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Sonata
Overview
What is Sonata?
Zaleplon 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 CHNO, and its molecular weight is 305.34. The structural formula
is shown below.
ZALEPLON
Zaleplon 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.
Sonata capsules contain zaleplon as the active
ingredient. Inactive ingredients 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.
What does Sonata look like?
What are the available doses of Sonata?
Sorry No records found.
What should I talk to my health care provider before I take Sonata?
Sorry No records found
How should I use Sonata?
Sonata is indicated for the short-term treatment of insomnia.
Sonata has been shown to decrease the time to sleep onset for up to 30 days in
controlled clinical studies (see under ). It has not been shown to
increase total sleep time or decrease the number of awakenings.
The clinical trials performed in support of efficacy ranged from a single
night to 5 weeks in duration. The final formal assessments of sleep latency were
performed at the end of treatment.
The dose of Sonata should be individualized. The 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 should be taken immediately before bedtime or after the patient has
gone to bed and has experienced difficulty falling asleep (see ). Taking Sonata with or
immediately after a heavy, high-fat meal results in slower absorption and would
be expected to reduce the effect of Sonata on sleep latency (see under ).
Elderly patients and debilitated patients appear to be more
sensitive to the effects of hypnotics, and respond to 5 mg of Sonata. The
recommended dose for these patients is therefore 5 mg. Doses over 10 mg are not
recommended.
Hepatic insufficiency: Patients with mild to moderate hepatic impairment
should be treated with Sonata 5 mg because clearance is reduced in this
population. Sonata is not recommended for use in patients with severe hepatic
impairment.
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.
An initial dose of 5 mg should be given to patients concomitantly taking
cimetidine because zaleplon clearance is reduced in this population (see under ).
What interacts with Sonata?
Hypersensitivity to zaleplon or any excipients in the formulation (see also ).
What are the warnings of Sonata?
Array
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. 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 Sonata. Because some of the
important adverse effects of Sonata appear to be dose-related, it is important
to use the lowest possible effective dose, especially in the elderly (see ).
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 (eg, aggressiveness and
extroversion that seem out of character), similar to effects produced by alcohol
and other CNS depressants. Other reported behavioral changes have included
bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and
other neuropsychiatric symptoms may occur unpredictably. In primarily depressed
patients, worsening of depression, including suicidal thinking, 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 above 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.
Following rapid dose decrease or abrupt discontinuation of the use of
sedative/hypnotics, there have been reports of signs and symptoms similar to
those associated with withdrawal from other CNS-depressant drugs (see ).
Sonata, like other hypnotics, has CNS-depressant effects. . Patients receiving Sonata
should be cautioned against engaging in hazardous occupations requiring complete
mental alertness or motor coordination (eg, 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
Sonata. Sonata, as well as other hypnotics, may produce additive CNS-depressant
effects when coadministered with other psychotropic medications,
anticonvulsants, antihistamines, narcotic analgesics, anesthetics, ethanol, and
other drugs that themselves produce CNS depression. Sonata should not be taken
with alcohol. Dosage adjustment may be necessary when Sonata is administered
with other CNS-depressant agents because of the potentially additive effects.
What are the precautions of Sonata?
Sonata should be taken immediately before bedtime or after the
patient has gone to bed and has experienced difficulty falling asleep. As with
all sedative/hypnotics, taking Sonata while still up and about may result in
short-term memory impairment, hallucinations, impaired coordination, dizziness,
and lightheadedness.
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. A dose of 5 mg is recommended
for elderly patients to decrease the possibility of side effects (see ). Elderly
and/or debilitated patients should be monitored closely.
Clinical experience with Sonata in patients with concomitant
systemic illness is limited. Sonata should be used with caution in patients with
diseases or conditions that could affect metabolism or hemodynamic responses.
Although preliminary studies did not reveal respiratory depressant effects at
hypnotic doses of Sonata in normal subjects, caution should be observed if
Sonata (zaleplon) is prescribed to patients with compromised respiratory
function, because sedative/hypnotics have the capacity to depress respiratory
drive. Controlled trials of acute administration of Sonata 10 mg in patients
with mild to moderate chronic obstructive pulmonary disease or moderate
obstructive sleep apnea showed no evidence of alterations in blood gases or
apnea/hypopnea index, respectively. However, patients with compromised
respiration due to preexisting illness should be monitored carefully.
The dose of Sonata should be reduced to 5 mg in patients with mild to
moderate hepatic impairment (see ). It is not recommended for use in patients with
severe hepatic impairment.
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.
As with other sedative/hypnotic drugs, Sonata 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 overdosage is more common in this group of
patients (see );
therefore, the least amount of drug that is feasible should be prescribed for
the patient at any one time.
This product contains FD&C Yellow No. 5 (tartrazine) which may cause
allergic-type reactions (including bronchial asthma) in certain susceptible
persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine)
sensitivity in the general population is low, it is frequently seen in patients
who also have aspirin hypersensitivity.
Patient information is printed at the end of this insert. To
assure safe and effective use of Sonata, the information and instructions
provided in the patient information section should be discussed with patients.
There are no specific laboratory tests recommended.
As with all drugs, the potential exists for interaction with
other drugs by a variety of mechanisms.
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 zaleplon's 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 of
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.
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 C 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.
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.
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.
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
C and AUC of zaleplon. An initial dose of 5 mg should
be given to patients who are concomitantly being treated with cimetidine (see
).
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.
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.
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.
Lifetime carcinogenicity studies of zaleplon were conducted in
mice and rats. Mice received doses of 25 mg/kg/day, 50 mg/kg/day, 100 mg/kg/day,
and 200 mg/kg/day in the diet for two years. These doses are equivalent to 6 to
49 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m basis. There was a significant increase in the incidence of
hepatocellular adenomas in female mice in the high dose group. Rats received
doses of 1 mg/kg/day, 10 mg/kg/day, and 20 mg/kg/day in the diet for two years.
These doses are equivalent to 0.5 to 10 times the maximum recommended human dose
(MRHD) of 20 mg on a mg/m basis. Zaleplon was not
carcinogenic in rats.
Zaleplon was clastogenic, both in the presence and absence of
metabolic activation, causing structural and numerical aberrations (polyploidy
and endoreduplication), when tested for chromosomal aberrations in the in vitro
Chinese hamster ovary cell assay. In the in vitro human lymphocyte assay,
zaleplon caused numerical, but not structural, aberrations only in the presence
of metabolic activation at the highest concentrations tested. In other in vitro
assays, zaleplon was not mutagenic in the Ames bacterial gene mutation assay or
the Chinese hamster ovary HGPRT gene mutation assay. Zaleplon was not
clastogenic in two in vivo assays, the mouse bone marrow micronucleus assay and
the rat bone marrow chromosomal aberration assay, and did not cause DNA damage
in the rat hepatocyte unscheduled DNA synthesis assay.
In a fertility and reproductive performance study in rats,
mortality and decreased fertility were associated with administration of an oral
dose of zaleplon of 100 mg/kg/day to males and females prior to and during
mating. This dose is equivalent to 49 times the maximum recommended human dose
(MRHD) of 20 mg on a mg/m basis. Follow-up studies
indicated that impaired fertility was due to an effect on the female.
In embryofetal development studies in rats and rabbits, oral
administration of up to 100 mg/kg/day and 50 mg/kg/day, respectively, to
pregnant animals throughout organogenesis produced no evidence of
teratogenicity. These doses are equivalent to 49 (rat) and 48 (rabbit) times the
maximum recommended human dose (MRHD) of 20 mg on a mg/m
basis. In rats, pre- and postnatal growth was reduced in the offspring of dams
receiving 100 mg/kg/day. This dose was also maternally toxic, as evidenced by
clinical signs and decreased maternal body weight gain during gestation. The
no-effect dose for rat offspring growth reduction was 10 mg/kg (a dose
equivalent to 5 times the MRHD of 20 mg on a mg/m
basis). No adverse effects on embryofetal development were observed in rabbits
at the doses examined.
In a pre- and postnatal development study in rats, increased stillbirth and
postnatal mortality, and decreased growth and physical development, were
observed in the offspring of females treated with doses of 7 mg/kg/day or
greater during the latter part of gestation and throughout lactation. There was
no evidence of maternal toxicity at this dose. The no-effect dose for offspring
development was 1 mg/kg/day (a dose equivalent to 0.5 times the MRHD of 20 mg on
a mg/m basis). When the adverse effects on offspring
viability and growth were examined in a cross-fostering study, they appeared to
result from both and lactational exposure to
the drug.
There are no studies of zaleplon in pregnant women; therefore, Sonata (zaleplon)is not recommended for use in women during
pregnancy.
Sonata has no established use in labor and delivery.
A study in lactating mothers indicated that the clearance and
half-life of zaleplon is similar to that in young normal subjects. A small
amount of zaleplon is excreted in breast milk, with the highest excreted amount
occurring during a feeding at approximately 1 hour after Sonata administration.
Since the small amount of the drug from breast milk may result in potentially
important concentrations in infants, and because the effects of zaleplon on a
nursing infant are not known, it is recommended that nursing mothers not take
Sonata.
The safety and effectiveness of Sonata in pediatric patients have
not been established.
A total of 628 patients in double-blind, placebo-controlled,
parallel-group clinical trials who received Sonata were at least 65 years of
age; of these, 311 received 5 mg and 317 received 10 mg. In both sleep
laboratory and outpatient studies, elderly patients with insomnia responded to a
5 mg dose with a reduced sleep latency, and thus 5 mg is the recommended dose in
this population. During short-term treatment (14 night studies) of elderly
patients with Sonata, no adverse event with a frequency of at least 1% occurred
at a significantly higher rate with either 5 mg or 10 mg Sonata than with
placebo.
What are the side effects of Sonata?
The premarketing development program for Sonata included zaleplon
exposures in patients and/or normal subjects from 2 different groups of studies:
approximately 900 normal subjects in clinical pharmacology/pharmacokinetic
studies; and approximately 2,900 exposures from patients in placebo-controlled
clinical effectiveness studies, corresponding to approximately 450 patient
exposure years. The conditions and duration of treatment with Sonata varied
greatly and included (in overlapping categories) open-label and double-blind
phases of studies, inpatients and outpatients, and short-term or longer-term
exposure. Adverse reactions were assessed by collecting adverse events, results
of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
Adverse events during exposure were obtained primarily by general inquiry and
recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the
proportion of individuals experiencing adverse events without first grouping
similar types of events into a smaller number of standardized event categories.
In the tables and tabulations that follow, COSTART terminology has been used to
classify reported adverse events.
The stated frequencies of adverse events represent the proportion of
individuals who experienced, at least once, a treatment-emergent adverse event
of the type listed. An event was considered treatment-emergent if it occurred
for the first time or worsened while receiving therapy following baseline
evaluation.
In premarketing placebo-controlled, parallel-group phase 2 and
phase 3 clinical trials, 3.1% of 744 patients who received placebo and 3.7% of
2,149 patients who received Sonata discontinued treatment because of an adverse
clinical event. This difference was not statistically significant. No event that
resulted in discontinuation occurred at a rate of greater than or equal to 1%.
Table 1
The prescriber should be aware that these figures cannot be used to predict
the incidence of adverse events in the course of usual medical practice where
patient characteristics and other factors differ from those which prevailed in
the clinical trials. Similarly, the cited frequencies cannot be compared with
figures obtained from other clinical investigations involving different
treatments, uses, and investigators. The cited figures, however, do provide the
prescribing physician with some basis for estimating the relative contribution
of drug and non-drug factors to the adverse event incidence rate in the
population studied.
Listed below are COSTART terms that reflect treatment-emergent
adverse events as defined in the introduction to the section. These events were
reported by patients treated with Sonata (zaleplon) at doses in a range of 5
mg/day to 20 mg/day during premarketing phase 2 and phase 3 clinical trials
throughout the United States, Canada, and Europe, including approximately 2,900
patients. All reported events are included except those already listed in or elsewhere in labeling, those events for which a drug
cause was remote, and those event terms that were so general as to be
uninformative. It is important to emphasize that although the events reported
occurred during treatment with Sonata, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of
decreasing frequency according to the following definitions: adverse events are those occurring on one or more
occasions in at least 1/100 patients; adverse
events are those occurring in less than 1/100 patients but at least 1/1,000
patients; events are those occurring in fewer than
1/1,000 patients.
Body as a whole
Frequent:
Infrequent:
Cardiovascular system
Frequent:
Infrequent:
Rare:
Digestive system
Frequent:
Infrequent:
Rare:
Endocrine system
Rare:
Hemic and lymphatic system
Infrequent:
Rare:
Metabolic and nutritional
Infrequent:
Rare:
Musculoskeletal system
Frequent:
Infrequent:
Rare:
Nervous system
Frequent:
Infrequent:
Rare:
Respiratory system
Frequent:
Infrequent:
Rare:
Skin and appendages
Frequent:
Infrequent:
Rare:
Special senses
Frequent:
Infrequent:
Rare:
Urogenital system
Infrequent:
Rare:
Anaphylactic/anaphylactoid reactions, including severe reactions.
| Body System | Placebo | Sonata 5 mg or 10 mg | Sonata 20 mg |
| Preferred Term | (n = 344) | (n = 569) | (n = 297) |
| Body as a whole | |||
| Abdominal pain | 3 | 6 | 6 |
| Asthenia | 5 | 5 | 7 |
| Headache | 35 | 30 | 42 |
| Malaise | less than 1 | less than 1 | 2 |
| Photosensitivity reaction | less than 1 | less than 1 | 1 |
| Digestive system | |||
| Anorexia | less than 1 | less than 1 | 2 |
| Colitis | 0 | 0 | 1 |
| Nausea | 7 | 6 | 8 |
| Metabolic and nutritional | |||
| Peripheral edema | less than 1 | less than 1 | 1 |
| Nervous system | |||
| Amnesia | 1 | 2 | 4 |
| Confusion | less than 1 | less than 1 | 1 |
| Depersonalization | less than 1 | less than 1 | 2 |
| Dizziness | 7 | 7 | 9 |
| Hallucinations | less than 1 | less than 1 | 1 |
| Hypertonia | less than 1 | 1 | 1 |
| Hypesthesia | less than 1 | less than 1 | 2 |
| Paresthesia | 1 | 3 | 3 |
| Somnolence | 4 | 5 | 6 |
| Tremor | 1 | 2 | 2 |
| Vertigo | less than 1 | less than 1 | 1 |
| Respiratory system | |||
| Epistaxis | less than 1 | less than 1 | 1 |
| Special senses | |||
| Abnormal vision | less than 1 | less than 1 | 2 |
| Ear pain | 0 | less than 1 | 1 |
| Eye pain | 2 | 4 | 3 |
| Hyperacusis | less than 1 | 1 | 2 |
| Parosmia | less than 1 | less than 1 | 2 |
| Urogenital system | |||
| Dysmenorrhea | 2 | 3 | 4 |
What should I look out for while using Sonata?
Hypersensitivity to zaleplon or any excipients in the formulation (see also
).
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. 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 Sonata. Because some of the
important adverse effects of Sonata appear to be dose-related, it is important
to use the lowest possible effective dose, especially in the elderly (see ).
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 (eg, aggressiveness and
extroversion that seem out of character), similar to effects produced by alcohol
and other CNS depressants. Other reported behavioral changes have included
bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and
other neuropsychiatric symptoms may occur unpredictably. In primarily depressed
patients, worsening of depression, including suicidal thinking, 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 above 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.
Following rapid dose decrease or abrupt discontinuation of the use of
sedative/hypnotics, there have been reports of signs and symptoms similar to
those associated with withdrawal from other CNS-depressant drugs (see ).
Sonata, like other hypnotics, has CNS-depressant effects. . Patients receiving Sonata
should be cautioned against engaging in hazardous occupations requiring complete
mental alertness or motor coordination (eg, 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
Sonata. Sonata, as well as other hypnotics, may produce additive CNS-depressant
effects when coadministered with other psychotropic medications,
anticonvulsants, antihistamines, narcotic analgesics, anesthetics, ethanol, and
other drugs that themselves produce CNS depression. Sonata should not be taken
with alcohol. Dosage adjustment may be necessary when Sonata is administered
with other CNS-depressant agents because of the potentially additive effects.
What might happen if I take too much Sonata?
There is limited pre-marketing clinical experience with the
effects of an overdosage of Sonata. Two cases of overdose were reported. One was
the accidental ingestion by a 2½ year old boy of 20 mg to 40 mg of zaleplon. The
second was a 20 year old man who took 100 mg zaleplon plus 2.25 mg of triazolam.
Both were treated and recovered uneventfully.
Signs and symptoms of overdose effects of CNS depressants can be
expected to present as exaggerations of the pharmacological effects noted in
preclinical testing. Overdose is usually manifested by degrees of central
nervous system depression ranging from drowsiness to coma. In mild cases,
symptoms include drowsiness, mental confusion, and lethargy; in more serious
cases, symptoms may include ataxia, hypotonia, hypotension, respiratory
depression, rarely coma, and very rarely death.
General symptomatic and supportive measures should be used along
with immediate gastric lavage where appropriate. Intravenous fluids should be
administered as needed. Animal studies suggest that flumazenil is an antagonist
to zaleplon. However, there is no pre-marketing clinical experience with the use
of flumazenil as an antidote to a Sonata overdose. 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.
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.
How should I store and handle Sonata?
Sonata (zaleplon) capsules are supplied as follows: Sonata is a registered trademark of Jones Pharma Inc., a wholly owned subsidiary of King Pharmaceuticals, Inc. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F).Dispense in a light-resistant container as defined in the USP.Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Sonata (zaleplon) capsules are supplied as follows: Sonata is a registered trademark of Jones Pharma Inc., a wholly owned subsidiary of King Pharmaceuticals, Inc. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F).Dispense in a light-resistant container as defined in the USP.Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Sonata (zaleplon) capsules are supplied as follows: Sonata is a registered trademark of Jones Pharma Inc., a wholly owned subsidiary of King Pharmaceuticals, Inc. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F).Dispense in a light-resistant container as defined in the USP.Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Sonata (zaleplon) capsules are supplied as follows: Sonata is a registered trademark of Jones Pharma Inc., a wholly owned subsidiary of King Pharmaceuticals, Inc. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F).Dispense in a light-resistant container as defined in the USP.Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146 Sonata (zaleplon) capsules are supplied as follows: Sonata is a registered trademark of Jones Pharma Inc., a wholly owned subsidiary of King Pharmaceuticals, Inc. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F).Dispense in a light-resistant container as defined in the USP.Repackaging and Relabeling by:Physicians Total Care, Inc.Tulsa, OK 74146
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
While Sonata (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 (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 GABA/chloride ion channel receptor complex and potentiates
t-butyl-bicyclophosphorothionate (TBPS) binding. Studies of binding of zaleplon
to recombinant GABA receptors (αβγ [omega-1]
and αβγ
[omega-2]) have shown that zaleplon has a low affinity for these receptors, with
preferential binding to the omega-1 receptor.
The pharmacokinetics of zaleplon have been investigated in more
than 500 healthy subjects (young and elderly), nursing mothers, and patients
with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic
profile has been examined after single doses of up to 60 mg and once-daily
administration at 15 mg and 30 mg for 10 days. Zaleplon was rapidly absorbed
with a time to peak concentration (t) of approximately
1 hour and a terminal-phase elimination half-life (t)
of approximately 1 hour. Zaleplon does not accumulate with once-daily
administration and its pharmacokinetics are dose proportional in the therapeutic
range.
Zaleplon 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.
Zaleplon 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, zaleplon 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 P (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, zaleplon is rapidly
eliminated with a mean t 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. Assuming normal hepatic blood flow
and negligible renal clearance of zaleplon, the estimated hepatic extraction
ratio of zaleplon is approximately 0.7, indicating that zaleplon is subject to
high first-pass metabolism.
After administration of a radiolabeled dose of zaleplon, 70% of the
administered dose is recovered in urine within 48 hours (71% recovered within 6
days), almost all as zaleplon metabolites and their glucuronides. An additional
17% is recovered in feces within 6 days, most as 5-oxo-zaleplon.
In healthy adults a high-fat/heavy meal prolonged the absorption
of zaleplon compared to the fasted state, delaying t
by approximately 2 hours and reducing C by
approximately 35%. Zaleplon AUC and elimination half-life were not significantly
affected. These results suggest that the effects of Sonata on sleep onset may be
reduced if it is taken with or immediately after a high-fat/heavy meal.
Age: The pharmacokinetics of Sonata (zaleplon) have been
investigated in three studies with elderly men and women ranging in age from 65
to 85 years. The pharmacokinetics of Sonata in elderly subjects, including those
over 75 years of age, are not significantly different from those in young
healthy subjects.
Gender: There is no significant difference in the
pharmacokinetics of Sonata in men and women.
Race: The pharmacokinetics of zaleplon have been studied in
Japanese subjects as representative of Asian populations. For this group, C and AUC were increased 37% and 64%, respectively. This
finding can likely be attributed to differences in body weight, or
alternatively, may represent differences in enzyme activities resulting from
differences in diet, environment, or other factors. The effects of race on
pharmacokinetic characteristics in other ethnic groups have not been well
characterized.
Hepatic impairment: Zaleplon is metabolized primarily by the
liver and undergoes significant presystemic metabolism. Consequently, the oral
clearance of zaleplon was reduced by 70% and 87% in compensated and
decompensated cirrhotic patients, respectively, leading to marked increases in
mean C and AUC (up to 4-fold and 7-fold in compensated
and decompensated patients, respectively), in comparison with healthy subjects.
The dose of Sonata should therefore be reduced in patients with mild to moderate
hepatic impairment (see ). 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.
Because zaleplon is primarily metabolized by aldehyde oxidase,
and to a lesser extent by CYP3A4, inhibitors of these enzymes might be expected
to decrease zaleplon's clearance and inducers of these enzymes might be expected
to increase its clearance. Zaleplon has been shown to have minimal effects on
the kinetics of warfarin (both R- and S- forms), imipramine, ethanol, ibuprofen,
diphenhydramine, thioridazine, and digoxin. However, the effects of zaleplon on
inhibition of enzymes involved in the metabolism of other drugs have not been
studied. (See under )
Sonata (typically administered in doses of 5 mg, 10 mg, or 20 mg)
has been studied in patients with chronic insomnia (n = 3,435) in 12 placebo-
and active-drug-controlled trials. Three of the trials were in elderly patients
(n = 1,019). It has also been studied in transient insomnia (n = 264). Because
of its very short half-life, studies focused on decreasing sleep latency, with
less attention to duration of sleep and number of awakenings, for which
consistent differences from placebo were not demonstrated. Studies were also
carried out to examine the time course of effects on memory and psychomotor
function, and to examine withdrawal phenomena.
Normal adults experiencing transient insomnia during the first
night in a sleep laboratory were evaluated in a double-blind, parallel-group
trial comparing the effects of two doses of Sonata (5 mg and 10 mg) with
placebo. Sonata 10 mg, but not 5 mg, was superior to placebo in decreasing
latency to persistent sleep (LPS), a polysomnographic measure of time to onset
of sleep.
Adult outpatients with chronic insomnia were evaluated in three
double-blind, parallel-group outpatient studies, one of 2 weeks duration and two
of 4 weeks duration, that compared the effects of Sonata at doses of 5 mg (in
two studies), 10 mg, and 20 mg with placebo on a subjective measure of time to
sleep onset (TSO). Sonata 10 mg and 20 mg were consistently superior to placebo
for TSO, generally for the full duration of all three studies. Although both
doses were effective, the effect was greater and more consistent for the 20-mg
dose. The 5-mg dose was less consistently effective than were the 10-mg and
20-mg doses. Sleep latency with Sonata 10 mg and 20 mg was on the order of 10-20
minutes (15%-30%) less than with placebo in these studies.
Adult outpatients with chronic insomnia were evaluated in six double-blind,
parallel-group sleep laboratory studies that varied in duration from a single
night up to 35 nights. Overall, these studies demonstrated a superiority of
Sonata 10 mg and 20 mg over placebo in reducing LPS on the first 2 nights of
treatment. At later time points in 5-, 14-, and 28-night studies, a reduction in
LPS from baseline was observed for all treatment groups, including the placebo
group, and thus, a significant difference between Sonata and placebo was not
seen beyond 2 nights. In a 35-night study, Sonata 10 mg was significantly more
effective than placebo in reducing LPS at the primary efficacy endpoint on
nights 29 and 30.
Elderly outpatients with chronic insomnia were evaluated in two
2-week, double-blind, parallel-group outpatient studies that compared the
effects of Sonata 5 mg and 10 mg with placebo on a subjective measure of time to
sleep onset (TSO). Sonata at both doses was superior to placebo on TSO,
generally for the full duration of both studies, with an effect size generally
similar to that seen in younger persons. The 10-mg dose tended to have a greater
effect in reducing TSO.
Elderly outpatients with chronic insomnia were also evaluated in a 2-night
sleep laboratory study involving doses of 5 mg and 10 mg. Both 5-mg and 10-mg
doses of Sonata were superior to placebo in reducing latency to persistent sleep
(LPS).
Generally in these studies, there was a slight increase in sleep duration,
compared to baseline, for all treatment groups, including placebo, and thus, a
significant difference from placebo on sleep duration was not demonstrated.
Studies involving the exposure of normal subjects to single fixed
doses of Sonata (10 mg or 20 mg) with structured assessments of short-term
memory at fixed times after dosing (eg, 1, 2, 3, 4, 5, 8, and 10 hours)
generally revealed the expected impairment of short-term memory at 1 hour, the
time of peak exposure to zaleplon, for both doses, with a tendency for the
effect to be greater after 20 mg. Consistent with the rapid clearance of
zaleplon, memory impairment was no longer present as early as 2 hours post
dosing in one study, and in none of the studies after 3-4 hours. Nevertheless,
spontaneous reporting of adverse events in larger premarketing clinical trials
revealed a difference between Sonata and placebo in the risk of next-day amnesia
(3% vs 1%), and an apparent dose-dependency for this event (see ).
Studies involving the exposure of normal subjects to single fixed
doses of Sonata (zaleplon) (10 mg or 20 mg) with structured assessments of
sedation and psychomotor function (eg, reaction time and subjective ratings of
alertness) at fixed times after dosing (eg, 1, 2, 3, 4, 5, 8, and 10 hours)
generally revealed the expected sedation and impairment of psychomotor function
at 1 hour, the time of peak exposure to zaleplon, for both doses. Consistent
with the rapid clearance of zaleplon, impairment of psychomotor function was no
longer present as early as 2 hours post dosing in one study, and in none of the
studies after 3-4 hours. Spontaneous reporting of adverse events in larger
premarketing clinical trials did not suggest a difference between Sonata and
placebo in the risk of next-day somnolence (see ).
During nightly use for an extended period, pharmacodynamic
tolerance or adaptation to some effects of hypnotics may develop. If the drug
has a short elimination half-life, it is possible that a relative deficiency of
the drug or its active metabolites (ie, in relationship to the receptor site)
may occur at some point in the interval between each night's use. This sequence
of events is believed to be responsible for two clinical findings reported to
occur after several weeks of nightly use of other rapidly eliminated hypnotics:
increased wakefulness during the last quarter of the night and the appearance of
increased signs of daytime anxiety.
Zaleplon has a short half-life and no active metabolites. At the primary
efficacy endpoint (nights 29 and 30) in a 35-night sleep laboratory study,
polysomnographic recordings showed that wakefulness was not significantly longer
with Sonata than with placebo during the last quarter of the night. No increase
in the signs of daytime anxiety was observed in clinical trials with Sonata. In
two sleep laboratory studies involving 14- and 28-nightly doses of Sonata (5 mg
and 10 mg in one study and 10 mg and 20 mg in the second) and structured
assessments of daytime anxiety, no increases in daytime anxiety were detected.
Similarly, in a pooled analysis (all the parallel-group, placebo-controlled
studies) of spontaneously reported daytime anxiety, no difference was observed
between Sonata and placebo.
Rebound insomnia, defined as a dose-dependent temporary worsening in sleep
parameters (latency, total sleep time, and number of awakenings) compared to
baseline following discontinuation of treatment, is observed with short- and
intermediate-acting hypnotics. Rebound insomnia following discontinuation of
Sonata relative to baseline was examined at both nights 1 and 2 following
discontinuation in three sleep laboratory studies (14, 28, and 35 nights) and
five outpatient studies utilizing patient diaries (14 and 28 nights). Overall,
the data suggest that rebound insomnia may be dose dependent. At 20 mg, there
appeared to be both objective (polysomnographic) and subjective (diary) evidence
of rebound insomnia on the first night after discontinuation of treatment with
Sonata. At 5 mg and 10 mg, there was no objectiveand minimal subjective evidence
of rebound insomnia on the first night after discontinuation of treatment with
Sonata. At all doses, the rebound effect appeared to resolve by the second night
following withdrawal. In the 35-night study, there was a worsening in sleep on
the first night off for both the 10-mg and 20-mg groups compared to placebo, but
not to baseline. This discontinuation-emergent effect was mild, had the
characteristics of the return of the symptoms of chronic insomnia, and appeared
to resolve by the second night after zaleplon discontinuation.
The potential for other withdrawal phenomena was also assessed in
14- to 28-night studies, including both the sleep laboratory studies and the
outpatient studies, and in open-label studies of 6- and 12-month durations. The
Benzodiazepine Withdrawal Symptom Questionnaire was used in several of these
studies, both at baseline and then during days 1 and 2 following
discontinuation. Withdrawal was operationally defined as the emergence of 3 or
more new symptoms after discontinuation. Sonata was not distinguishable from
placebo at doses of 5 mg, 10 mg, or 20 mg on this measure, nor was Sonata
distinguishable from placebo on spontaneously reported withdrawal-emergent
adverse events. There were no instances of withdrawal delirium, withdrawal
associated hallucinations, or any other manifestations of severe
sedative/hypnotic withdrawal.
Non-Clinical Toxicology
Hypersensitivity to zaleplon or any excipients in the formulation (see also ).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. 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 Sonata. Because some of the important adverse effects of Sonata appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly (see ).
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 (eg, aggressiveness and extroversion that seem out of character), similar to effects produced by alcohol and other CNS depressants. Other reported behavioral changes have included bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thinking, 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 above 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.
Following rapid dose decrease or abrupt discontinuation of the use of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs (see ).
Sonata, like other hypnotics, has CNS-depressant effects. . Patients receiving Sonata should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination (eg, 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 Sonata. Sonata, as well as other hypnotics, may produce additive CNS-depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistamines, narcotic analgesics, anesthetics, ethanol, and other drugs that themselves produce CNS depression. Sonata should not be taken with alcohol. Dosage adjustment may be necessary when Sonata is administered with other CNS-depressant agents because of the potentially additive effects.
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See ) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, didanosine chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. (See for concurrent administration of these agents with ciprofloxacin.)
Histamine H-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies.
Sonata should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep. As with all sedative/hypnotics, taking Sonata while still up and about may result in short-term memory impairment, hallucinations, impaired coordination, dizziness, and lightheadedness.
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. A dose of 5 mg is recommended for elderly patients to decrease the possibility of side effects (see ). Elderly and/or debilitated patients should be monitored closely.
Clinical experience with Sonata in patients with concomitant systemic illness is limited. Sonata should be used with caution in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Although preliminary studies did not reveal respiratory depressant effects at hypnotic doses of Sonata in normal subjects, caution should be observed if Sonata (zaleplon) is prescribed to patients with compromised respiratory function, because sedative/hypnotics have the capacity to depress respiratory drive. Controlled trials of acute administration of Sonata 10 mg in patients with mild to moderate chronic obstructive pulmonary disease or moderate obstructive sleep apnea showed no evidence of alterations in blood gases or apnea/hypopnea index, respectively. However, patients with compromised respiration due to preexisting illness should be monitored carefully.
The dose of Sonata should be reduced to 5 mg in patients with mild to moderate hepatic impairment (see ). It is not recommended for use in patients with severe hepatic impairment.
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.
As with other sedative/hypnotic drugs, Sonata 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 overdosage is more common in this group of patients (see ); therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
Patient information is printed at the end of this insert. To assure safe and effective use of Sonata, the information and instructions provided in the patient information section should be discussed with patients.
There are no specific laboratory tests recommended.
As with all drugs, the potential exists for interaction with other drugs by a variety of mechanisms.
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 zaleplon's 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 of 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.
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 C 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.
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.
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.
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 C and AUC of zaleplon. An initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine (see ).
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.
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.
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.
Lifetime carcinogenicity studies of zaleplon were conducted in mice and rats. Mice received doses of 25 mg/kg/day, 50 mg/kg/day, 100 mg/kg/day, and 200 mg/kg/day in the diet for two years. These doses are equivalent to 6 to 49 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m basis. There was a significant increase in the incidence of hepatocellular adenomas in female mice in the high dose group. Rats received doses of 1 mg/kg/day, 10 mg/kg/day, and 20 mg/kg/day in the diet for two years. These doses are equivalent to 0.5 to 10 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m basis. Zaleplon was not carcinogenic in rats.
Zaleplon was clastogenic, both in the presence and absence of metabolic activation, causing structural and numerical aberrations (polyploidy and endoreduplication), when tested for chromosomal aberrations in the in vitro Chinese hamster ovary cell assay. In the in vitro human lymphocyte assay, zaleplon caused numerical, but not structural, aberrations only in the presence of metabolic activation at the highest concentrations tested. In other in vitro assays, zaleplon was not mutagenic in the Ames bacterial gene mutation assay or the Chinese hamster ovary HGPRT gene mutation assay. Zaleplon was not clastogenic in two in vivo assays, the mouse bone marrow micronucleus assay and the rat bone marrow chromosomal aberration assay, and did not cause DNA damage in the rat hepatocyte unscheduled DNA synthesis assay.
In a fertility and reproductive performance study in rats, mortality and decreased fertility were associated with administration of an oral dose of zaleplon of 100 mg/kg/day to males and females prior to and during mating. This dose is equivalent to 49 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m basis. Follow-up studies indicated that impaired fertility was due to an effect on the female.
In embryofetal development studies in rats and rabbits, oral administration of up to 100 mg/kg/day and 50 mg/kg/day, respectively, to pregnant animals throughout organogenesis produced no evidence of teratogenicity. These doses are equivalent to 49 (rat) and 48 (rabbit) times the maximum recommended human dose (MRHD) of 20 mg on a mg/m basis. In rats, pre- and postnatal growth was reduced in the offspring of dams receiving 100 mg/kg/day. This dose was also maternally toxic, as evidenced by clinical signs and decreased maternal body weight gain during gestation. The no-effect dose for rat offspring growth reduction was 10 mg/kg (a dose equivalent to 5 times the MRHD of 20 mg on a mg/m basis). No adverse effects on embryofetal development were observed in rabbits at the doses examined.
In a pre- and postnatal development study in rats, increased stillbirth and postnatal mortality, and decreased growth and physical development, were observed in the offspring of females treated with doses of 7 mg/kg/day or greater during the latter part of gestation and throughout lactation. There was no evidence of maternal toxicity at this dose. The no-effect dose for offspring development was 1 mg/kg/day (a dose equivalent to 0.5 times the MRHD of 20 mg on a mg/m basis). When the adverse effects on offspring viability and growth were examined in a cross-fostering study, they appeared to result from both and lactational exposure to the drug.
There are no studies of zaleplon in pregnant women; therefore, Sonata (zaleplon)is not recommended for use in women during pregnancy.
Sonata has no established use in labor and delivery.
A study in lactating mothers indicated that the clearance and half-life of zaleplon is similar to that in young normal subjects. A small amount of zaleplon is excreted in breast milk, with the highest excreted amount occurring during a feeding at approximately 1 hour after Sonata administration. Since the small amount of the drug from breast milk may result in potentially important concentrations in infants, and because the effects of zaleplon on a nursing infant are not known, it is recommended that nursing mothers not take Sonata.
The safety and effectiveness of Sonata in pediatric patients have not been established.
A total of 628 patients in double-blind, placebo-controlled, parallel-group clinical trials who received Sonata were at least 65 years of age; of these, 311 received 5 mg and 317 received 10 mg. In both sleep laboratory and outpatient studies, elderly patients with insomnia responded to a 5 mg dose with a reduced sleep latency, and thus 5 mg is the recommended dose in this population. During short-term treatment (14 night studies) of elderly patients with Sonata, no adverse event with a frequency of at least 1% occurred at a significantly higher rate with either 5 mg or 10 mg Sonata than with placebo.
The premarketing development program for Sonata included zaleplon exposures in patients and/or normal subjects from 2 different groups of studies: approximately 900 normal subjects in clinical pharmacology/pharmacokinetic studies; and approximately 2,900 exposures from patients in placebo-controlled clinical effectiveness studies, corresponding to approximately 450 patient exposure years. The conditions and duration of treatment with Sonata varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, and short-term or longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, COSTART terminology has been used to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.
In premarketing placebo-controlled, parallel-group phase 2 and phase 3 clinical trials, 3.1% of 744 patients who received placebo and 3.7% of 2,149 patients who received Sonata discontinued treatment because of an adverse clinical event. This difference was not statistically significant. No event that resulted in discontinuation occurred at a rate of greater than or equal to 1%.
Table 1
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.
Listed below are COSTART terms that reflect treatment-emergent adverse events as defined in the introduction to the section. These events were reported by patients treated with Sonata (zaleplon) at doses in a range of 5 mg/day to 20 mg/day during premarketing phase 2 and phase 3 clinical trials throughout the United States, Canada, and Europe, including approximately 2,900 patients. All reported events are included except those already listed in or elsewhere in labeling, those events for which a drug cause was remote, and those event terms that were so general as to be uninformative. It is important to emphasize that although the events reported occurred during treatment with Sonata, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: adverse events are those occurring on one or more occasions in at least 1/100 patients; adverse events are those occurring in less than 1/100 patients but at least 1/1,000 patients; events are those occurring in fewer than 1/1,000 patients.
Body as a whole
Frequent:
Infrequent:
Cardiovascular system
Frequent:
Infrequent:
Rare:
Digestive system
Frequent:
Infrequent:
Rare:
Endocrine system
Rare:
Hemic and lymphatic system
Infrequent:
Rare:
Metabolic and nutritional
Infrequent:
Rare:
Musculoskeletal system
Frequent:
Infrequent:
Rare:
Nervous system
Frequent:
Infrequent:
Rare:
Respiratory system
Frequent:
Infrequent:
Rare:
Skin and appendages
Frequent:
Infrequent:
Rare:
Special senses
Frequent:
Infrequent:
Rare:
Urogenital system
Infrequent:
Rare:
Anaphylactic/anaphylactoid reactions, including severe reactions.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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