Approval date: xxxx, xx, xx, xx
Modification date: xxxx xx date
Dexzopiclone Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug name]
Generic name: Dexrazopiclone Tablets
Trade name: Auyujing®
English name: Dexzopiclone Tablets
Hanyu Pinyin: Youzuopikelong Pian
Ingredients
The active ingredient of this product is Dexzopiclone.
Chemical name: (+)-(7S)-6-(5-chloro-2-pyridyl)-7-[(4-methylpiperazin-1-yl)formyloxy]-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one.
Chemical structure formula.
Molecular formula: C17H17ClN6O3
Molecular weight: 388.81
Properties
This product is a film-coated tablet, which appears white or off-white after removing the film coating.
Indications
For the treatment of insomnia.
Specification
3mg
Dosage and Administration
The recommended starting dose for adults is 1mg, which may be increased to 2mg or 3mg if clinically indicated. 2mg or 3mg doses in some patients may result in high morning blood levels, which may increase the risk of next morning hangover, i.e. impairment of function in driving or activities requiring mental acuity (see [Precautions]).
The recommended starting dose for elderly patients complaining of difficulty falling asleep is 1 mg before bedtime and may be increased to 2 mg if necessary. the recommended dose for elderly patients with sleep maintenance disorders is 2 mg before falling asleep (see Precautions).
If dexrazopiclone is taken immediately after a high-fat diet there is a risk of slow absorption of the drug, resulting in a reduced effect of dexrazopiclone on sleep latency (see Pharmacokinetics).
Special Populations: This product should be used with caution in patients with severe liver damage at an initial dose of 1 mg.
Combination with CYP inhibitors: In combination with strong inhibitors of CYP3A4, the initial dose of this product should not be greater than 1 mg and may be increased to 2 mg if necessary.
Considering the potential synergistic effects of CNS depression, when combined with other CNS depressants, the dose of dexrazopiclone may need to be adjusted appropriately.
[Adverse Reactions].
Given that clinical trials are conducted under different conditions, the incidence of adverse reactions observed in clinical trials cannot be directly compared with the incidence in clinical trials of other drugs, nor can they directly reflect the incidence of adverse reactions in actual clinical use of the drug.
Approximately 400 normal subjects were enrolled in clinical pharmacology/pharmacokinetic studies and approximately 1500 patients were enrolled in placebo-controlled clinical effectiveness studies (equivalent to approximately 263 patient exposure years) in the pre-marketing study of dexzopiclone. The conditions and duration of treatment with dexrazopiclone varied widely in pre-marketing studies, including open and double-blind trials (categories), inpatient and outpatient, long-term and short-term trials, and adverse reactions were evaluated by collecting adverse events and assessing the results of physical examination, vital signs, weight, laboratory tests, and electrocardiogram.
The incidence of adverse reactions is defined as the proportion of occurrences in which the subject has had at least one of the adverse reactions listed below. Subjects should be treated as an emergency when it occurs for the first time after the initial evaluation or when the original symptoms worsen.
Adverse events leading to discontinuation of the drug
In a placebo-parallel controlled trial in the elderly, 3.8% of 208 patients taking placebo, 2.3% of 215 patients taking 2 mg dexrazopiclone, and 1.4% of 72 patients taking 1 mg dexrazopiclone discontinued treatment due to adverse events. In a 6-week parallel controlled study in adult patients, there were no discontinuations due to adverse events in the 3 mg dexrazopiclone treatment group. In a 6-month long-term controlled trial study of adult insomnia patients, 7.2% of 195 patients taking placebo and 12.8% of 593 patients taking 3 mg dexrazopiclone discontinued the trial due to adverse events. In contrast, the incidence of withdrawal from the trial for reasons other than the occurrence of an adverse event was greater than 2%.
Adverse events with an incidence greater than 2% in the control trial
Table 1 shows the incidence of adverse events in a 44-day, phase III, placebo-controlled clinical trial in non-elderly adult patients treated with 2 mg or 3 mg dexrazopiclone. Only adverse reactions with an incidence of ≥2% in the dexrazopiclone 2mg or 3mg treatment group and a higher incidence than in the placebo group are included in this table.
Table 1: Incidence of adverse events in non-elderly adult patients treated with dexrazopiclone in a 6-week placebo-controlled study1
Adverse events Placebo group
(n=99) 2 mg dexzopiclone treatment group (n=104) 3 mg dexzopiclone treatment group (n=105) General headache 132117 Viral infection 133 Digestive system Dry mouth 357 Dyspepsia 445 Nausea 454 Vomiting 130 Neurological system Anxiety 031 Unconsciousness 003 Depression 041 Vertigo 457 Hallucinations 013 Loss of libido 003 Nervousness 350 drowsiness 3108 respiratory infections 3510 skin rash 134 sensory abnormalities taste abnormalities 31734 genitourinary system dysmenorrhea (female) 030 gynecomastia (male) 030 Note 1: Adverse events of comparable or lesser incidence in the dexrazopiclone treatment group than in the placebo group are not listed, except for the following adverse reactions, abnormal dreams, accidental trauma, stomach pain, diarrhea, influenza, myalgia, pain, sore throat, and rhinitis.
Table 1 shows a dose-related pattern of adverse reactions such as viral infections, dry mouth, dizziness, hallucinations, infections, rash, and taste abnormalities in adult patients, with the most pronounced dose-related pattern of taste abnormalities.
Table 2 presents the incidence of adverse events in elderly (65-86 years old) subjects treated with dexrazopiclone 1 mg or 2 mg in a 14-day, phase III, placebo-controlled clinical trial. Only adverse reactions with an incidence of ≥2% in the dexzopiclone 1 mg or 2 mg treatment group and a higher incidence than in the placebo group are included in this table.
Table 2: Incidence of adverse events in elderly (65-86 years) subjects treated with dexrazopiclone in a 2-week placebo-controlled study1
Adverse events Placebo group
(n=208) 1 mg dexzopiclone treatment group (n=72) 2 mg dexzopiclone treatment group (n=215) Systemic reactions Accidental trauma 103 Headache 141513 Pain 245 Digestive system Diarrhea 242 Dry mouth 237 Dyspepsia 262 Central nervous system abnormalities Dreams 031 Vertigo 216 Tension 102 Neuralgia 030 Skin pruritus 141 Sensory abnormalities Taste Abnormal 0812 Genitourinary system urinary infection 030 Note 1: Adverse events with comparable or lesser incidence in the dexrazopiclone treated group than in the placebo group are not listed, except for the following adverse reactions, abdominal pain, weakness, nausea, rash and drowsiness. As seen in Table 2, adverse reactions such as pain, dry mouth and abnormal taste were dose-related in elderly patients, with abnormal taste being the most dose-related.
Due to differences in patient characteristics and other factors in clinical trials, these data cannot be used to predict the incidence of adverse events in normal medical practice. Similarly, the data cited in this trial are not comparable to data from other clinical trials due to differences in the therapeutic agents, methods of use, and clinical evaluators. However, these data can provide some reference for clinicians.
Other adverse reactions observed in pre-marketing safety studies of dexzopiclone tablets
The following is a revised COSTART list of terms defined in the instructions as adverse reactions, derived from Phase II and Phase III clinical trials conducted in the United States and Canada with approximately 1550 cases treated with dexrazopiclone at doses of 1 to 3.5 mg/day. All reported reactions are included, in addition to those already listed in Tables 1 and 2 and in the labeling, as well as some minor reactions that are common in the general population and unlikely to be drug-related. Although the reported reactions occurred during treatment with dexzopiclone tablets, they were not necessarily caused by the drug.
Adverse reactions were further classified by body system and listed in the following categories in decreasing order of frequency: common adverse reactions were those with an incidence of ≥1/100 adverse reactions; occasional adverse reactions were those with an incidence of ≥1/1000 and <1/100. Rare adverse reactions are those with an incidence <1/1000 adverse reactions. Gender-specific reactions are incidence statistics by gender.
Systemic reactions: common: chest pain; occasional: allergic reactions, cellulitis, facial edema, fever, halitosis, heat stroke, hernia, atrophy, neck stiffness, photosensitivity.
Cardiovascular system: common: migraine; occasional: hypertension; rare: thrombophlebitis.
Digestive system: occasional: anorexia, cholelithiasis, increased appetite, black stools, mouth ulcers, thirst, ulcerative stomatitis; rare: colitis, dysphagia, gastritis, hepatitis, hepatomegaly, liver damage, gastric ulcers, stomatitis, tongue edema, and rectal bleeding.
Blood and lymphatic system: Occasionally: anemia, enlarged lymph nodes.
Metabolic and nutritional: common: peripheral edema; occasional: hypercholesterolemia, weight gain, weight loss; rare: dehydration, gout, hyperlipidemia and hypokalemia.
Musculoskeletal system: occasional: arthritis, bursitis, joint disease (mainly swelling, stiffness, and pain), leg cramps, muscle weakness, and convulsions; rare: arthropathy, myopathy, and ptosis.
Neurological: occasional: agitation, apathy, ataxia, mood swings, hostility, hypertonia, hypersensitivity, dysesthesia, insomnia, memory deficits, neurasthenia, nystagmus, sensory abnormalities, hyporeflexia, abnormal thinking (mainly difficulty concentrating), vertigo; rare: gait abnormalities, euphoria, sensory hypersensitivity, hypokinesia, neuritis, neuropathy, wood stiffness and tremors.
Respiratory system: Occasionally: asthma, bronchitis, dyspnea, rhinorrhea, eruption, laryngitis.
Skin and subcutaneous tissue: Occasionally: acne, alopecia, contact dermatitis, dry skin, eczema, skin discoloration, sweating, urticaria; Rarely: erythema multiforme, boils, herpes zoster, hirsutism, maculopapular rash, blistering rash.
Atopic sensations: occasional: conjunctivitis, dry eyes, otalgia, otitis externa, otitis media, tinnitus, vestibular disorder; rare: auditory hypersensitivity, iritis, dilated pupils, photophobia.
Genitourinary system: Occasionally: amenorrhea, breast distension, breast enlargement, breast tumor, breast pain, cystitis, dyspareunia, breast overflow, hematuria, kidney stones, renal pain, mastitis, menorrhagia, hematochezia, dysuria, urinary frequency, urinary incontinence, uterine bleeding, vaginal bleeding, vaginitis; Rarely: oliguria, pyelonephritis, urethritis.
In addition to the adverse reactions observed during clinical trials, olfactory dysfunction characterized by olfactory dysfunction has been reported in post-marketing safety monitoring of dexzopiclone tablets. Because this adverse event was spontaneously reported from a group of unknown size, the frequency of this adverse reaction cannot yet be assessed.
Contraindications
This product is contraindicated in persons with known hypersensitivity to dexzopiclone. Allergic reactions include hypersensitivity and anaphylactoid reactions (see [Precautions]). It is contraindicated in patients with hypersensitivity to the product and its components, in patients with decompensated respiratory insufficiency, in patients with myasthenia gravis, and in patients with severe sleep apnea syndrome.
[Precautions].
Central nervous system depressant effect and next morning hangover
Dexzopiclone is a central nervous system depressant and some patients may experience impairment of daytime function at higher doses (2mg or 3mg) even when administered as prescribed. Prescribers should monitor for the occurrence of excessive depression, but sometimes impairment occurs without accompanying symptoms (and may even appear subjectively improved), and impairment cannot be accurately detected by routine clinical examination (e.g., informal psychomotor testing). Because of the potential for pharmacodynamic resistance to dexrazopiclone or adaptation to its adverse CNS depressant effects, patients taking dexrazopiclone 3 mg should be aware that driving or activities requiring mental acuity should not be performed after dosing.
Combinations with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) can enhance CNS depressant effects, including those seen with daytime applications. When combining medications, lower doses of dexrazopiclone and combination medications should be considered (see [Dosage and Administration]).
Concomitant administration of dexzopiclone and other sedative-hypnotics at bedtime or in the middle of the night is not recommended.
The risk of next morning hangover is increased when dezopiclone is taken without adequate sleep (7-8 h), or when dezopiclone is taken in excess of the recommended dose, or in combination with other CNS depressants or with other drugs that may cause elevated blood levels of dezopiclone.
Need for evaluation of comorbidities
Because sleep disturbances may be the clinical manifestation of physical and/or psychological disorders, patients need to be carefully evaluated before starting symptomatic treatment for insomnia. After 7 to 10 days of treatment, if insomnia symptoms do not resolve, a possible primary somatic and/or psychiatric disorder is indicated and a clinical evaluation should be performed. Exacerbation of insomnia symptoms or the development of new thinking/behavioral abnormalities may be caused by a primary physical and/or psychological disorder that has not yet been recognized. Such reactions have occurred during treatment with sedative/hypnotic medications, including dexrazopiclone. Considering that many of the important adverse reactions to dexrazopiclone are dose-related, it is essential to use the lowest effective dose during treatment, especially in elderly patients.
Severe allergic and anaphylactic-like reactions
Rarely, cases involving angioedema of the tongue, vocal cords or larynx have been reported after the first or sequential application of sedative-hypnotic drugs including dexrazopiclone. Some patients also experience other symptoms of an allergic reaction, such as dyspnea, throat closure, or nausea and vomiting in the presence of an allergic reaction. Some patients also need to go to the emergency department to receive medication. If angioedema involves the tongue, vocal cords, or larynx, airway obstruction or even death may occur. Patients who develop angioedema after treatment with dexrazopiclone should not be re-treated with this drug.
Abnormal thinking or behavioral changes
A range of abnormal thoughts and behavioral changes have been reported with sedative/hypnotic drugs. Some of the changes are similar to the diminished inhibitory effects produced by alcohol and other CNS depressants, such as aggressiveness and extraversion inconsistent with personality. Other behavioral changes that have been reported include bizarre behavior, agitation, hallucinations, and split personality; amnesia and other neuropsychiatric symptoms may also occur without warning. Increased depression, including suicidal thoughts, has been reported in depressed patients taking sedative/hypnotic medications.
Complex behaviors such as “sleep driving” (i.e., driving while not fully awake after taking sedative-hypnotic drugs with amnesia) have been reported; this reaction may occur in patients who are using sedative-hypnotic drugs for the first time or who have already used sedative-hypnotic drugs. Although complex behaviors such as sleep driving may occur with therapeutic doses of dexrazopiclone given alone, the risk of such behaviors appears to be increased when dexrazopiclone is combined with alcohol and other CNS depressants, as concomitant administration would cause dexrazopiclone to be administered in excess of the maximum recommended dose. Considering the risks to patients and the public, discontinuation of dexrazopiclone should be strongly recommended in patients who report “sleep driving” behavior. Other complex behaviors (e.g., preparing and eating, talking on the phone, or having sex) have also been reported in patients who are not fully awake after taking sedative-hypnotic drugs. As with sleep driving, patients usually forget these events.
It is difficult to determine whether the abnormal behaviors described above are drug-induced, spontaneous, or the result of an underlying somatic/psychological disorder. Nevertheless, the presence of any new behavioral signs or symptoms requires prompt and careful evaluation.
Withdrawal reactions
Signs and symptoms of withdrawal similar to those seen with other CNS depressants have been reported with abrupt dose reductions or discontinuation of sedative/hypnotic drugs.
Dosing time
Dexrazopiclone should be taken immediately before bedtime. If sedative/hypnotic medication is taken, remaining out of bed and walking around may result in transient memory deficits, hallucinations, coordination disorders, dizziness and lightheadedness.
Medication for Special Populations
Elderly and/or frail individuals
The use of sedative/hypnotic drugs in elderly and/or frail patients should take into account motor impairment and/or cognitive impairment due to repeated use or drug sensitivity. In elderly or frail individuals, the total daily dose of dexrazopiclone should not exceed 2 mg.
Dosing in patients with other medical conditions
There is limited clinical experience with dexrazopiclone in patients with co-morbidities. Dexrazopiclone should be used with caution in patients with concomitant conditions that affect the metabolism or hemodynamics of dexrazopiclone.
In a clinical study in healthy volunteers, no respiratory depression was observed in subjects receiving 2.5 times the recommended dose (7 mg) of dexrazopiclone. However, dexzopiclone should still be used with caution in patients with impaired respiratory function.
In patients with severe hepatic insufficiency, the systemic drug exposure is approximately twice that of normal patients, so the dose of dexrazopiclone should not exceed 2 mg in such patients. no dose adjustment is required in patients with mild to moderate hepatic insufficiency. Since less than 10% of the prototype drug is excreted in the urine, no dose adjustment is necessary in patients with any degree of renal insufficiency.
The dose of dexrazopiclone should be reduced when patients taking dexrazopiclone are also given a potent CYP3A4 inhibitor such as ketoconazole. Appropriate dose reductions are also recommended when dexrazopiclone is given in combination with drugs known to have CNS depressant effects.
Medication for depressed patients
Sedative/hypnotic drugs should be used with caution in patients with signs or symptoms of depression. Such patients are suicidal and may require appropriate protective measures. Artificial overdose is common in this population, and only the lowest effective dose should be prescribed at any time for such patients.
Hepatic insufficiency
No dose adjustment is required in patients with mild to moderate hepatic insufficiency. Patients with severe hepatic insufficiency will have elevated blood levels compared to healthy volunteers. Dose should not exceed 2 mg in patients with severe hepatic insufficiency. dexrazopiclone should be used with caution in patients with hepatic insufficiency.
Pregnant women and nursing mothers
Pregnancy
Risk Overview
Validated pharmacovigilance data for dexzopiclone in pregnant women are insufficient to assess the pharmacological relevance of major birth defects, miscarriage, and consequences such as maternal or fetal harm. Animal reproduction studies throughout organogenesis in rats and rabbits during gestation have not found teratogenic effects of this product. Dexrazopiclone administration to rats during gestation and lactation resulted in toxicity in offspring at all doses tested; the lowest dose was approximately 200 times the maximum recommended human dose (MRHD) of 3 mg/day based on mg/m2 extrapolation.
The predicted risk profile for major birth defects and miscarriage in the described population is unknown. The maternal population is already at risk for birth defects, miscarriage, or other adverse events. In the general U.S. population, the clinically recognized risks of major birth defects and miscarriage in pregnancy are approximately 2% to 4% and 15% to 20%, respectively.
Lactation
Risk Summary
No data are available on this product in human or animal milk, and on the effects on lactation and milk production. The developmental and health benefit effects of breastfeeding need to be integrated, taking into account the maternal clinical need for dexzopiclone and any potential risk of this product on breastfeeding or the underlying maternal condition.
Pediatric Use]
The safety and efficacy of this drug in pediatric and adolescent patients under the age of 18 years has not been established, and this drug is not recommended.
Geriatric Use]
When administering the drug, start with a small dose and gradually increase the dose in order to obtain the appropriate dose for the patient, see [Dosage] item.
In a double-blind, parallel, placebo-controlled clinical study that included 287 cases treated with dexrazopiclone, the subjects were between 65 and 86 years of age. In the 2-week study, elderly subjects (mean age 71 pairs) had an overall adverse effect profile similar to that of non-elderly adults after taking 2 mg of dexzopiclone at bedtime. Dexrazopiclone 2 mg significantly shortened sleep latency and improved sleep maintenance in elderly patients. Dexrazopiclone has a longer elimination time and higher drug exposure in older adults aged 65 years and older compared to non-elderly adults. Therefore, the dose should be reduced appropriately in elderly patients.
Drug Interactions]
Central nervous system agonists
Alcohol: Increased effects on psychomotor activity were observed when dexzopiclone was combined with alcohol.
Olanzapine: The combination of dexzopiclone and olanzapine decreased DSST scores. There was a pharmacodynamic interaction between the two and no effect between pharmacokinetics.
CYP3A4 inhibitors or inducers
CYP3A4 inhibitors (ketoconazole)
Dexrazopiclone is mainly metabolized by CYP3A4. The combination of dexrazopiclone and the potent CYP3A4 inhibitor ketoconazole increases the blood concentration of this product. Combination with other potent CYP3A4 inhibitors may produce similar effects (itraconazole, clarithromycin, nefazodone, dexrazoxane, ritonavir, nelfinavir). Dose reductions are required when dexrazopiclone is combined with potent CYP3A4 inhibitors.
CYP3A4 inducers (rifampicin)
The exposure of racemic zopiclone was reduced by 80% when combined with the potent CYP3A4 inducer rifampicin. It was inferred that dexrazopiclone might have similar effects. Therefore, when used in combination with a potent CYP3A4 inducer, the exposure of dezopiclone may be reduced and its efficacy reduced.
Drug overdose]
In the clinical trial of dexzopiclone, a complete recovery was reported in a patient who took an overdose of 36 mg of dexzopiclone. Complete recovery of a patient with spontaneous overdose of dexzopiclone 270 mg (equivalent to 90 times the maximum recommended dose of the product) has also been reported since the product was marketed. Deaths associated with dexrazopiclone overdose have only been reported when dexrazopiclone was combined with other CNS drugs or alcohol.
Signs and Symptoms
Amplification of preclinical pharmacological effects may be considered a sign and symptom of an overdose of CNS depressants. This can manifest as varying degrees of impairment of consciousness ranging from drowsiness to coma. There have also been rare reports of overdose fatalities since the introduction of elimination zopiclone in Europe, and such events have been associated with overdoses of other CNS depressants.
Recommended treatment measures
Gastric lavage, symptomatic and supportive treatment should be administered as soon as possible. Intravenous rehydration if necessary, flumazenil may be useful. In all cases of overdose, the patient’s respiration, pulse, blood pressure and other appropriate signs should be monitored, along with some systemic supportive therapy, and cases of hypotension and CNS depression should be monitored and treated accordingly. The treatment of dialysis for drug overdose is not known.
As with all drug overdose management measures, the possibility of multiple drug intake should be considered. Physicians may consider contacting a poison control center for the latest information on overdose management of hypnotic drug products.
Drug Abuse and Dependence
In abuse studies conducted in individuals with a known history of benzodiazepine abuse, 6 mg and 12 mg doses of dexrazopiclone produced euphoric effects similar to those produced by diazepam 20 mg. Studies have shown that dexrazopiclone and diazepam produce dose-related amnesia and hallucinations at doses of two or more times the maximum recommended dose, and the incidence increases with increasing dose.
No severe withdrawal symptoms were reported in the results of clinical trials of dexzopiclone. However, in clinical trials where placebo replacement therapy was given after the last treatment, the following adverse reactions included in the American Psychiatric Diagnostic Criteria-IV occurred within 48 hours of placebo replacement therapy: anxiety, abnormal dreams, nausea, and gastric upset. The incidence of these adverse reactions was 2% or less. The use of benzodiazepines and similar drugs may lead to physical and psychological dependence. The risk of abuse and dependence increases with increasing dose and duration of treatment and with the combination of other psychotropic medications. Patients with a history of alcohol or drug abuse or a history of psychiatric disorders are also at greater risk. These patients should be closely monitored while receiving dexrazopiclone or any other hypnotic drug.
Pharmacology and Toxicology]
Mechanism of action
The exact mechanism of action of dexrazopiclone as a hypnotic is not known, but its mechanism of action is generally thought to be due to its action on the GABA receptor complex coupled to the benzodiazepine receptor. Dexrazopiclone is a non-benzodiazepine hypnotic, pyrrolizidine derivative of cyproheptadine, which has a chemical structure unrelated to pyrazolopyrimidines, imidazolopyridines, benzodiazepines, barbiturates or other drugs known to have hypnotic properties.
Toxicological studies
According to foreign literature.
Carcinogenic effects
In a carcinogenicity study in rats, no increase in tumors was observed after 97 weeks (male rats) or 104 weeks (female rats) of oral administration of dexrazopiclone, and plasma dexrazopiclone accumulation levels at the highest dose (16 mg/kg/d) were approximately 80 times (female rats) and 20 times (male rats) the plasma accumulation levels achieved at the maximum recommended human dose of 3 mg/d. However, in a 2-year carcinogenicity study in rats given racemic zopiclone orally (1, 10 or 100 mg/kg/d), there was an increased incidence of mammary adenocarcinoma (females) and thyroid follicular cell adenoma and carcinoma (males) in the highest dose group. At this dose, plasma dexrazopiclone accumulation levels were approximately 150 times (female rats) and 70 times (male rats) the plasma accumulation levels achieved at the maximum recommended human dose. The mechanism for the increased incidence of mammary adenocarcinoma is not known. The increased incidence of thyroid follicular cell adenoma may be due to increased circulating thyroid hormone metabolism and secondary elevated TSH levels, a mechanism that is not relevant in humans.
In a 2-year carcinogenicity study in mice given racemic zopiclone (1, 10, or 100 mg/kg/d) orally, there was an increased incidence of lung cancer and cancer-complicating adenomas (female mice) and dermal fibromas and sarcomas (male mice) in the highest dose group. Skin tumors are caused by skin damage due to invasive behavior, a mechanism that has no relevance to humans. Although the dose in this study did not reach the maximum tolerated dose in mice to allow a full assessment of the carcinogenicity of this product, the blood levels resulting from this dose were already approximately 90 times the cumulative plasma levels achieved at the maximum recommended dose in humans (12 times higher than in the racemic study), and no increase in the incidence of lung or skin tumors was observed. Increased.
No increase in tumor incidence was observed in p53 transgenic mice given dexrazopiclone at doses up to 300 mg/kg/d orally.
Mutagenic effects
Dexrazopiclone was positive in mammalian cells in vitro (mouse lymphoma cells and chromosomal aberrations). The in vitro bacterial mutation (Ames) test and the in vivo mouse micronucleus test were negative.
The dexrazopiclone metabolite (S)-N-demethyl-zopiclone was positive in the in vitro chromosomal aberration test in mammalian cells. In vitro bacterial mutation (Ames) test, in vivo chromosomal aberration and micronucleus test in mice were all negative.
Reproductive toxicity
Continuous oral administration of dexrazopiclone (up to 45 mg/kg/d in males and 180 mg/kg/d in females) to male and female rats before mating, during mating and up to day 7 of gestation showed reduced fertility in both sexes; no pregnancy occurred in females at the highest dose given to both males and females. A prolonged estrous cycle was seen in female rats given the highest dose. Decreased sperm count and motility, as well as increased number of teratogenic sperm, were observed in male rats given moderate to high doses. The dose that did not produce adverse effects in rats (5 mg/kg/d) was 16 times the maximum recommended human dose.
No teratogenic effects were observed at the highest dose in studies of dexzopiclone given orally to pregnant rats (62.5, 125 or 250 mg/kg/d) and rabbits (4, 8 or 16 mg/kg/d) during embryonic organogenesis. Reduced fetal weight and an increased incidence of skeletal changes and/or delayed ossification were observed at the intermediate and highest doses. The dose without adverse effects on embryonic development, extrapolated from mg/m2, was 200 times the maximum recommended human dose (MRHD) of 3 mg/d. No effects on embryonic development were observed in the rabbit study, and the maximum dose at mg/m2 is approximately 100 times the recommended maximum dose in humans.
Oral administration of dexrazopiclone (60, 120 or 180 mg/kg/d) to rats throughout gestation and lactation was associated with an increased incidence of failed implantation, low fetal weight and survival, and increased pup startle response in all dose groups. The lowest dose at mg/m2 was calculated to be 200 times the maximum recommended human dose. No effects on other developmental indicators or reproductive function of the offspring were observed in the trial.
Pharmacokinetics]
Pharmacokinetic studies of dexrazopiclone were conducted in healthy volunteers (adults and elderly) and in patients with liver or kidney disease. In healthy subjects, the pharmacokinetic profile of this product was investigated with single doses up to 7.5 mg administered once a day for 7 days, followed by doses of 1, 3 and 6 mg, respectively. The product was rapidly absorbed, with blood concentrations peaking at approximately 1 hour (tmax) and a terminal half-life (t1/2) of 6 h. Continuous dosing of dexrazopiclone in healthy adults did not result in accumulation, and drug exposure was linearly related to dose in the 1-6 mg dose range.
Absorption and distribution
The product is rapidly absorbed after oral administration. Peak plasma concentrations are reached approximately 1 hour after oral administration. The plasma protein binding rate is low at 52%-59%. Non-selective absorption by erythrocytes.
Metabolism
After oral administration, the product is mainly metabolized by oxidation and demethylation, with the main plasma metabolites being N-oxidized dexzopiclone and N-desmethyl dexzopiclone. n-Desmethyl dexzopiclone binds to GABA receptors at a much lower rate than dexzopiclone, and N-oxidized dexzopiclone does not bind tightly to GABA receptors. In vitro studies showed that dexzopiclone metabolism was associated with CYP3A4 and CYP2E1. Dexzopiclone did not show inhibition of CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4 in cryopreserved hepatocytes.
Elimination
After oral absorption, the elimination half-life of dexzopiclone is approximately 6 hours. With oral elimination of zopiclone, approximately 75% of the dose is excreted as a metabolite in the urine. Elimination of dezopiclone is similar to that of zopiclone, with urinary excretion of the prototype drug being less than 10% of the oral dose.
Effect of food
Oral administration of 3 mg of dezopiclone after high-fat food in healthy adults resulted in no change in AUC, a 21% decrease in mean Cmax, and a 1-hour delay in tmax. The half-life was unchanged and was approximately 6 hours. The effect of dexzopiclone on sleep latency may be reduced if given with a meal or immediately after a high-fat/overdose diet.
Dosing in special populations
Age
Compared to non-elderly adults, patients over 65 years of age had a 41% increase in AUC, a slightly prolonged half-life of approximately 9 hours, and no significant change in Cmax. Therefore, the dose for elderly patients should not exceed 2 mg.
Gender
The pharmacokinetic parameters were similar in males and females.
Race
Analysis of data from all subjects in the phase I clinic for dexzopiclone showed similar pharmacokinetic results for all races.
Liver injury
The pharmacokinetics of dexrazopiclone after administration of 2 mg were studied in 16 healthy volunteers and 8 patients with mild, moderate and severe liver disease. Patients with severe liver injury had a 2-fold increase in exposure compared to healthy volunteers, with no change in Cmax and tmax. No dose adjustment was required in patients with mild to moderate liver injury. Appropriate dose reductions should be made in patients with severe liver injury. Dexrazopiclone should be used with caution in patients with hepatic insufficiency.
Renal injury
A pharmacokinetic study was performed in 24 patients with mild, moderate or severe renal injury. The AUC and Cmax in patients with renal impairment were similar to those in healthy subjects. Only less than 10% of the oral dose of dexzopiclone was metabolized in the urine; therefore, no dose adjustment was required in patients with renal impairment.
Drug Interactions
Dexzopiclone is metabolized by oxidation and demethylation via CYP3A4 and CYP2E1. There are no pharmacokinetic or pharmacodynamic interactions between dexzopiclone and paroxetine. When dexzopiclone and olanzapine were combined, there was no effect on their pharmacokinetics, but there was a pharmacodynamic effect on measures of psychomotor function. When dexzopiclone was used in combination with lorazepam, the Cmax of both was reduced by 22%. When dexzopiclone 3 mg was combined with the potent CYP3A4 inhibitor ketoconazole 400 mg/day for 5 days, the total exposure of dexzopiclone increased 2.2-fold. the Cmax and t1/2 increased 1.4-fold and prolonged 1.3-fold, respectively. Presumably, dexzopiclone does not alter drug elimination via common CYP450 enzyme metabolism.
Paroxetine: There was no pharmacokinetic or pharmacodynamic interaction between single-dose dexrazopiclone and paroxetine when the two were administered in combination. The absence of interaction after single-dose administration does not mean that long-term administration is also completely free of pharmacodynamic interactions.
Lorazepam: There were no clinically relevant effects on pharmacodynamics and pharmacodynamics when single doses of dexrazopiclone were combined with lorazepam. The absence of interaction after single dose administration does not mean that there is no pharmacodynamic interaction for long-term administration.
Drugs with narrow therapeutic indices
Digoxin: Digoxin 0.5 mg/dose twice/day on the first day, followed by 0.25 mg/day for 6 days, did not affect the pharmacokinetics of a single dose of 3 mg dexrazopiclone.
Warfarin: Dexzopiclone, 3 mg/day for 5 days, did not affect the pharmacokinetic parameters of (R) and (S) warfarin; a single dose of 25 mg of oral warfarin also did not affect the pharmacodynamics of dexzopiclone.
Drugs with strong plasma protein binding
Plasma protein binding of dexzopiclone was low (52%-59%). Therefore, it is presumed that changes in protein binding do not have an effect on the distribution of this product. If a patient takes a drug with strong protein binding and 3mg of dexrazopiclone at the same time, the free blood concentration of both drugs will not change.
Storage
Seal and store in a dry place.
Package
Aluminum-plastic blister package, 7 tablets/plate×1 plate box, 7 tablets/plate×2 plate/box, 14 tablets/plate×1 plate/box.
Expiration date
24 months
Execution Standard
Approval number】
State Drug Certificate H20120001
Manufacturer
Company Name: Shanghai ShangPharma Chinese and Western Pharmaceutical Co.
Production Address: No. 446, Wai-Qingsong Highway, Jiading District, Shanghai
Postal Code: 201806
Telephone number: 800-720-5277 021-51653688
Fax number: 021-51653689
Website: www.zhongxisunve.com