Date of approval.
Date of revision.
Quetiapine Fumarate Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
Increased Mortality in Elderly Patients with Dementia-Related Psychosis
Antipsychotic treatment in elderly patients with dementia-related psychosis may result in an increased risk of death (see WARNINGS section). This product is not approved for use in elderly patients with dementia-related psychosis (see WARNINGS section).
Suicidal thoughts and suicidal behavior
Antidepressants have been shown to increase the risk of suicidal thoughts and suicidal behavior in short-term studies in children, adolescents, and young adults. These studies did not show an increased risk of suicidal thoughts and suicidal behavior in patients over 24 years of age who used antidepressants. In patients 65 years of age and older, antidepressant use reduced the risk of suicidal thoughts and suicidal behavior [see Warnings and Precautions].
Patients of any age who begin antidepressant therapy should be closely monitored for the emergence and worsening of suicidal thoughts and behaviors. Families and caregivers should be informed of the need to closely monitor patients and to communicate and interact with their physicians [see Warnings and Precautions].
Drug name].
Generic Name: Quetiapine Fumarate Extended Release Tablets
Hanyu Pinyin: Fumasuan Kuiliuping Huanshipian
English Name: Quetiapine Fumarate Extended-Release Tablets
Ingredients
Main components.
Quetiapine Fumarate.
Chemical Name.
11-{4-[2-(2-hydroxyethoxy)ethyl-1-piperazinyl]}dibenzo(b,f)(1,4)thiazepine fumarate (2:1)
Chemical structure formula.
Molecular formula: (C21H25N3O2S)2. C4H4O4
Molecular weight: 883.08
【Properties】.
This product is a yellow capsule-like biconvex film-coated tablet, which appears white or off-white after removing the coating.
Indications
This product is used to treat depressive episodes of schizophrenia and bipolar disorder. Specification
0.2g (based on C21H25N3O2S)
Dosage and Administration
The tablets should be swallowed whole, not broken, chewed or crushed. It is not related to eating or not.
Adults.
Treatment of schizophrenia
Dose selection – This product is recommended for once a day use at night (3-4 hours before bedtime). The recommended starting daily dose is 300 mg. The dose may be titrated between 400 mg and 800 mg daily depending on the efficacy and tolerability of the individual patient. The minimum interval between dose increases is 1 day, and daily dose increases should not exceed 300 mg.
Maintenance Therapy – A trial of maintenance therapy with this product in adult patients with schizophrenia demonstrated that it was effective in delaying the time to disease relapse in patients treated at a stable dose range of 400 mg to 800 mg/day for 16 weeks. Patients are re-evaluated periodically to determine the need for maintenance therapy and the appropriate dose required for maintenance therapy.
Treatment of depressive episodes in bipolar disorder
A therapeutic dose of 300 mg/day is reached on day 4 once a night. The recommended dosing regimen is 50mg on day 1, 100mg on day 2, 200mg on day 3, and 300mg on day 4.
Switching from Quetiapine Fumarate Tablets to this product.
Patients currently treated with quetiapine fumarate tablets may be switched to this product once daily at the same total daily dose. Dose adjustment may be required on an individual patient basis.
Restarting therapy after discontinuation.
Although there are no data specifically regarding restart of therapy, for patients who have discontinued this product for more than 1 week and wish to restart therapy, it is recommended that the initial dosing regimen be followed. If the product has been discontinued for less than 1 week, the maintenance dose may be restarted without a gradual increase from the initial dose.
Geriatric patients.
As with other antipsychotics, this product should be used with caution in elderly patients, especially at the time of initiation of dosing. The titration rate and daily therapeutic dose should be lower in elderly patients than in younger patients. The mean plasma clearance of quetiapine is reduced by 30% to 50% in elderly patients compared to younger patients. The starting dose for elderly patients should be 50 mg/day. Depending on individual efficacy and tolerability, the dose may be increased by 50 mg day by day until an effective dose is achieved.
Children and Adolescents.
This product is not approved for the treatment of patients under 18 years of age in China.
Renal Impairment.
No dose adjustment is required in patients with renal impairment. Clinical experience with this product in patients with renal impairment is limited.
Hepatic Impairment.
Quetiapine is extensively metabolized in the liver. Blood levels may be elevated in patients with hepatic impairment and dose adjustments may be necessary. The starting dose for patients with known hepatic impairment should be 50 mg/day. Depending on individual efficacy and tolerability, the dose may be increased by 50 mg day by day until an effective dose is achieved.
Adverse Reactions
The most common (³10%) adverse drug reactions (ADRs) to quetiapine are drowsiness, dizziness, dry mouth, withdrawal (discontinuation) symptoms, elevated serum triglycerides, elevated total cholesterol (primarily elevated low-density lipoprotein cholesterol (LDL)), decreased high-density lipoprotein cholesterol (HDL), weight gain, decreased hemoglobin, and extrapyramidal symptoms.
The following table shows the incidence of adverse reactions (ADRs) with treatment with this product, which was prepared according to the recommended format of the International Committee for the Organization of Medical Sciences (CIOMSIII Working Group; 1995).
Frequency System Organ Classification Events Very common (³10%) Gastrointestinal system disorders Dry mouth Systemic disorders and various reactions at the site of administration Withdrawal (withdrawal) symptomsa, j Various tests
Elevated serum triglyceridesa, k
Elevated total cholesterol (mainly LDL cholesterol) a, l
Decreased HDL cholesterola, r
Increased body weightc
Decreased hemoglobin s Various neurological disorders Dizzinessa, e, q
Drowsinessb, q
Extrapyramidal symptomsa, p Common (³1% – <10 %) Blood and lymphatic system disorders Leukopenia a, x Heart organ disorders Tachycardia a, e
Palpitations t Eye disorders Blurred vision Gastrointestinal disorders Constipation
Indigestion
Vomitingv Systemic diseases and various reactions at the drug administration site Mild weakness
Peripheral edema
Irritability
Fever Elevated serum alanine aminotransferase (ALT) on all types of testsd
Elevated gamma-glutamyltransferase (gamma-GT)d
Decreased neutrophil counta, g
Increased eosinophilsw
Elevated blood glucose to hyperglycemic levelsa, h
Elevated serum prolactino
Decrease in total tetraiodothyronine (T4)
u
Decrease in free T4u
Decrease in total triiodothyronine (T3) u
Elevated thyroid stimulating hormone (TSH) u Various neurologic disorders Dysarthria Metabolic and nutritional disorders Increased appetite Respiratory, thoracic and mediastinal disorders Dyspnea Vascular and lymphatic disorders Upright hypotensiona, e, q Psychiatric disorders Sleep abnormalities and nightmares Occasionally (³0.1% – <1%) Cardiac disorders Bradycardia y Gastrointestinal disorders Dysphagiaa, i Immune system Allergic diseases Elevated serum aspartate aminotransferase (AST) on various testsd
Decreased platelet count
n
Decreased free T3u
Various neurological disorders Seizuresa
Restless legs syndrome
Delayed-onset movement disordera
Syncopea, e, q Respiratory, thoracic, and mediastinal disorders
Renal and urinary disorders Rhinitis
Urinary retention rare
(³0.01% – <0.1%) Systemic diseases and various reactions at the site of administration Antipsychotic malignant syndromea
Hypothermia
Elevated blood creatine phosphokinase on various testsm
Granulocyte deficiencyz Psychiatric disorders Sleepwalking and other related events Reproductive and breast disorders Abnormal penile erection
Breast milk overflow Gastrointestinal system disorders Intestinal obstruction very rare (<0.01%) Immune system disorders Allergic reactionsf Unknown systemic disorders and various reactions at the site of administration Neonatal withdrawal symptoms aaa See warning signs.
b Drowsiness, which usually occurs within the first 2 weeks of treatment and usually decreases gradually under conditions of continued quetiapine administration.
c Based on a weight gain of ≥7% from baseline. Appears primarily within the first few weeks of treatment in adults.
d Some patients given quetiapine develop asymptomatic increases in serum transaminase (ALT, AST) or gamma-GT concentrations (from normal to more than three times the upper limit of normal (inclusive) at any time). These elevations are usually reversible with continued quetiapine therapy.
e As with other antipsychotics with α1-adrenergic blocking activity, quetiapine may cause upright hypotension, associated dizziness, tachycardia, and syncope in some patients, particularly during the initial dose titration period.
f Included allergic reactions are based on postmarketing reports.
g In all short-term, placebo-controlled monotherapy trials in patients applying a baseline neutrophil count ≥ 1.5 X 109/L
The incidence of at least one neutrophil count < 1.5 X 109/L in patients treated with quetiapine versus those treated with placebo was 1.9% and 1.3%, respectively. The incidence of neutrophil counts ³ 0.5 – < 1.0 X 109/L in patients treated with quetiapine versus those treated with placebo was 0.2% and 0.2%, respectively. In a trial of discontinuation in patients treated for sudden neutrophil counts <1.0 X 109/L
clinical trials conducted prior to the protocol amendment
In patients with baseline neutrophil counts ≥ 1.5 X 109/L, the incidence of at least one neutrophil count <0.5 X 109/L with quetiapine and placebo treatment was 0.21% and 0%, respectively.
h At least one measurement of fasting glucose ³ 7.0 mmol/L or non-fasting glucose ³ 11.1 mmol/L.
i Only in clinical trials of bipolar depression
found an increased incidence of dysphagia with quetiapine compared to placebo treatment.
j In an acute placebo-controlled monotherapy clinical trial evaluating discontinuation symptoms, the total incidence of discontinuation symptoms following abrupt discontinuation was 12.1% and 6.7% in the quetiapine and placebo treatment groups, respectively. The total incidence of individual adverse events (e.g., insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability) did not exceed 5.3 % in all treatment groups and usually subsided after 1 week of discontinuation.
k Triglyceride concentration ≥ 2.258 mmol/L (in patients ≥ 18 years of age) or ≥ 1.6936 mmol/L (<18 years of age) measured at least once.
l Cholesterol concentration ≥ 6.2064 mmol/L (in patients ≥ 18 years of age) or ≥ 5.1719 mmol/L (in patients <18 years of age) measured at least once
m
Elevated blood creatine phosphokinase was not associated with antipsychotic malignant syndrome based on reports of adverse events in clinical trials.
n Platelet count ≤ 100 x 109/L on at least one measurement.
o Prolactin concentration at any time (patients ≥ 18 years of age): > 20 µg/L (males); > 30 µg/L (females)
p See text below.
q May cause falls.
r HDL cholesterol at any time: < 1.0344 mmol/L (men); < 50 1.292 mmol/L (women).
s All tests
showed (including the open prolongation trial
), 11% of patients in the quetiapine group had at least one hemoglobin drop to ≤13 g/dL (men) and ≤12 g/dL (women). In the short-term placebo-controlled trial
In the quetiapine group, 8.3% of patients had at least one hemoglobin drop to ≤13 g/dL (men) and ≤12 g/dL (women) compared with 6.2% of patients in the placebo group.
t The above reports were usually seen in conditions of tachycardia, dizziness, upright position hypotension, and/or underlying cardiac/respiratory disease.
u Based on all trials
Change from baseline normal values to potentially clinically significant values after baseline at any time in Change in total T4, free T4, total T3 and free T3 at any time was defined as <0.8 xLLN (pmol/L) and change in TSH was defined as >5 mIU/L.
v Based on the rate of increase in vomiting in older patients (≥65 years).
w Based on all trials
Change in eosinophil count defined as ≥1 x 109/L at any time from baseline normal values to potentially clinically significant values after baseline.
x Change in eosinophil count defined as ≥1 x 109/L at any time based on all tests
change from baseline normal to potentially clinically meaningful post-baseline values at any time in all trials, change in white blood cell count was defined as
≤3 x 109/L at any time.
y May occur at or near the time of initiation of treatment and is associated with hypotension and/or syncope. Frequency of occurrence based on all quetiapine clinical trials
Process central bradycardia and associated adverse reactions reported.
z Based on all clinical trials of quetiapine
Frequency of severe neutrophil deficiency (<0.5 x 109/L) and infection in patients during the course
aa See Pregnancy and lactation dosing.
Extrapyramidal symptoms
The following clinical trials were conducted in adult patients
(monotherapy and combination therapy) included treatment with quetiapine fumarate tablets and this product.
Short-term placebo-controlled clinical trials for schizophrenia and bipolar mania showed a cumulative incidence of extrapyramidal symptoms similar to placebo (schizophrenia: 7.8% in the quetiapine group and 8.0% in the placebo group; bipolar mania: 11.2% in the quetiapine group and 11.4% in the placebo group). The placebo-controlled short-term clinical trial of bipolar depression showed a cumulative incidence of extrapyramidal disorders of 8.9% in the quetiapine group and 3.8% in the placebo group, but the incidence of individual adverse events (e.g., inability to sit still, extrapyramidal disorders, tremor, dyskinesia, dystonia, fidgeting, involuntary muscle contractions, psychomotor hyperactivity, muscle tonicity) was generally lower, with none of the treatment groups exceeded 4%. Clinical trials of placebo-controlled short-term monotherapy in depressed patients showed a cumulative incidence of extrapyramidal disorders of 5.4% in the treatment group and 3.2% in the placebo group. A placebo-controlled short-term monotherapy trial in elderly depressed patients showed a cumulative incidence of extrapyramidal symptoms of 9.0% in the placebo-treated group and 2.3% in the placebo group. A placebo-controlled short-term monotherapy clinical trial in generalized anxiety disorder showed a cumulative incidence of extrapyramidal symptoms of 4.9% in the placebo-treated group and 3.2% in the placebo group. A placebo-controlled short-term monotherapy clinical trial in elderly patients with generalized anxiety disorder showed a cumulative incidence of extrapyramidal symptoms of 5.4% in the treatment group and 2.2% in the placebo group.
The treatment-induced cumulative exposure-corrected incidence of extrapyramidal symptoms was similar between quetiapine and placebo in long-term trials in schizophrenia, bipolar disorder, depression, and generalized anxiety disorder.
Thyroid hormone levels
Quetiapine treatment was dose-related to a decrease in thyroid hormone levels. The incidence of potentially clinically significant changes in thyroid hormone levels in short-term placebo-controlled clinical trials was: total T4: 3.4 % in the quetiapine treatment group and 0.6 % in the placebo group; free T4: 0.7 % in the quetiapine treatment group and 0.1 % in the placebo group; total T3: 0.54 % in the quetiapine treatment group and 0.0 % in the placebo group; and free T3: 0.2 % in the quetiapine treatment group and 0.0 % in the placebo group. The incidence of TSH changes was 3.2 % in the quetiapine group and 2.7 % in the placebo group. Placebo-controlled short-term monotherapy trials showed potentially clinically significant changes in T3 and TSH of 0.0 % in both the quetiapine and placebo groups, and changes in T4 and TSH of 0.1 % in the quetiapine group and 0.0 % in the placebo group. The above changes in thyroid hormone levels were largely unrelated to clinically symptomatic hypothyroidism. The decrease in total T4 and free T4 was most pronounced during the first 6 weeks of quetiapine treatment and did not decrease further during long-term treatment. In almost all cases, cessation of quetiapine treatment was associated with reversal of total and free T4, independent of the duration of treatment. Thyroid-binding globulin (TBG) levels were unchanged in the eight patients who were tested.
Jaundice has been reported in post-marketing applications of quetiapine preparations.
Adverse reactions observed in other clinical studies for different indications.
Adverse reactions observed in a fixed-dose, placebo-controlled clinical study for the adjunctive treatment of manic episodes in bipolar disorder: observed in the therapeutic 150 mg group (sample size = 315) 7% nausea, 3% upper respiratory tract infection, 2% influenza, 2% dizziness, 2% depression; observed in the therapeutic 300 mg group (sample size = 312) 8% nausea, 2% upper respiratory tract infection, 2% vertigo, 1% depression, and 1% influenza.
Adverse effects observed in a 3-week clinical study of placebo as a control group for bipolar disorder: (sample size = 151) 3% back pain observed in the therapeutic drug group.
Adverse reactions observed in an 8-week placebo-controlled clinical study for bipolar depression: (sample size=137) 2% anxiety observed in the therapeutic use group.
[Contraindication].
Patients who are hypersensitive to any of the ingredients in this product.
Warnings]
Increased mortality in elderly patients with dementia-related psychosis.
Elderly patients with dementia-related psychosis are at increased risk of death when treated with antipsychotics. In 17 placebo-controlled trials (plural treatment duration of 10 weeks) completed in such patients, most of whom were on atypical antipsychotics, the risk of death was 1.6 to 1.7 times greater in the drug-treated group than in the placebo-controlled group. In a typical 10-week controlled clinical trial, the mortality rate was 4.5% in the medication group and 2.6% in the placebo control group. Although the causes of death varied, most deaths were due to cardiovascular disease (e.g., heart failure, sudden death) or infection (e.g., pneumonia). Observational trials suggest that, similar to atypical antipsychotics, conventional antipsychotics may also increase mortality. The extent to which the increase in mortality in these observational trials was due to the antipsychotic or to certain characteristics of the patient is not known. This product (quetiapine fumarate extended-release tablets) is not approved for the treatment of dementia-related psychosis (see the WARNINGS section).
Cerebrovascular Adverse Events (Including Stroke) in Elderly Patients with Dementia-Related Psychosis.
Cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including mortality were higher in placebo-controlled trials using risperidone, aripiprazole and olanzapine in elderly subjects with dementia than in placebo-treated subjects. This product is not approved for the treatment of patients with dementia-related psychosis.
Suicidal behavior/suicidal ideation or clinical deterioration.
Depression increases the risk of suicidal thoughts, self-injury, and the emergence of suicide (suicide-related events). This risk can persist until significant remission occurs. Because it is possible that no improvement will occur in the first few weeks or longer of treatment, patients should be monitored closely until such improvement occurs. General clinical experience suggests that the risk of suicide may also increase in the early stages of recovery.
Other psychiatric disorders for which quetiapine treatment is indicated have also been associated with an increased risk of suicide-related events. In addition, these may be co-morbidities of depression. Therefore, the considerations to be observed in the treatment of patients with depression are the same as those observed in the treatment of patients with other psychiatric disorders.
Patients with a history of suicide-related events, or who exhibit severe suicidal thoughts before treatment initiation, are at greater risk for suicidal thoughts or attempts and should be monitored closely during treatment. A U.S. Food and Drug Administration (FDA) meta-analysis of placebo-controlled clinical trials of antidepressants in approximately 4,400 children and adolescents and 77,000 adults with mental illness showed an increased risk of suicidal behavior in children, adolescents, and younger adults under 25 years of age in the antidepressant group compared with the placebo group. The meta-analysis did not include trials involving quetiapine.
Leukopenia, neutropenia and granulocyte deficiency.
The uncommon event reported in short-term placebo-controlled monotherapy clinical trials using quetiapine was severe neutropenia without infection (<0.5 X 109/L). Granulocyte deficiency (severe neutropenia with infection) in patients treated with quetiapine has been reported in both clinical trials and post-marketing reports, which included fatal cases. Most cases of severe neutropenia occurred within the first 2 months of quetiapine initiation, and there was no clear dose-response relationship. Possible risk factors for leukopenia/neutropenia include a preexisting low white blood cell count (WBC) and a previous history of pharmacogenic leukopenia/neutropenia.
Patients with a history of granulocyte deficiency do not have pre-existing risk factors. Patients with a history of low WBC or drug-associated leukopenia/neutropenia should have their complete blood count (CBC) checked frequently within the first few months of treatment initiation and discontinue the product once leukopenia is detected and there is no other explanation.
Patients with infections, especially in the absence of obvious precipitating factors, or fever of unknown origin should consider granulocyte deficiency and should be managed clinically appropriately.
Quetiapine should be discontinued in the presence of a neutrophil count less than 1.0 X 109/L. Signs and symptoms of infection in these patients should be observed and neutrophil counts should be followed up to 1.5 X 109/L (see Adverse Reactions).
[Caution].
Metabolic factors
Atypical antipsychotics are associated with metabolic changes, including hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain. Various types of drugs have been shown to produce some metabolic changes, and each drug has its own specific risk factors. In clinical trials, worsening of more than one metabolic factor, such as weight, glucose and lipids, has been observed in some patients, and appropriate clinical management of changes in these parameters should be undertaken.
Weight gain.
Cases of weight gain have been observed in clinical trials. Patients treated with this product should have their weight monitored regularly.
Deterioration in weight, glucose or lipid metabolic parameters has been observed in some patients in clinical studies, and changes in these parameters should be managed according to clinical discretion.
Elevated blood glucose, hyperglycemia and diabetes mellitus (DM).
Reports of elevated blood glucose, hyperglycemia, and incident diabetes mellitus have been observed in quetiapine clinical trials, and although a causal relationship between diabetes mellitus and the drug could not be established, appropriate clinical monitoring is recommended for patients at risk of developing diabetes mellitus. Monitoring should also be given to patients with existing diabetes for possible worsening of diabetes (see Adverse Reactions).
Lipids.
Elevated triglycerides and cholesterol and decreased HDL cholesterol have been observed in clinical trials with quetiapine (see Adverse Reactions). Clinical monitoring, including baseline examinations and periodic follow-up, is recommended for patients on quetiapine.
Pancreatitis
Pancreatitis events have been reported in clinical trials and post-marketing experience; however, a causal relationship has not been established. In post-marketing reports, many patients had factors known to be associated with pancreatitis, such as elevated triglycerides (see lipid section), gallstones, and alcohol consumption.
3. Concomitant diseases.
Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. As with other antipsychotics with alpha1-adrenergic blocking effects, this product may cause upright hypotension with dizziness, tachycardia, and, in some patients, syncope; these events tend to occur during the initial dose increase. Upright hypotension is more common in older patients than in younger patients.
4. Dysphagia
Dysphagia (see Adverse Reactions) and aspiration have been reported with quetiapine therapy. Esophageal motor dysfunction and misaspiration are thought to be associated with antipsychotic use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, especially those with advanced Alzheimer-type dementia. This and other antipsychotics should be used with caution in patients at risk for aspiration pneumonia.
Sleepiness
This treatment is associated with sleepiness and related symptoms (e.g., sedation), usually during the first two weeks of treatment, and usually resolves with continued administration.
Constipation and intestinal obstruction
Constipation is a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with quetiapine (see Adverse Reactions), and this includes fatal reports in patients at high risk for intestinal obstruction, including those who are receiving multiple concurrent medications that reduce bowel motility and/or who may not report symptoms of constipation.
Seizures
In controlled clinical trials, there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. As with other antipsychotics, caution should be taken when used to treat patients with a history of seizures (see Adverse Reactions).
Delayed-onset movement disorder and extrapyramidal symptoms (EPS)
Delayed-onset movement disorder is a syndrome of potentially irreversible, involuntary movement disorders that may occur in patients treated with antipsychotic medications, including quetiapine. If signs or symptoms of delayed dyskinesia develop, quetiapine dose reduction or discontinuation of treatment should be considered. Symptoms of delayed dyskinesia may worsen after discontinuation of therapy or may even appear after discontinuation of therapy.
Discontinuation may result in the development of tardive dyskinesia symptoms. In placebo-controlled clinical trials in schizophrenia and bipolar mania, extrapyramidal symptoms did not differ from placebo within each recommended therapeutic dose range. This point suggests that quetiapine is less likely to induce delayed movement disorders in patients with schizophrenia and bipolar mania than typical antipsychotics. In short-term, placebo-controlled clinical trials of bipolar depression, depressive disorder, and generalized anxiety disorder, the incidence of EPS was higher in quetiapine-treated patients than in placebo-treated patients.
Antipsychotic malignant syndrome.
Antipsychotic malignant syndrome is associated with antipsychotic (including quetiapine) treatment. Clinical manifestations include hyperthermia, altered mental status, muscle tonicity, autonomic dysfunction, and elevated creatine phosphokinase. In such cases, quetiapine therapy should be discontinued and appropriate medication administered.
QT prolongation
In clinical trials, quetiapine was not associated with a sustained increase in the absolute QT interval. There have been case reports of QT interval prolongation in post-marketing experience in patients taking an overdose of quetiapine (see Overdose) in patients with concomitant disease and in patients taking drugs known to cause electrolyte imbalance or QT interval prolongation (see Drug Interactions). As with other antipsychotics, patients with a family history of cardiovascular disease or QT interval prolongation should be treated with caution with quetiapine. Similarly, quetiapine should be used with caution in patients treated with medications that increase the QT interval, or in combination with antipsychotics, especially in patients at risk for QT interval prolongation, such as the elderly, patients with congenital prolonged Q-T interval syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia (see Drug Interactions and Other Forms of Interactions).
Withdrawal symptoms.
Acute withdrawal symptoms, such as insomnia, nausea, and vomiting, have been observed following abrupt discontinuation of antipsychotic medications, including quetiapine. A taper of at least one week or two weeks is recommended (see Adverse Reactions).
Interactions.
The combination of quetiapine and a hepatic enzyme inducer (e.g., carbamazepine) may result in a substantial reduction in systemic exposure to quetiapine. If a concomitant hepatic enzyme inducer is used, a higher dose of quetiapine should be considered as needed for clinical response.
In combination with strong CYP3A4 inhibitors (cytochrome 3A4 oxidase, such as azole antifungals, macrolide antibiotics, and protease inhibitors), plasma concentrations of quetiapine may be significantly higher than those observed in patients in clinical trials; therefore, lower doses of quetiapine should be used. Special attention should be paid to the dosing of elderly and frail patients. In all patients, the benefit-risk ratio needs to be determined on an individual basis.
Effects on the liver
Asymptomatic increases in serum aminotransferases (ALT, AST) or γ-GT levels have been observed in some patients taking this product. If jaundice develops, discontinue use.
Cataracts
Long-term treatment trials in dogs have shown that quetiapine can cause the development of cataracts. Lens alterations have also been found in adults, children and adolescents on long-term treatment, but it is not clear whether there is a causal relationship with quetiapine. The possibility of lens alterations cannot be ruled out at this time. Therefore, early detection of cataracts by slit lamp or other appropriate more sensitive method of examining the lens at the beginning of treatment or for a short period of time after the start of treatment and during long-term treatment is recommended at 6-month intervals.
Hyperprolactinemia
In clinical trials, the incidence of elevated prolactin levels to clinically significant values was 3.6% (158/4416) and 2.6% (51/1968) in the quetiapine-treated and placebo-treated groups, respectively. As with other drugs that antagonize the dopamine D2 receptor, quetiapine can increase prolactin levels in some patients and may persist during long-term treatment. Hyperprolactinemia suppresses hypothalamic gonadotropin-releasing hormone (GnRH) and reduces pituitary gonadotropin secretion, regardless of the etiology. This in turn can suppress reproductive system function by impairing gonadal steroid production in both male and female patients. Overflow of breast milk, amenorrhea, gynecomastia, and impotence have been reported in patients taking compounds that elevate prolactin. Chronic hyperprolactinemia, when coexisting with hypogonadism, can lead to decreased bone mineral density in both male and female patients.
Hypotension
Dizziness, tachycardia and syncope may occur, especially during initial dose titration. Use with caution in patients with known cardiovascular or cerebrovascular disease.
Hypothyroidism
Clinical trials with quetiapine have demonstrated dose-related reductions in thyroid hormone levels. The reduction in total and free T4 was approximately 20% around the upper therapeutic dose limit, with the greatest magnitude in the first 6 weeks of treatment, and was maintained without improvement or progression over the longer treatment period. The effects of quetiapine on total and free T4 can be reversed after discontinuation of treatment in almost all cases, regardless of the duration of treatment (see Adverse Reactions, Thyroid Levels).
Abnormal penile erection
Drugs with alpha-adrenergic blocking effects can induce abnormal penile erections, and quetiapine may also have this effect. Severe abnormal penile erections require surgical intervention.
Thermoregulation
Antipsychotic drugs can disrupt the body’s ability to lower core body temperature. This product should be used with appropriate care in patients with conditions that may elevate core body temperature (e.g., excessive exercise, exposure to extreme heat, combination of drugs with anticholinergic activity, or the presence of dehydration).
Lactose
This product contains lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption disorders should not take this product.
Effects on the ability to drive and operate machinery
As this product may cause drowsiness. Therefore, caution should be given to patients who operate dangerous machinery including driving vehicles.
Pregnant women and nursing mothers
The efficacy and safety of this product when used in human pregnancy is not known (see [Pharmacology and Toxicology] for information on reproductive toxicity in animals). Therefore, this product should be used in pregnant patients only if the benefits outweigh the potential risks.
Some patients who became pregnant during treatment with quetiapine have reported withdrawal symptoms in their newborns.
It has been reported in the published literature that quetiapine is secreted into human breast milk, but the concentration of secretion is inconsistent. Therefore, lactating women are advised to avoid breastfeeding while taking quetiapine.
Pediatric Dosage]
There are no data supporting the use of this product in children and adolescents under 18 years of age in China, and it is not approved for use in children and adolescents under 18 years of age.
Geriatric use]
See [Dosage and Administration] for details.
Drug Interactions
1. Since quetiapine has mainly central nervous system effects, caution should be exercised when combining with other drugs or alcoholic beverages that act on the central nervous system.
2. Caution should be exercised when combining quetiapine with drugs that may cause electrolyte imbalance or prolonged QTc interval.
3, Combination with lithium salt preparations will not affect the pharmacokinetics of lithium.
4. When co-administered with valproate hemisodium, the pharmacokinetics of valproate and quetiapine will not be altered in a clinically meaningful manner. (Sodium valproate is a stable coordination compound containing 1:1 molar ratio of sodium valproate and valproic acid).
5. The pharmacokinetics of quetiapine are not significantly altered by the combination of the antipsychotics risperidone or haloperidol. However, the combination with thioridazine will increase the clearance of quetiapine.
6. Quetiapine does not induce the hepatic enzyme system associated with the metabolism of antipyrine. However, in a multi-dose clinical trial, the pharmacokinetics of quetiapine were evaluated in patients prior to or during treatment with carbamazepine, a known hepatic enzyme inducer. The results showed that co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase reduced the systemic absorption level of quetiapine (as measured by the area under the drug-time curve (AUC)) by 13% compared to administration alone; while in some patients a more significant effect was observed, i.e., lower plasma concentrations occurred, and therefore higher doses of this product should be considered for each patient based on clinical response. It should be noted that the maximum recommended daily dose of quetiapine fumarate is 750 mg/day for the treatment of schizophrenia and 800 mg/day for the treatment of manic episodes in bipolar disorder, and that continued use of higher doses should only be considered after careful evaluation of the risks and benefits in individual patients.
7. Combination with another microsomal enzyme inducer, phenytoin, may also increase the clearance of quetiapine. If quetiapine is combined with phenytoin or other hepatic enzyme inducers (e.g., barbiturates, rifampin), the dose should be increased to maintain the antipsychotic effect. If phenytoin or carbamazepine or other hepatic enzyme inducers are discontinued and replaced by a non-inducing agent (e.g. sodium valproate), the dose of this product should be reduced.
8. In cytochrome P450 (CYP450), the major enzyme mediating the metabolism of quetiapine is CYP3A4. Combining with cimetidine (a known P450 enzyme inhibitor) does not alter the pharmacokinetics of quetiapine. Combination with the antidepressants promethazine (a known CYP2D6 inhibitor) or fluoxetine (a known inhibitor of CYP3A4 and CYP2D6) does not significantly alter the pharmacokinetics of quetiapine. In a multi-dose clinical trial evaluating the pharmacokinetics of quetiapine before and during treatment with ketoconazole in healthy volunteers, co-administration of treatment with ketoconazole increased the mean plasma peak concentration (Cmax) and AUC of quetiapine by 235% and 522%, respectively, with a corresponding mean reduction in oral clearance of 84%. The mean half-life of quetiapine increased from 2.6 hours to 6.8 hours due to a potentially similar degree of interaction in clinical applications. However, caution is required if combined with strong inhibitors of CYP3A4 (e.g., azole antifungals, macrolide antibiotics, or protease inhibitors) (see [Pharmacokinetics]).
9. False-positive urine enzyme immunoassays for methadone and tricyclic antidepressants have been reported in patients treated with quetiapine. Caution should be exercised in interpreting the results of positive urine drug screens for these drugs and should be verified using alternative analytical techniques (e.g., chromatographic methods).
10. Because this product can induce hypotension, it may enhance the antihypertensive effect of certain antihypertensive drugs.
11. This product may antagonize the efficacy of levodopa and dopamine agonists.
Drug overdose]
There are reports of acute drug overdose up to 30g still surviving in clinical trials. Most patients who overdosed had no adverse events or recovered completely from the reported events. There have been reports from clinical trials of quetiapine overdoses of up to 13.6 g alone resulting in patient death.
In post-marketing experience, there have been rare reports of quetiapine overdose alone resulting in patient death or coma.
In post-marketing experience, there have been reports of prolonged QT interval in patients due to quetiapine overdose.
Patients with pre-existing severe cardiovascular disease are at elevated risk for the effects of drug overdose. In general, the signs and symptoms reported with this overdose are an enhancement of the known pharmacologic effects of the drug, i.e., sleepiness and sedation, tachycardia, and hypotension.
Treatment
There is no specific antidote for quetiapine. Patients encountering severe toxicity should be considered for the possibility of multiple drugs being involved and aggressive monitoring measures are recommended, including establishing and maintaining airway patency and ensuring adequate oxygenation and ventilation, while monitoring and maintaining cardiovascular function. In this setting, reports have described the reversal of severe central nervous system reactions including coma and delirium with intravenous administration of toxaprine (1-2 mg) under conditions of continuous ECG monitoring.
In the event of quetiapine overdose, appropriate measures should be used to treat intractable hypotension, such as intravenous fluids and/or adrenergic agonists (epinephrine and dopamine should be avoided because beta stimulation may worsen hypotension under conditions of quetiapine-induced alpha blockade).
Close medical supervision and monitoring should be undertaken until the patient recovers.
[Clinical trials].
1 Clinical efficacy
Schizophrenia
The efficacy of this product in the treatment of schizophrenia was demonstrated in a 6-week placebo-controlled trial (in patients meeting criteria for severe schizophrenia) and in a positive-controlled quetiapine fumarate tablets/this product conversion trial (in clinically stable outpatients with schizophrenia).
The primary outcome variable in the placebo-controlled trial was the change from baseline in the final Positive versus Negative Symptom Scale (PANSS) total score. Treatment with doses of 400 mg/day, 600 mg/day and 800 mg/day resulted in statistically significant improvements in psychotic symptoms compared to placebo. the effect values for the 600 mg and 800 mg doses were greater than the effect values for the 400 mg dose.
The primary outcome variable in the 6-week positive-controlled conversion trial was the percentage of patients who lacked efficacy, that is, the percentage of patients who discontinued trial treatment for lack of efficacy or whose total PANSS score increased by 20% or more from randomization to either visit time point. In patients on stable doses of quetiapine fumarate tablets 400 mg to 800 mg, patients maintained efficacy after switching to an equivalent daily dose of this product once daily.
In a long-term trial, patients with stable schizophrenia treated with this product for 16 weeks were superior to placebo in preventing relapse. The predicted risk of relapse after 6 months of treatment was 14.3% in the placebo group and 68.2% in the placebo group. The mean dose was 669 mg.
A 6-week multicenter, double-blind, double-model, randomized chlorpromazine controlled study in China evaluated the efficacy and safety of this product in the treatment of patients with acute schizophrenia. In patients with acute schizophrenia treated with once-daily monotherapy, the improvement in PANSS total score at the end of day 42 compared to baseline was non-inferior to that of chlorpromazine, and the incidence of EPS and cardiovascular adverse events was lower compared to that of chlorpromazine, EPS incidence: 8.7 vs. 30.2%, and cardiac events: 13.3 vs.
Cardiac events: 13.3 vs. 21.4%, and vascular events: 3.6 vs. 9.9%.
In a long-term clinical trial
In a long-term clinical trial, adult outpatients (n=171) who met DSM-IV criteria for schizophrenia, were clinically stable, and remained stable after 16 weeks of open treatment with variable doses of 400 mg/day to 800 mg/day were randomized to one group treated with placebo and one group continued with the current regimen (400 mg/day to 800 mg/day) to observe relapse of disease in patients during the double-blind maintenance phase. Patients were considered stable during the open trial phase if they were treated with a constant dose of this product and had a Clinical General Impressions Scale-Severity of Illness Subscale (CGI-S) score of £4 and a PANSS score of £60 (total PANSS score increased <10) from the beginning to the end of the open-label phase. A relapse was considered to occur during the double-blind trial phase if the PANSS total score increased by ³30%, or if the CGI score improved by ³6, or if the patient was hospitalized due to worsening schizophrenia or required any other antipsychotic medication. The prolonged time to relapse was statistically significant in patients treated with this product compared with the placebo group.
Depressive episodes in bipolar disorder
A clinical trial including patients with bipolar I, bipolar II and patients with and without rapid cycling bipolar disorder showed that a dose of 300 mg/day was effective in treating patients with bipolar depression and that this product was superior to placebo in reducing total MADRS scores. The antidepressant effect was significant at day 8 (week 1) and was maintained until the end of the trial (week 8).
A similar study was conducted in Chinese patients to evaluate the efficacy and safety of this product in patients with bipolar I and bipolar II depression. Patients eligible for DSM-IV-TR for bipolar I and bipolar II depression were randomized to the experimental group (300 mg/day) and the placebo group for 8 weeks, with an initial 4-day dose titration period. The primary study endpoint was the change in total MADRS score from baseline to the end of the study. 296 patients were equally assigned to the two treatment groups, with a 1:1 ratio of type I to type II patients among all randomized patients. the change in total MADRS score from baseline to the end of the study was significantly greater in the experimental drug group than in the placebo group (18.48 vs. 15.27; treatment difference of 3.22, p= 0.004). The proportion of patients experiencing any AE in the study was higher in the quetiapine XR group (65.3%) than in the placebo group (49.0%). the five most common AEs were drowsiness (24.5% vs. 7.5%), dizziness (19.7% vs. 10.9%), dry mouth (14.3% vs. 4.8%), constipation (11.6% vs. 2.7%), and fatigue ( 8.8% vs. 1.4%). The adverse effects of this product were similar to previous studies. Studies have shown that quetiapine XR given once daily at night was superior to the placebo group for the treatment of bipolar I and bipolar II depression in China and was generally safe and tolerable.
Two clinical trials including patients with bipolar I, bipolar II and patients with and without rapid cycling bipolar disorder showed that siren doses of 300 and 600 mg/day were effective in treating patients with bipolar depression, but with no additional benefit compared to the 600 mg dose used for short-term treatment.
In both studies, Sericem was superior to placebo in reducing total MADRS scores. The antidepressant effect of Sericam was significant on day 8 (week 1) and was maintained until the end of the trial (week 8). Treatment with Sericam 300 or 600 mg at bedtime reduced depressive symptoms and anxiety symptoms in bipolar depressed patients. Treatment with either dose of Sericom triggered fewer manic episodes than the placebo group. For the 300 mg administration group, statistically significant improvements in the reduction of suicidal thoughts (as measured by the MADRS 10 items and overall quality of life) and in the satisfaction status of related functional areas (as measured by the Q-LES-Q (SF)) were observed compared to the placebo group.
The role of Seroquel in maintaining antidepressant efficacy has been established in two clinical trials for the treatment of adult patients with bipolar depression. These trials consisted of an 8-week placebo-controlled acute phase trial followed by a placebo-controlled continuous phase trial (at least 26 weeks but up to 52 weeks). At the end of the acute phase treatment, patients were required to be stable so that they could be randomized to the ongoing phase trial. In both trials, Seroquel was superior to placebo in prolonging any mood event (depression, mixed or mania). Based on the pooled trial results, the risk was reduced by 49%. Compared to placebo, the 300 mg dose of Sericem had a 41% risk reduction in mood events and the 600 mg dose had a 55% risk reduction.
For relapse prevention during maintenance treatment for bipolar disorder
The efficacy of Sericem monotherapy for relapse prevention has been established in 1 placebo-controlled trial enrolling 1226 patients with DSM-IV-eligible type I bipolar disorder. This trial included patients with recent episodes of manic, mixed, or depressed mood, with or without occasional episodes of psychotic features. During the developmental trial, patients were required to be stable with Sericem for at least 4 weeks before randomization could occur. During the randomized trial, patients could continue treatment with Sericem (300 to 800 mg/day; mean dose 546 mg/day) or receive lithium or placebo for up to 104 weeks. Sericam was superior to placebo in prolonging the time to relapse (i.e., the primary endpoint) of any mood event (manic, mixed, or depressive). The risk reductions for mood, manic, and depressive events were 74%, 73%, and 73%, respectively.
The efficacy of the combination treatment with Seroquel in preventing relapse has been established in 2 placebo-controlled trials that included 1,326 patients with DSM-IV-eligible type I bipolar disorder. These trials included patients with recent episodes of manic, mixed, or depressed mood, with or without occasional episodes of psychotic features.
During the developmental trials, patients were required to be stable for at least 12 weeks with treatment with Sericem combined with a mood stabilizer (lithium or valproate) before randomization could occur. During the randomized trial, patients could receive either continued treatment with Sericem (400 to 800 mg/day; mean dose 507 mg/day) and a mood stabilizer or placebo combined with a mood stabilizer for up to 104 weeks. Sericem was superior to placebo in prolonging the time to relapse (i.e., the primary endpoint) of any mood event (manic, mixed, or depressive). The risk reductions for mood, manic, and depressive events were 70%, 67%, and 74%, respectively.
2 Clinical safety
Suicidal behavior/suicidal ideation or clinical deterioration
In short-term placebo-controlled clinical trials that included all indications and all age groups, the incidence of suicide-related events was 0.8% in both the quetiapine treatment group (76/9327) and the placebo treatment group (37/4845).
In these trials, the incidence of suicide-related events in patients with schizophrenia aged 18 to 24 years: 1.4% (3/212) in the quetiapine group and 1.6% (1/62) in the placebo group; 0.8% (13/1663) in the quetiapine group and 1.1% (5/463) in the placebo group in patients aged ≥ 25 years; <1.4% (2/147) in the quetiapine group in patients aged 18 years and 1.3% (1/75) in the placebo group.
Pharmacology and Toxicology
Pharmacodynamic properties
Mechanism of action.
Quetiapine is an atypical antipsychotic drug. Quetiapine and its active human plasma metabolite, desmethylquetiapine, act on a wide range of neurotransmitter receptors. The affinity between quetiapine and desmethylquetiapine and cerebral serotonin (5HT2) and dopamine D1 and D2 receptors, with relatively higher selectivity for 5HT2 receptor antagonism than for dopamine D2 receptors, underlies the clinical antipsychotic properties of quetiapine and the low number of extrapyramidal side effects (EPS) compared to typical antipsychotics. Quetiapine has no affinity for norepinephrine transporter protein (NET) and low affinity for serotonin 5HT1A receptors, whereas desmethylquetiapine has high affinity for both receptors. NET inhibition and partial agonism at the 5HT1A site of desmethylquetiapine
NET inhibition and partial agonism at the 5HT1A site give quetiapine potential therapeutic efficacy as an antidepressant. Quetiapine and desmethylquetiapine have high affinity for histamine and adrenergic α1 receptors and moderate affinity for adrenergic α2 receptors. Quetiapine has low or no affinity for muscarinic receptors, whereas desmethylquetiapine has high affinity for a variety of muscarinic receptor subtypes.
Non-clinical efficacy
Quetiapine has positive results for antipsychotic activity assays such as the conditioned avoidance reflex. It also blocks the effects of dopamine antagonists, both in behavioral and electrophysiological tests, and elevates dopamine metabolite concentrations, a neurochemical indicator of D2 receptor blockade. Animal tests
The likelihood of EPS as predicted by the results showed that: doses of quetiapine that effectively blocked dopamine D2 receptors resulted in only mild tonicity; quetiapine selectively reduced the firing of A10 dopaminergic neurons in the limbic system of the midbrain and had a weak effect on A9 neurons in the substantia nigra, which are involved in motor function; and quetiapine showed only a mild effect on dystonia in monkeys sensitized to antipsychotics .
The strength of the pharmacological effect of N-deshydroquinothiopine metabolites on this product in humans is not known.
Toxicological tests
1. Acute toxicity
The acute toxicity of quetiapine is low. Typical antipsychotic effects, including decreased activity, ptosis, loss of the righting reflex, salivation, and convulsions, were observed in mice and rats following oral (500 mg/kg) or intraperitoneal (100 mg/kg) administration.
2. Repeated dosing toxicity
The expected antipsychotic-like CNS effects (e.g., sedation at low doses, tremors, convulsions, or weakness at high doses) were seen with repeated administration of quetiapine to rats, dogs, and monkeys.
Hyperprolactinemia due to antagonism of dopamine D2 receptors by quetiapine or its metabolites varies in different strains of animals, but is most prominent in rats, where a range of resulting effects, including mammary hyperplasia, increased pituitary weight, decreased uterine weight, and accelerated female development, were found in a 12-month serial trial.
Reversible morphological and functional effects on the liver consistent with liver enzyme induction were seen in mice, rats and monkeys.
Thyroid cell hyperplasia and corresponding changes in plasma thyroid hormone levels were seen in rats and monkeys.
Hyperpigmentation of several tissues, especially the thyroid, was not accompanied by any morphological or functional effects.
A transient increase in heart rate has occurred in dogs, but was not accompanied by effects on blood pressure.
Posterior delta cataracts were found after 6 months of administration to dogs at 100 mg/kg per day, consistent with inhibition of crystalloid biosynthesis. No cataracts were observed in rhesus monkeys or rodents given at doses up to 225 mg/kg/day. In clinical trials in humans
No drug-related corneal clouding was observed in monitoring.
Neutropenia or granulocyte deficiency was not observed in any of the toxicity tests.
3. Carcinogenicity
In rat tests
(0, 20, 75, 250 mg/kg/day), an increased incidence of breast cancer followed by prolonged hyperprolactinemia was observed in female rats at all dose groups.
In male rats (250 mg/kg daily) and mice (250 and 750 mg/kg daily), there was an increased incidence of benign adenoma-like changes in thyroid blastocytes. This is consistent with the results known to be specific to rodents due to increased hepatic clearance of thyroxine.
4. Reproductive toxicity
Effects associated with increased prolactin levels (slight reduction in male fertility and pseudopregnancy, prolonged estrus, prolonged intercrossing interval and reduced probability of conception) were seen in rats, but this is not directly relevant in humans because the hormonal control of reproductive processes differs between species.
Quetiapine is not teratogenic.
5. Genotoxicity
Genotoxicological tests have shown that quetiapine is not mutagenic or mutagenic.
Pharmacokinetics]
Quetiapine is well absorbed and completely metabolized after oral administration. The bioavailability of quetiapine is not significantly affected by food intake. The plasma protein binding rate of quetiapine is 83%. The steady-state peak concentration of the active metabolite N-desmethylquetiapine was 35% of that of quetiapine.
The pharmacokinetics of quetiapine and desmethylquetiapine were linear over the range of approved doses administered. There were no gender differences in the kinetics of quetiapine.
Peak plasma concentrations occur approximately 6 hours after administration, i.e., the time to peak plasma concentration (Tmax) is 6 hours. The pharmacokinetic changes are proportional to the dose at doses up to 800 mg once daily. Plasma Cmax and AUC after once-daily dosing were comparable to those of twice-daily dosing of quetiapine fumarate tablets at the same total daily dose. The AUC of quetiapine was equivalent but the Cmax was 13% lower when the once-daily dose was similar to the twice-daily dose of quetiapine fumarate tablets at the same total daily dose. The AUC of quetiapine was equivalent when given once daily compared to quetiapine fumarate tablets given once daily at the same total daily dose; the Cmax was 59% lower. The AUC and Cmax of the metabolite desmethylquetiapine were lower than those of quetiapine fumarate tablets by 18% and 37%, respectively.
The elimination half-lives of quetiapine and desmethylquetiapine were approximately 7 hours and 12 hours, respectively.
In a trial evaluating the pharmacokinetics of this product at 300 mg (n=13), 600 mg (n=13) and 800 mg (n=14) in Chinese patients with schizophrenia, mean steady-state blood concentrations (Css,max) and the area under the steady-state drug-time curve
(AUCss) increased with increasing dose over the range of measured dose levels, and the geometric mean terminal half-lives were 7 and 18 hours for quetiapine and N-desalkylquetiapine, respectively.
The mean clearance of quetiapine in the elderly is approximately 30% to 50% lower than in adults aged 18 to 65 years.
In patients with severe renal impairment (creatinine clearance 10-30 ml/min/1.73m2 ,n=8), the mean plasma clearance of quetiapine is reduced by approximately 25% compared to the normal population (creatinine clearance >80 ml/min/1.73m2 ,n=8), but individual renal clearance values are within the normal population range. Therefore, no dose adjustment is required in these patients.
Quetiapine is extensively metabolized in the liver and the parent compound in urine or feces after administration of radiolabeled quetiapine represents less than 5% of the unchanged drug-related material. Approximately 73% of the radioactive material is excreted in the urine and 21% in the feces. The mean plasma clearance of quetiapine in patients with known liver injury (stable alcoholic liver fibrosis) is decreased by approximately 25%. Due to the extensive metabolism of quetiapine in the liver, plasma quetiapine concentrations are bound to be elevated in patients with hepatic injury. Dosing adjustments may be required for these patients (see [Dosage] for details).
In vitro tests have confirmed that the primary metabolizing enzyme for quetiapine is CYP3A4 of the cytochrome P450 enzyme system, and that N-dehydroxylated quetiapine is formed and eliminated primarily by CYP3A4.
In vitro tests have shown that quetiapine and several of its metabolites (including desmethylquetiapine) are weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities. In vitro CYP inhibition was only observed at concentrations 5 to 50 times higher than the human dose range of 300 to 800 mg/day. Based on these in vitro results, it is unlikely that the combination of quetiapine with other drugs would result in clinically significant pharmacological inhibition of cytochrome P450-mediated metabolism of other drugs.
A trial evaluating the effect of food on quetiapine bioavailability showed that a high-fat meal resulted in statistically significant increases in Cmax and AUC values of 44% to 52% and 20% to 22% for quetiapine 50 mg and 300 mg tablets, respectively. Comparison showed that a light diet had no significant effect on Cmax or AUC of quetiapine. This increase in exposure was not clinically significant and therefore the product may be taken with or without food.
【Storage】.
Store under 30℃ in a sealed container.
Package】
Aluminum-plastic blister package, 2×10 tablets/plate/box.
Expiration date
24 months
Execution Standard
Approval number】
[Drug Marketing Licensee
Name: Beijing Tianheng Drug Research Institute Nanyang Tianheng Pharmaceutical Factory
Registered address: East section of Nanhuan Road, Dengzhou City, Henan Province
Postal Code: 474150
Contact: 0377-62185923
Fax number: 0377-62185923
Manufacturer
Company name: Beijing Tianheng Drug Research Institute Nanyang Tianheng Pharmaceutical Factory
Production Address: East section of Nanhuan Road, Dengzhou City
Postal Code: 474150
Telephone number: 0377-62185923
Fax number: 0377-62185923
Website: www.nythpharm.com