It is a nonbenzodiazepine
hypnotic from the pyrazolopyrimidine class. The chemical name of zaleplon is N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide. Its empirical formula is C17H15N5O, and its molecular weight is 305.34.
It is a white to off-white powder that is practically insoluble in water and sparingly soluble in alcohol
or propylene glycol. Its partition coefficient in octanol/water is constant (log PC = 1.23) over the pH range of 1 to 7.
Inactive ingredients of Sonata capsules consist of microcrystalline cellulose, pregelatinized starch, silicon dioxide, sodium lauryl sulfate, magnesium stearate, lactose, gelatin, titanium dioxide, D&C yellow #10, FD&C blue #1, FD&C green #3, and FD&C yellow #5.
It interacts with the gamma-aminobutyric acid-benzodiazepine
(GABA-BZ) receptor complex. Subunit modulation of the GABA-BZ 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.
Other nonclinical studies have also shown that zaleplon binds selectively to the brain omega-1 receptor situated on the alpha subunit of the GABAA/chloride ion channel receptor complex and potentiates t-butyl-bicyclophosphorothionate (TBPS) binding. Studies of binding of zaleplon to recombinant GABAA receptors (a1b1g2 [omega-1] and a2b1g2 [omega-2]) have shown that zaleplon has a low affinity for these receptors, with preferential binding to the omega-1 receptor.
It is rapidly absorbed with a time to peak concentration of approximately 1 hour and a half-life
of approximately 1 hour. It does not accumulate with once-daily administration and its pharmacokinetics are dose proportional in the therapeutic range.
It is rapidly and almost completely absorbed following oral administration. Peak plasma concentrations are attained within approximately 1 hour after oral administration. Although zaleplon is well absorbed, its absolute bioavailability is approximately 30% because it undergoes significant presystemic metabolism.
It is a lipophilic compound with a volume of distribution of approximately 1.4 L/kg following intravenous (IV) administration, indicating substantial distribution into extravascular tissues. The in vitro plasma protein binding is approximately 60%±15% and is independent of zaleplon concentration over the range of 10 ng/mL to 1000 ng/mL. This suggests that zaleplon disposition should not be sensitive to alterations in protein binding. The blood to plasma ratio for zaleplon is approximately 1, indicating that zaleplon is uniformly distributed throughout the blood with no extensive distribution into red blood cells.
After oral administration, it is extensively metabolized, with less than 1% of the dose excreted unchanged in urine. Zaleplon is primarily metabolized by aldehyde oxidase to form 5-oxo-zaleplon. Zaleplon is metabolized to a lesser extent by cytochrome P450
(CYP) 3A4 to form desethylzaleplon, which is quickly converted, presumably by aldehyde oxidase, to 5-oxo-desethylzaleplon. These oxidative metabolites are then converted to glucuronides and eliminated in urine. All of zaleplon’s metabolites are pharmacologically inactive.
After either oral or IV administration, is rapidly eliminated with a mean half life of of approximately 1 hour. The oral-dose plasma clearance of zaleplon is about 3 L/h/kg and the IV zaleplon plasma clearance is approximately 1 L/h/kg. It is subject to high first pass metabolism by the liver.
It is metabolized primarily by the liver and undergoes significant presystemic metabolism. Consequently, the clearance of zaleplon was reduced by 70%and 87% in compensated and decompensated cirrhotic patients, respectively, leading to marked increases in plasma concentration in comparison with healthy subjects. The dose of Sonata should therefore be reduced in patients with mild to moderate hepatic impairment. Sonata is not recommended for use in patients with severe hepatic impairment.
Renal impairment: Because renal excretion of unchanged zaleplon accounts for less than 1% of the administered dose, the pharmacokinetics of zaleplon are not altered in patients with renal insufficiency. No dose adjustment is necessary in patients with mild to moderate renal impairment. Sonata has not been adequately studied in patients with severe renal impairment.
Sonata is indicated for the short term treatment of insomnia. It reduces the time to sleep onset for up to 30 days (controlled studies). It has not been shown to increase sleep time or to reduce the number of awakenings.
Recommended dose of Sonata for most nonelderly adults is 10 mg. For certain low weight individuals, 5 mg may be a sufficient dose. Although the risk of certain adverse events associated with the use of Sonata appears to be dose dependent, the 20 mg dose has been shown to be adequately tolerated and may be considered for the occasional patient who does not benefit from a trial of a lower dose. Doses above 20 mg have not been adequately evaluated and are not recommended.
Sonata capsules are available in bottles of 100 capsules in the following dosage strengths:
5 mg, NDC 0008-0925, opaque green cap and opaque pale green body with "5 mg" on the cap and "SONATA" on the body.
10 mg, NDC 0008-0926, opaque green cap and opaque light green body with "10 mg" on the cap and "SONATA" on the body.
Adverse effects include: Abdominal pain, altered sensation, fatigue/malaise, photosensitivity, anorexia, nausea, diarrhoea, oedema, confusion, depersonalization, dizziness, hallucinations, drowsiness, tremor, vertigo, blurred vision, painful/heavy periods, headache/migraine and hangover effect, myalgia, arthralgia, anxiety (including rebound), increased sputum production
Infrequently: Angina, hypertension
, cardiac arryhthmias, gastritis, mouth ulceration, diabetes, hypothyroidism, anaemia, gout, raised blood lipids, ataxia
, lowered libido, exacerbation of asthma, and anaphylaxis
Sonata is a schedule IV substance in the US (as far as SWIM
aware not available in UK)
Two studies have assessed the abuse liability of Sonata at doses of 25 mg, 50 mg, and 75 mg in subjects with known histories of sedative drug
abuse. The results of these studies indicate that Sonata has an abuse potential similar to benzodiazepine and benzodiazepine-like hypnotics
The potential for developing physical dependence
on Sonata and a subsequent withdrawal
syndrome has been assessed in controlled studies. Some patients (mostly those treated with 20 mg) experienced a mild rebound insomnia on the first night that appears to resolve quickly.
There is no other current evidence regarding a withdrawal syndrome, however seizures and death have been observed in animal studies with withdrawal of high dose Sonata.
Sonata is contrindicated in those with a history of drug or alcohol dependance.
Tolerance to Sonata quickly develops at doses of 10mg and 20mg.
Sonata has an additive effect with alcohol, benzodiazepines, and tricyclics, but not SSRI
which induce hepatic enzymes are likely to reduce efficacy. Hepatic enzyme inhibitors increase plasma concentrations.
In overdose: Central nervous system depression ranging from drowsiness to coma. In mild cases, confusion, and lethargy; in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma, and very rarely death.
(with thanks to rxlist)