Andante^® (Capsules) Instructions for Use

ATC Code

N05CF03 (Zaleplon)

Active Substance

Zaleplon (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hypnotic drug

Pharmacotherapeutic Group

Hypnotic agent

Pharmacological Action

Hypnotic drug of the pyrazolo-pyrimidine series, which differs in chemical structure from benzodiazepines and other hypnotic drugs. It selectively binds to type I benzodiazepine receptors.

The pharmacokinetic profile of zaleplon is characterized by rapid absorption and elimination. Combined with the selective binding receptor subtype characteristics, high selectivity, and low affinity for type I benzodiazepine receptors, these properties define the overall characteristics of zaleplon.

It significantly reduces sleep latency, prolongs sleep time (in the first half of the night), and does not cause changes in sleep phase ratios. It does not cause pharmacological tolerance when taken for 2-4 weeks.

Pharmacokinetics

Absorption

When taken orally, it is rapidly and almost completely (approximately 71%) absorbed, reaching C_max in plasma within 1 hour. Due to presystemic metabolism, the absolute bioavailability is approximately 30%.

Distribution

It is a fat-soluble compound, V_d after intravenous administration is about 1.4±0.3 L/kg. The likelihood of interaction with other drugs is very low, as approximately 60% is bound to plasma proteins.

Plasma concentrations of zaleplon increased linearly, depending on the dose. No accumulation is observed when taken in daily doses up to 30 mg.

Metabolism

Aldehyde oxidase is involved in the primary metabolism, leading to the formation of 5-oxo-zaleplon. The CYP3A4 isoenzyme is also involved in the metabolism of zaleplon, forming desethylzaleplon, which in turn is converted by aldehyde oxidase into 5-oxo-desethylzaleplon. The oxidation products subsequently undergo conjugation with glucuronic acid. All metabolites of zaleplon are devoid of activity.

Excretion

It is excreted as inactive metabolites, mainly by the kidneys (71%) and through the intestines (17%). 57% of the administered dose is found in the urine as 5-oxo-zaleplon or its metabolites in the form of glucuronides, 9% of the dose as 5-oxo-desethylzaleplon or its metabolite (glucuronide). The remaining part of the dose is in the form of less significant metabolites. Among the metabolites excreted through the intestines, 5-oxo-zaleplon predominates. T_1/2 is about 1 hour.

Pharmacokinetics in special patient groups

Zaleplon is metabolized primarily in the liver and, to a large extent, undergoes presystemic metabolism. In patients with compensated and decompensated liver cirrhosis, the clearance of zaleplon after oral administration was reduced by 70% and 87%, respectively, leading to a significant increase in mean C_max and AUC values (up to 4 and 7 times in patients with compensated and decompensated liver cirrhosis, respectively) compared to healthy volunteers.

In patients with mild to moderate hepatic impairment, the dose of zaleplon should be reduced. The drug is not recommended for patients with severe hepatic impairment.

The pharmacokinetics of zaleplon in patients with mild to moderate renal impairment do not differ significantly from those in healthy individuals, although the concentration of inactive metabolites is higher. The pharmacokinetics of zaleplon in patients with severe renal impairment have not been studied.

Indications

• For the treatment of patients with insomnia who have difficulty falling asleep. The drug is indicated only in cases where the disorder is severe, leads to excessive fatigue, and causes decreased performance.

ICD codes

Dosage Regimen

Capsules

The drug is taken orally, immediately before going to bed, 2 hours after a meal or after the patient feels that they cannot fall asleep.

The duration of therapy should not exceed 2 weeks.

The recommended dose for adults is 10 mg. The maximum daily dose is 10 mg (the patient must be warned about the harm of taking a repeated dose within one night). For elderly patients, the drug is prescribed at a dose of 5 mg (due to greater sensitivity to hypnotics).

For mild to moderate hepatic impairment, the daily dose is 5 mg (due to slower elimination from the body).

For mild to moderate renal impairment, dose adjustment is not required. There are no data on the safety of the drug in severe renal impairment.

There are no data on the use of the drug in children and adolescents under 18 years of age, therefore Zaleplon is not recommended for this age group.

Adverse Reactions

The most common adverse effects of zaleplon are amnesia, paresthesia, drowsiness, and dysmenorrhea.

The adverse effects listed below are presented by system-organ class according to the MedDRA classification and with the following frequency: very common (≥1/10); common (from ≥1/100 to <1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥1/10,000 to <1/1000); very rare (<1/10,000); unknown (cannot be estimated from the available data). Within each group, adverse effects are presented in order of decreasing severity.

Amnesia

When using the drug in recommended therapeutic doses, anterograde amnesia may develop. This risk increases with higher doses. Amnesia may be accompanied by inappropriate behavior.

Depression

Latent depression may manifest during treatment with benzodiazepines and benzodiazepine-like drugs.

Psychiatric and paradoxical reactions

Reactions such as restlessness, anxiety, irritability, reduced control, aggression, thinking disorders, delusions, outbursts of intense anger, nightmares, depersonalization, hallucinations, psychosis, inappropriate behavior, uncharacteristic extroversion, and other adverse behavioral reactions may develop during the use of benzodiazepines or benzodiazepine-like drugs. They develop more often in elderly people.

Dependence

Taking the drug (even in therapeutic doses) can lead to the development of physical dependence: discontinuation of treatment may be accompanied by withdrawal syndrome. Mental dependence may form. Abuse of benzodiazepines and benzodiazepine-like substances has been described.

Contraindications

• Hypersensitivity to the components of the drug;
• Severe hepatic impairment;
• Severe renal impairment;
• Obstructive sleep apnea syndrome;
• Severe respiratory failure;
• Severe myasthenia gravis;
• Pregnancy;
• Lactation period (breastfeeding);
• Childhood and adolescence under 18 years;
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution chronic respiratory failure, mild to moderate hepatic and/or renal impairment, alcohol or drug dependence (including history), depression.

Use in Pregnancy and Lactation

Pregnancy

Animal studies have not shown teratogenic or embryotoxic effects, but the available data are insufficient to assess the safety of zaleplon during pregnancy and lactation.

The drug Andante^® is contraindicated during pregnancy. Women of childbearing age should be warned about the need to consult a doctor immediately in case of conception or when planning pregnancy.

If, for compelling medical reasons, Zaleplon was used in late pregnancy or in high doses during childbirth, the newborn may develop hypothermia, muscle hypotonia, and moderate respiratory depression due to the pharmacological action of the drug.

Infants born to mothers who continuously took benzodiazepines or benzodiazepine-like drugs in late pregnancy may develop physical dependence and are at risk of developing withdrawal symptoms in the postnatal period.

Lactation period

Zaleplon passes into breast milk, therefore it is contraindicated for use during breastfeeding.

Use in Hepatic Impairment

The drug should be prescribed with caution in hepatic impairment.

Use is contraindicated in severe hepatic impairment.

Use in Renal Impairment

The drug should be prescribed with caution in renal impairment.

Use is contraindicated in severe renal impairment.

Pediatric Use

Use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

For elderly patients, the drug is prescribed at a dose of 5 mg (due to greater sensitivity to hypnotics).

Special Precautions

Complex behaviors such as “sleep-driving” (i.e., driving a car while not fully awake after taking a sedative/hypnotic drug, with subsequent amnesia) have been described in patients taking sedative/hypnotic drugs. These phenomena can develop both in individuals taking sedative/hypnotic drugs and in those not taking them.

Although behaviors such as “sleep-driving” can occur when taking sedative/hypnotic drugs alone in therapeutic doses, it is clear that the use of alcohol and other CNS depressants along with sedative/hypnotic drugs may contribute to an increased risk of such behavior, as well as exceeding the maximum recommended daily dose.

Due to the risk to the patient and others in the event of “sleep-driving” episodes, it is recommended to discontinue zaleplon. After taking sedative/hypnotic drugs, patients may experience other complex behaviors while not fully awake (e.g., preparing and eating food, making phone calls, having sexual intercourse). As with sleep-driving, patients usually do not remember these events.

Severe anaphylactic/anaphylactoid reactions have been described in patients taking sedative/hypnotic drugs, including Zaleplon: angioedema of the tongue, vocal cords, or larynx after taking the first or subsequent doses of sedative/hypnotic drugs, including Zaleplon.

In some patients taking sedative/hypnotic drugs, shortness of breath, throat spasm, or nausea and vomiting additionally developed. Some patients required emergency medical care. If angioedema involves the tongue, vocal cords, or larynx, airway obstruction may develop, which can be fatal. Patients who have developed angioedema during treatment with zaleplon should not take drugs containing this substance again.

Insomnia may be a symptom of a physical or mental illness. If insomnia persists or worsens after short-term treatment with zaleplon, re-diagnosis should be performed to establish the diagnosis.

Zaleplon is characterized by a short T_1/2 from plasma. If the patient wakes up soon after midnight, alternative treatment options should be considered. Taking a second dose of the drug within one night is prohibited. Concomitant use of zaleplon with other drugs that have a known effect on the CYP3A4 isoenzyme may lead to changes in plasma concentrations of zaleplon.

Risk when used concomitantly with opioid analgesics

Concomitant use of Andante^® with opioid analgesics may lead to pronounced sedative effect, respiratory depression, coma, and death. Due to these risks, concomitant prescription of sedative drugs, such as benzodiazepines, or similar active substances, such as Zaleplon, with opioid analgesics should be considered only for those patients for whom alternative treatment options are not possible.

If a decision is made to prescribe Andante^® concomitantly with opioid analgesics, the lowest effective dose should be used, and the duration of treatment should be as short as possible. Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. In this regard, it is strongly recommended to inform patients and their caregivers (if applicable) so that they are aware of these symptoms.

Tolerance

Taking short-acting benzodiazepines and benzodiazepine-like drugs for several weeks may be accompanied by a reduction in the hypnotic effect.

Dependence

Taking benzodiazepines and benzodiazepine-like drugs can lead to the development of physical and mental dependence, the likelihood of which increases with the use of high doses, long-term therapy, chronic alcoholism, and a history of drug dependence.

In established physical dependence, abrupt withdrawal of the drug leads to the development of withdrawal syndrome: headache, muscle pain, pronounced anxiety, increased tension and irritability, restlessness, confusion. In severe cases, derealization, depersonalization, hyperacusis, numbness and tingling in the extremities, increased reaction to light, sound and physical stimuli, hallucinations, and epileptic seizures are possible.

Post-marketing use of the drug has received reports of dependence associated with the use of zaleplon, mainly in combination with other psychotropic substances.

Insomnia and anxiety upon drug withdrawal

Upon withdrawal of treatment, a transient syndrome may develop, which is characterized by the return of the symptoms that were indications for treatment with benzodiazepines or benzodiazepine-like substances, to a more pronounced degree. This syndrome may be accompanied by other reactions, including mood changes, anxiety, or sleep disturbances and restlessness.

Duration of treatment

The duration of treatment should be as short as possible and should not exceed 2 weeks. Increasing the duration of treatment is possible only after a repeated clinical assessment.

At the beginning of treatment, it is advisable to inform the patient that the duration of therapy is limited. It is important that the patient is informed about the possibility of developing withdrawal syndrome, which may help reduce anxiety if such symptoms appear after discontinuation of treatment.

Memory and psychomotor impairments

Benzodiazepines and benzodiazepine-like substances can cause anterograde amnesia and psychomotor impairments. This most often occurs within a few hours after taking the drug. To reduce the risk of such impairments, patients should not perform activities that require psychomotor coordination for 4 hours or more after taking zaleplon.

Psychiatric and paradoxical reactions

It is known that reactions such as restlessness, anxiety, irritability, reduced control, aggression, thinking disorders, delusions, outbursts of intense anger, nightmares, depersonalization, hallucinations, psychosis, inappropriate behavior, uncharacteristic extroversion, and others may develop during the use of benzodiazepines or benzodiazepine-like substances.

They may be caused by the active substance, develop spontaneously, or be the result of an underlying mental or physical illness. They develop more often in the elderly. If they develop, the drug should be discontinued. Any new behavioral disorder requires careful and immediate evaluation.

Alcohol or drug abuse

Benzodiazepines and benzodiazepine-like substances should be prescribed with particular caution to patients with a history of alcohol or drug dependence.

Hepatic impairment

Benzodiazepines and benzodiazepine-like substances are contraindicated in patients with severe hepatic impairment, as they may contribute to the development of encephalopathy. In patients with mild to moderate hepatic impairment, the bioavailability of zaleplon is increased due to reduced clearance. In such patients, dose adjustment should be performed.

Respiratory failure

Caution should be exercised when prescribing sedative drugs to patients with chronic respiratory failure.

Psychosis

Benzodiazepines and benzodiazepine-like drugs are not recommended for the initial therapy of psychotic disorders.

Depression

Benzodiazepines and benzodiazepine-like drugs should not be used as monotherapy for depression or anxiety associated with depression (in such patients they may provoke suicidal behavior).

Furthermore, due to the increased risk of intentional overdose in patients with depression, medicinal products, including Zaleplon, should be prescribed in the minimum necessary doses.

In case of lactose intolerance, it should be taken into account that one 10 mg capsule contains 134 mg of lactose monohydrate; therefore, the drug should not be taken by patients with lactose intolerance, lactase deficiency, and glucose-galactose malabsorption.

Effect on the Ability to Drive Vehicles and Operate Machinery

Zaleplon has a pronounced effect on the ability to drive vehicles and operate machinery due to the possibility of sedative effects, amnesia, impaired concentration, and impaired muscle function.

If the sleep duration was insufficient, the likelihood of impaired attention may be increased.

Patients performing work requiring special skills are advised to exercise caution.

Overdose

Clinical data on zaleplon overdose are limited, and human doses have not been established.

Similar to benzodiazepines and other benzodiazepine-like drugs, overdose does not cause life-threatening conditions unless Zaleplon was taken in combination with other central nervous system depressants (including ethanol).

In case of overdose, the possibility of combined poisoning should never be forgotten.

Symptoms CNS depression, ranging from drowsiness to coma.

In mild cases, confusion and lethargy are possible; in more severe cases – ataxia, muscle hypotonia, decreased blood pressure, respiratory depression, blue-green discoloration of urine (chromaturia), less commonly – coma, and in very rare cases with a fatal outcome.

Treatment The antagonist of zaleplon is flumazenil, which can be used as an antidote for overdose of Andante^® and benzodiazepine-like drugs.

Within the first hour after overdose, vomiting should be induced in a conscious patient; gastric lavage should be performed in an unconscious patient.

If gastric lavage is insufficiently effective, activated charcoal is prescribed to reduce absorption.

Monitoring of cardiac and respiratory function is carried out in the intensive care unit.

Drug Interactions

Concomitant use with ethanol is not recommended. Alcohol enhances the sedative effect of zaleplon, which may affect the ability to drive vehicles and operate machinery.

Concomitant use with other substances acting on the CNS requires caution.

Simultaneous administration of antipsychotic (neuroleptic) drugs, other hypnotics, anxiolytics, sedatives, antidepressants, antiepileptic drugs, general anesthetics, H₁-histamine receptor blockers with sedative effect enhances the sedative effect of zaleplon.

Concomitant use of sedative medicinal products, such as benzodiazepines or similar active substances like Zaleplon, with opioid analgesics increases the risk of pronounced sedative effect, respiratory depression, coma, and death due to additive depressant effects on the CNS.

The dose and duration of concomitant use should be limited.

When used concomitantly with narcotic analgesics, the euphoric effect of the latter may occur, leading to the development of drug dependence.

Cimetidine, a non-selective moderate inhibitor of some liver enzymes, including both aldehyde oxidase and the CYP3A4 isoenzyme, caused an 85% increase in zaleplon plasma concentration, which is due to its inhibitory effect on both the primary (aldehyde oxidase) and secondary (CYP3A4 isoenzyme) enzymes metabolizing Zaleplon.

Therefore, caution is recommended when using cimetidine and zaleplon concomitantly.

Single administration of zaleplon with erythromycin (a strong selective inhibitor of the CYP3A4 isoenzyme) at a dose of 800 mg caused a 34% increase in zaleplon plasma concentration.

Dosage adjustment of zaleplon is not required, but the patient should be informed about the possible enhancement of the sedative effect.

Rifampicin, being a potent inducer of some liver enzymes, including CYP3A4, caused a 4-fold decrease in zaleplon plasma concentration.

Concomitant use of zaleplon and CYP3A4 inducers, such as rifampicin, carbamazepine, and phenobarbital, may lead to a decrease in the efficacy of zaleplon.

Zaleplon does not affect the pharmacodynamics and pharmacokinetics of digoxin and warfarin, substances with a narrow therapeutic range; dosage adjustment of these drugs is not required due to their low therapeutic index.

No interaction between ibuprofen and zaleplon was identified.

Use of zaleplon as a single 10 mg dose and venlafaxine (extended-release) at a dose of 75 mg or 150 mg per day did not affect memory (immediate or delayed word recall) or psychomotor activity (digit symbol substitution test).

Furthermore, no pharmacokinetic interaction between zaleplon and venlafaxine (extended-release) was observed.

Storage Conditions

The drug should be stored in the original packaging to protect from moisture, in a place inaccessible to children, at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 5 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.