Study design
The English researchers used data from 27,090 patients with dementia.
The study authors compared the side effects of 3,532 patients prescribed Z-drugs for the first time with 1,833 patients with sleep disorders prescribed non-sedating medications, 10,214 patients prescribed non-sedating medications in a general practitioner setting, and 5,172 patients prescribed benzodiazepines for the first time.
High dose Z-drugs and benzodiazepines were equivalent to ≥7.5 mg zopiclone or >5 mg diazepam.
As primary endpoints
examined fracture, falls, mortality, acute bacterial infections, ischemic stroke/transient ischemic attack, and venous thromboembolism over 2 years of follow-up.
Pharmacological properties of the drug Andante
Zaleplon has high selectivity and low affinity for type 1 benzodiazepine receptors. In patients with primary psychophysiological insomnia, depending on age, taking zaleplon at a dose of 5–10 mg reduces the latent time elapsed before falling asleep. Zaleplon prolongs the duration of sleep in the first half of the night, while the drug does not affect the percentage ratio between different phases of sleep. 2- and 4-week use in any of the doses was not accompanied by the development of tolerance to the drug. When taken orally, it is quickly and almost completely (about 71%) absorbed, reaching a maximum concentration in the blood serum after 1 hour. As a result of first-pass metabolism, absolute bioavailability is about 30%. The degree of binding to plasma proteins is about 60%. Passes into breast milk. Aldehyde oxidase is involved in primary metabolism, resulting in the formation of 5-oxozaleplon. CYP 3A4 is also involved in the metabolism of zaleplon to form desethyl zaleplon, which in turn is converted to 5-oxo-desethyl zaleplon by aldehyde oxidase. Subsequently, the oxidation products undergo conjugation with glucuronic acid. All zaleplon metabolites do not have pharmacological activity. As the dose increases, the concentration of zaleplon in the blood serum increases proportionally. When used in a daily dose of up to 30 mg, no accumulation was detected. The half-life of zaleplon is about 1 hour. Excretion occurs in the form of inactive metabolites, mainly in urine (71%) and feces (17%). 57% of the dose taken is detected in the urine in the form of 5-oxo-zaleplon or its metabolites, 9% of the dose is detected in the form of 5-oxo-desethyl-zaleplon or its metabolites. Among the metabolites detected in feces, 5-oxozaleplon predominates. It is quickly eliminated from the body.
results
- The average age of the patients was 83 years. 62% of patients were women. It was noted that among 3532 patients who started taking Z-drugs, 17% started taking them at a high dose.
- In patients receiving high-dose Z-drugs, compared with patients with sleep disorders who did not receive drugs, the risk of fractures increased by 1.67 times, femoral fracture by 1.96 times, falls by 1.33 times, and ischemic heart failure. stroke by 1.88 times.
- Similar results were observed when compared with non-sedative medications prescribed by primary care physicians.
- Minimal risks were observed when using doses ≤ 3.75 mg of zopiclone.
- There was no significant increase in risk with the use of Z-drugs compared with non-sedative drugs in terms of mortality, infections and venous thromboembolism.
- There were no significant differences in the incidence of adverse events between Z-drugs and benzodiazepines, excluding a 27% reduction in mortality for Z-drugs (hazard ratio, 0.73 [95% CI, 0.64 to 0.83]).
Instructions for use ANDANTE
Prescribing the drug to patients with alcohol and drug dependence requires special caution.
When prescribing hypnotics and sedatives to patients with chronic pulmonary insufficiency, special caution is required.
The drug is not recommended as a primary drug for psychosis.
The drug is contraindicated in patients with severe liver failure due to the risk of developing encephalopathy.
Sleep disturbance can be the result of a physical or mental illness. If, after short-term treatment with Andante, sleep does not normalize or the sleep disorder progresses, the diagnosis should be reconsidered.
The drug is not intended for the treatment of depression and conditions of increased anxiety that accompany depression, because may provoke suicide attempts. If it is necessary to use it in patients with depression, the drug should be prescribed in the minimum effective dose to avoid deliberate overdose.
Thanks to the short T1/2 of zaleplon, if the patient wakes up in the early hours, an alternative treatment can be used after midnight.
Before starting treatment, the patient should be warned about the need to use no more than 1 capsule of the drug per night, the duration of the course of treatment and the possibility of developing withdrawal syndrome.
It is possible to develop anterograde amnesia and impaired psychomotor functions, most often occurring several hours after taking the drug. To avoid the development of these symptoms, the drug should be taken only when the patient has the opportunity to sleep uninterruptedly, at least in the first 4 hours after taking the drug.
Treatment should be short-term, no more than 2 weeks. Treatment can be extended only after a thorough clinical examination of the patient.
After several weeks of treatment, addiction to the drug may develop and its hypnotic effect may decrease.
It is possible to develop physical and mental dependence, the likelihood of which is associated with taking the drug in high doses, long-term treatment and the presence of alcohol and drug dependence.
When physical dependence has developed, sudden cessation of taking the drug leads to the development of withdrawal symptoms:
- headache, muscle pain, severe anxiety, increased tension, restlessness, confusion and irritability. In severe cases, autoaggression, depersonalization, hearing loss, paresthesia in the extremities, increased reaction to light, sound and physical stimuli, hallucinations, and epileptic seizures are possible.
After stopping treatment, transient symptoms of insomnia may develop, but in a more severe form. In this case, other accompanying symptoms may develop, such as mood disturbances, increased anxiety, sleep disturbances or restlessness.
Treatment with zaleplon should be discontinued if increased feelings of anxiety, agitation, irritability, aggressiveness, disturbances in perception, attacks of anger, nightmares, hallucinations and especially behavioral disorders occur. Older patients are most likely to develop such symptoms.
If you are lactose intolerant, please note that a 5 mg capsule contains 67 mg of lactose, a 10 mg capsule contains 134 mg of lactose.
Use in pediatrics
Data on the use of the drug in children under 18 years of age
are absent, therefore zaleplon is not prescribed to patients in this age group.
Impact on the ability to drive vehicles and operate machinery
The drug impairs the ability to drive vehicles and perform other activities, because Providing a sedative effect, it can cause amnesia, reduce the ability to concentrate and muscle strength. With insufficient sleep duration, a similar decrease in concentration is observed. When performing mental and physical activities that require increased attention, the patient must take special care.
Experimental results
In experimental studies, with repeated administration of zaleplon to rats and dogs, an increase in the weight of the liver and adrenal glands was observed. This was noted only at doses several times higher than the maximum therapeutic dose, and was reversible, i.e. was not accompanied by microscopic degenerative changes in the liver and adrenal glands. Other compounds that bind to benzodiazepine receptors have caused a similar reaction. In prepubertal dogs, prostate and testicular weights were significantly reduced in 3-month trials at doses several times the maximum therapeutic dose. In 2-year trials on rats, zaleplon at a dose of 20 mg/kg/day did not provoke the development of tumor formations. In mice, the incidence of benign liver tumors increased significantly when the drug was administered orally at high doses (≥100 mg/kg/day) during 65- and 104-week trials. No malignant neoplasms were found. An increase in the frequency of tumor changes in mice is regarded as an adaptive process. In general, according to preclinical studies, the use of zaleplon in recommended doses does not pose a significant danger to humans.
Drug interactions Andante
Alcohol intake enhances the sedative effect of zaleplon. The simultaneous use of antipsychotic (neuroleptic), hypnotics, anxiolytic/sedative, antidepressant, antiepileptic, anesthetic, sedative antihistamines, narcotic analgesics enhances the sedative effect of zaleplon. When used simultaneously with zaleplon, a euphoric effect of narcotic analgesics may occur, causing the development of addiction. Cimetidine, as a nonspecific inhibitor of liver enzymes (aldehyde oxidase and CYP 3A4), increases the concentration of zaleplon in the blood plasma by 85%. Caution should be exercised when prescribing these drugs in combination. Selective CYP3A4 blockers (ketoconazole, erythromycin) increase the concentration of zaleplon in the blood plasma; the patient should be warned about the increased sedative effect of zaleplon, but no dose adjustment is required. Strong inducers of liver enzymes (CYP 3A4), for example rifampicin, carbamazepine, phenobarbital derivatives, can reduce the concentration of zaleplon in the blood plasma and its effectiveness by 1/4. Zaleplon does not affect the pharmacodynamics and pharmacokinetics of digoxin and warfarin, so dose adjustment of these drugs is not required. Ibuprofen does not interact with zaleplon. When taken simultaneously in combination with other known CYP 3A4 inhibitors, the concentration of zaleplon in the blood plasma may change.
Andante drug overdose, symptoms and treatment
An overdose, as a rule, does not cause life-threatening conditions if the patient is not taking antidepressants or alcoholic drinks at the same time. In case of overdose, the fact of combined intoxication should be excluded. Typically, in case of overdose, symptoms of central nervous system depression are noted, manifested by drowsiness and coma. In case of a slight overdose, drowsiness, confusion, lethargy are possible, in more severe cases - ataxia, arterial hypotension, respiratory failure, less often - coma, very rarely - with death. If the fact of overdose is established in the 1st hour after taking the drug, vomiting should be induced in a conscious patient. For an unconscious patient, gastric lavage is performed and the function of the respiratory system is supported. Cardiac and respiratory monitoring is carried out in the intensive care unit. Flumazenil can be used as an antidote. Clinical experience, however, does not support the effectiveness of flumazenil in zaleplon overdose.
Side effects
- Digestive reactions: vomiting, abdominal pain, nausea, diarrhea .
- Reactions from nervous activity: weakness, headache , drowsiness , anterograde amnesia , dizziness , depression , anxiety, aggressiveness, excitability, paresthesia , nightmares, attacks of rage, hallucinations , behavioral disorders, psychosis , the appearance of physical dependence even when used in therapeutic doses , withdrawal syndrome , the appearance of mental dependence, tremor, ataxia , irritability, changes in perception. of auto-aggression, epileptic seizures, hearing loss, depersonalization , and hypersensitivity to light, sound and other physical stimuli may appear
- Allergic reactions: skin rash , itching .
Contraindications
- Sleep apnea.
- Severe forms of liver failure .
- Severe forms of respiratory failure .
- gravis .
- Pregnancy or lactation .
- Age less than 18 years.
- Sensitization to the components of the drug.
Andante should be prescribed with caution in case of renal or liver failure, chronic respiratory failure , tendency to drug addiction, alcoholism, depression.
Pharmacodynamics and pharmacokinetics
Pharmacodynamics
A hypnotic from the pyrazolo-pyrimidine group , it differs in chemical structure from benzodiazepines and other hypnotics. Selectively binds to type 1 benzodiazepine ω1 receptors.
Significantly reduces the time it takes to fall asleep, lengthens sleep time, and does not change the ratio of different phases of sleep. When used in recommended doses, it does not cause tolerance. It has a sedative , weak anxiolytic, anticonvulsant and systemic muscle relaxant effect.
Interacts with benzodiazepine receptors A-type GABA complexes . This leads to the opening of ionoform neuronal channels for chlorine molecules, the appearance of hyperpolarization and stimulation of inhibitory processes in the brain.
Pharmacokinetics
After consumption, about 71% of the dose taken is quickly absorbed from the intestines. The time for maximum concentration in the blood is one hour. Absolute bioavailability approaches 30%. Plasma concentrations are dose dependent. Eating slows down the time to reach the highest concentration without affecting the absorption of the drug.
Plasma protein binding by 60%. Able to be excreted in breast milk. Transformed in the liver to form inactive derivatives. The half-life of zaleplon is approximately 1 hour. Excreted in the form of inactive derivatives by the kidneys (71%) and through the intestines (17%).
special instructions
The patient should be warned that the drug does not serve as a means for long-term therapy and withdrawal syndrome may occur after stopping its use. The course of treatment should in no case exceed two weeks.
The drug is approved for use in elderly patients.
After stopping the use of benzodiazepine-like drugs, there is a possibility of temporary symptoms of insomnia , as well as other associated reactions (anxiety, mood changes, restlessness).
During the period of use of Andante, it is advised to refrain from operating mobile mechanisms.
