. Additionally, paroxetine did not alter the
pharmacokinetics of Sonata, reflecting the absence of a role of CYP2D6 in zaleplonís metabolism.
Thioridazine: Coadministration of single doses of Sonata 20 mg and thioridazine 50 mg produced
additive effects on decreased alertness and impaired psychomotor performance for 2 to 4 hours after administration.
The interaction was pharmacodynamic with no alteration of the pharmacokinetics of either drug.
Venlafaxine: Coadministration of a single dose of zaleplon 10 mg and multiple doses of
venlafaxine ER (extended release) 150 mg did not result in any significant changes in the pharmacokinetics of either
zaleplon or venlafaxine. In addition, there was no pharmacodynamic interaction as a result of coadministration of
zaleplon and venlafaxine ER.
Promethazine: Coadministration of a single dose of zaleplon and promethazine (10 and 25 mg,
respectively) resulted in a 15% decrease in maximal plasma concentrations of zaleplon, but no change in the area
under the plasma concentration-time curve. However, the pharmacodynamics of coadministration of zaleplon and
promethazine have not been evaluated. Caution should be exercised when these 2 agents are coadministered.
Drugs That Induce CYP3A4
Rifampin: CYP3A4 is ordinarily a minor metabolizing enzyme of zaleplon. Multiple-dose
administration of the potent CYP3A4 inducer rifampin (600 mg every 24 hours, q24h, for 14 days), however, reduced
zaleplon Cmax and AUC by approximately 80%. The coadministration of a potent CYP3A4 enzyme inducer,
although not posing a safety concern, thus could lead to ineffectiveness of zaleplon. An alternative non-CYP3A4
substrate hypnotic agent may be considered in patients taking CYP3A4 inducers such as rifampin, phenytoin,
carbamazepine, and phenobarbital.
Drugs That Inhibit CYP3A4
CYP3A4 is a minor metabolic pathway for the elimination of zaleplon because the sum of
desethylzaleplon (formed via CYP3A4 in vitro) and its metabolites, 5-oxo-desethylzaleplon and 5-oxo-desethylzaleplon
glucuronide, account for only 9% of the urinary recovery of a zaleplon dose. Coadministration of single, oral doses
of zaleplon with erythromycin (10 mg and 800 mg, respectively), a strong, selective CYP3A4 inhibitor produced a 34%
increase in zaleplon's maximal plasma concentrations and a 20% increase in the area under the plasma
concentration-time curve. The magnitude of interaction with multiple doses of erythromycin is unknown. Other strong
selective CYP3A4 inhibitors such as ketoconazole can also be expected to increase the exposure of zaleplon. A routine
dosage adjustment of zaleplon is not considered necessary.
Drugs That Inhibit Aldehyde Oxidase
The aldehyde oxidase enzyme system is less well studied than the cytochrome P450 enzyme system.
Diphenhydramine: Diphenhydramine is reported to be a weak inhibitor of aldehyde oxidase in rat
liver, but its inhibitory effects in human liver are not known. There is no pharmacokinetic interaction between
zaleplon and diphenhydramine following the administration of a single dose (10 mg and 50 mg, respectively) of each
drug. However, because both of these compounds have CNS effects, an additive pharmacodynamic effect is possible.
Drugs That Inhibit Both Aldehyde Oxidase and CYP3A4
Cimetidine: Cimetidine inhibits both aldehyde oxidase (in vitro) and CYP3A4 (in vitro and in vivo),
the primary and secondary enzymes, respectively, responsible for zaleplon metabolism. Concomitant administration of
Sonata (10 mg) and cimetidine (800 mg) produced an 85% increase in the mean Cmax and AUC of zaleplon. An
initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine.
Drugs Highly Bound to Plasma Protein
Zaleplon is not highly bound to plasma proteins (fraction bound 60%±15%); therefore, the disposition of zaleplon is not expected to be sensitive to alterations in
protein binding. In addition, administration of Sonata to a patient taking another drug that is highly protein bound
should not cause transient increase in free concentrations of the other drug.
Drugs with a Narrow Therapeutic Index
Digoxin: Sonata (10 mg) did not affect the pharmacokinetic or pharmacodynamic profile of
digoxin (0.375 mg q24h for 8 days).
Warfarin: Multiple oral doses of Sonata (20 mg q24h for 13 days) did not affect the
pharmacokinetics of warfarin (R+)- or (S-)-enantiomers or the pharmacodynamics (prothrombin
time) following a single 25-mg oral dose of warfarin.
Drugs That Alter Renal Excretion
Ibuprofen: Ibuprofen is known to affect renal function and, consequently, alter the renal
excretion of other drugs. There was no apparent pharmacokinetic interaction between zaleplon and ibuprofen following
single dose administration (10 mg and 600 mg, respectively) of each drug. This was expected because zaleplon is
primarily metabolized and renal excretion of unchanged zaleplon accounts for less than 1% of the administered
dose.
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