zaleplon 10 MG Oral Capsule
WARNINGS
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.
The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.
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 Zaleplon.
Because some of the important adverse effects of Zaleplon appear to be dose-related, it is important to use the lowest possible effective dose, especially in the elderly (see DOSAGE AND ADMINISTRATION).
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.
Abnormal Thinking and Behavioral Changes Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported.
These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons.
Although behaviors such as sleep-driving may occur with Zaleplon alone at therapeutic doses, the use of alcohol and other CNS depressants with Zaleplon appears to increase the risk of such behaviors, as does the use of Zaleplon at doses exceeding the maximum recommended dose.
Due to the risk to the patient and the community, discontinuation of Zaleplon should be strongly considered for patients who report a “sleep-driving” episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic.
As with sleep-driving, patients usually do not remember these events.
Amnesia and other neuropsychiatric symptoms may occur unpredictably.
In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), 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 DRUG ABUSE AND DEPENDENCE).
Zaleplon, like other hypnotics, has CNS-depressant effects.
Because of the rapid onset of action, Zaleplon should only be ingested immediately prior to going to bed or after the patient has gone to bed and has experienced difficulty falling asleep.
Patients receiving Zaleplon 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 Zaleplon.
Zaleplon, 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.
Zaleplon should not be taken with alcohol.
Dosage adjustment may be necessary when Zaleplon is administered with other CNS-depressant agents because of the potentially additive effects.
Severe anaphylactic and anaphylactoid reactions Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including Zaleplon .
Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis.
Some patients have required medical therapy in the emergency department.
If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal.
Patients who develop angioedema after treatment with Zaleplon should not be rechallenged with the drug.
DRUG INTERACTIONS
Drug Interactions As with all drugs, the potential exists for interaction with other drugs by a variety of mechanisms.
CNS-Active Drugs Ethanol: Zaleplon 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 Zaleplon 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 Zaleplon 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 Zaleplon, reflecting the absence of a role of CYP2D6 in zaleplon’s metabolism.
Thioridazine: Coadministration of single doses of Zaleplon 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 C max 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 Zaleplon (10 mg) and cimetidine (800 mg) produced an 85% increase in the mean C max and AUC of zaleplon.
An initial dose of 5 mg should be given to patients who are concomitantly being treated with cimetidine (see DOSAGE AND ADMINISTRATION).
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 Zaleplon 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: Zaleplon (10 mg) did not affect the pharmacokinetic or pharmacodynamic profile of digoxin (0.375 mg q24h for 8 days).
Warfarin: Multiple oral doses of Zaleplon (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.
OVERDOSAGE
Signs and Symptoms 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.
Loss of consciousness, in addition to signs and symptoms consistent with CNS depressants as described above, have been reported following zaleplon overdose.
Individuals have fully recovered from zaleplon overdoses of greater than 200 mg (10 times the maximum recommended dose of zaleplon).
Rare instances of fatal outcomes following overdose with zaleplon, most often associated with overdose of additional CNS depressants, have been reported.
Recommended Treatment 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 Zaleplon 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.
Poison Control Center 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.
DESCRIPTION
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 C 17H 15N 5O, and its molecular weight is 305.34.
The structural formula is shown below.
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.
Zaleplon capsules contain zaleplon as the active ingredient.
Inactive ingredients consist of microcrystalline cellulose, pregelatinized starch, colloidal silicon dioxide, sodium lauryl sulfate, magnesium stearate, lactose, gelatin, titanium dioxide, FD&C blue #1, FD&C red #40 and black iron oxide.
Zaleplon 5mg capsules also contain FD&C yellow #5.
Zaleplon Strcture
HOW SUPPLIED
Zaleplon capsules 5 mg are available as hard gelatin capsules with light blue cap and light blue body imprinted with “ASC” on cap and “210” on the body in black ink along the horizontal axis.
Bottles of 30’s: NDC 67877-210-30 Bottles of 100’s: NDC 67877-210-01 Bottles of 500’s: NDC 67877-210-05 Zaleplon capsules 10 mg are available as hard gelatin capsules with dark blue cap and dark blue body imprinted with “ASC” on cap and “211” on the body in black ink along the horizontal axis.
Bottles of 100’s: NDC 67877-211-01 Bottles of 500’s: NDC 67877-211-05 Bottles of 1000’s: NDC 67877-211-10 STORAGE CONDITIONS Store at controlled room temperature, 20°C to 25°C (68°F to 77°F) [see USP].
Dispense in a light-resistant container as defined in the USP.
Manufactured by: UNICHEM LABORATORIES LTD.
Pilerne Ind.
Estate, Pilerne, Bardez, Goa 403 511, India
GERIATRIC USE
Geriatric Use A total of 628 patients in double-blind, placebo-controlled, parallel-group clinical trials who received Zaleplon 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 Zaleplon, no adverse event with a frequency of at least 1% occurred at a significantly higher rate with either 5 mg or 10 mg Zaleplon than with placebo.
INDICATIONS AND USAGE
INDICATIONS & USAGE Zaleplon is indicated for the short-term treatment of insomnia.
Zaleplon has been shown to decrease the time to sleep onset for up to 30 days in controlled clinical studies (see Clinical Trials under CLINICAL PHARMACOLOGY).
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.
PEDIATRIC USE
Pediatric Use The safety and effectiveness of Zaleplon in pediatric patients have not been established.
PREGNANCY
Pregnancy Pregnancy Category C 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 2 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 2 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 2 basis).
When the adverse effects on offspring viability and growth were examined in a cross-fostering study, they appeared to result from both in utero and lactational exposure to the drug.
There are no studies of zaleplon in pregnant women; therefore, Zaleplon is not recommended for use in women during pregnancy.
NUSRING MOTHERS
Nursing Mothers 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 Zaleplon 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 Zaleplon.
INFORMATION FOR PATIENTS
Information for Patients Patient information is printed at the end of this insert.
To assure safe and effective use of Zaleplon, the information and instructions provided in the patient information section should be discussed with patients.
A patient Medication Guide is also available for Zaleplon.
The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions that they may have.
SPECIAL CONCERNS “Sleep-Driving” and other complex behaviors There have been reports of people getting out of bed after taking a sedative hypnotic medicine and driving their cars while not fully awake, often with no memory of the event.
If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous.
This behavior is more likely to occur when Zaleplon is taken with alcohol or other central nervous system depressants (see WARNINGS).
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sleep medicine.
As with sleep-driving, patients usually do not remember these events.
DOSAGE AND ADMINISTRATION
DOSAGE & ADMINISTRATION The dose of Zaleplon should be individualized.
The recommended dose of Zaleplon 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 Zaleplon 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.
Zaleplon should be taken immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep (see PRECAUTIONS).
Taking Zaleplon with or immediately after a heavy, high-fat meal results in slower absorption and would be expected to reduce the effect of Zaleplon on sleep latency (see Pharmacokinetics under CLINICAL PHARMACOLOGY).
Special Populations Elderly patients and debilitated patients appear to be more sensitive to the effects of hypnotics, and respond to 5 mg of Zaleplon.
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 Zaleplon 5 mg because clearance is reduced in this population.
Zaleplon 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.
Zaleplon 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 Drug Interactions under PRECAUTIONS).