Megazon 50mg Prolonged-Release Tablets Pharmathen Treatment of schizophrenia (3 blisters x 10 tablets)

Treatment of anxiety disorders (gad).

Pharmacokology

Pharmacological group: Anti -psychotic, Diazepines, Oxazepines, Thiazepines and Oxepines.

ATC code: n05ah.

Mechanism of action:

quetiapine is an aligned anti -psychotic drug. Quetiapine and metabolites are active in human plasma, Norquetiapine has the effects on many types of neurotransmitter receptors. Quetiapine and norquetiapine have a affinity for serotonin receptors (5HT2) in the brain and with Dopamine D1 and D2 receptors. The antagonism on these swears and the selection with the serotonin receptor (5HT2) in the brain is higher than the Dopamine D2 receptor, which is considered to contribute to the clinical anti -psychotic properties and the risk of unwanted effects on the quote system (EPS) of Quetiapine compared to typical anti -psychotic drugs. In addition, Norquetiapine has high affinity with norepinephrin transportation (net). Quetiapine has negligible affinity for benzodiazepine receptors but has high affinity with histaminergic and adrenergic α1 receptors with average affinity with adrenergic α2 receptors and average -to -high affinity with several Muscarinic receptors. The inhibition of the net and the activity of the logistics partially at 5HT1A by Norquetiapine can contribute to the effectiveness of anti -depression treatment of Quetiapine XR.

Authority:

Quetiapine is active in anti -psychotic trials, such as conditioned evanged evanged testing. Quetiapine also claims the impact of dopamine agonities on behavioral or electrical tests, and increases the concentration of dopamine metabolites, a neurological index indicates the level of receptor clutches D2.

In preclinical trials forecasting the possibility of extracurricular symptoms (EPS), Quetiapine is not like typical anti -psychotic drugs and has no typical characteristics. Quetiapine does not cause too sensitive effects with Dopamine D2 receptors after long -term use. Quetiapine only causes the effect of keeping the weak at doses of Dopamine receptor inhibiting D2. Quetiapine proves the selection on the middle of the brain with the reducing inhibition effect of the neurons in the middle of the brain, but does not affect the dopamine neurons of the black mane after long -term use. Quetiapine can cause a minimum muscle hypertension in Haloperidol sensitive monkeys or have never used drugs (DRUG - Naive) after immediately taking the drug immediately and long term (see unwanted effects).

Please see more information about drugs in the instructions for the use of drugs attached.

Dynamic pharmacokinetics

absorption

Quetiapine is well absorbed and completely metabolized after drinking. The plasma concentration of Quetiapine and Norquetiapine is about 6 hours after taking the drug (TMAX). The maximum molarity in the stable state of metabolites is 35 % of this concentration of quetiapine.The pharmacokinetics of Quetiapine and Norquetiapine are linear and proportional to the dose for doses of up to 800 mg oral 1 time/day. When comparing the long -lasting Quetiapine, used with Quetiapine Fumarat, fast -release, use 2 times/day with a total daily dose equal, the area under the concentration curve over time (AUC) is equivalent, but the maximum plasma concentration in a stable state (CMAX) is lower than 13%. When comparing the extended Quetiapine and the rapid release of Quetiapine, the AUC of Norquetiapine metabolites lower than 18%.

In a study survey of the effects of food on the bioavailability of Quetiapine shows a significant increase in fat -rich meals CMAX and AUC of Quetiapine release lasting 50 mg and 300 mg in order of 50% and 20%. This cannot rule out the effects of a fat -rich meal on the pharmacokinetics of Quetiapine may be larger. A low -fat meal does not have a significant impact on CMAX or AUC of Quetiapine. Should drink Quetiapine Liberation at least 1 hour before meals.

distribution

Quetiapine is connected to plasma proteins about 83%.

transformation

quetiapine is completely metabolized by the liver, the original compound accounts for

In vitro studies determine that CYP3A4 is the main enzyme responsible for the quetiapine metabolism via cytochrom P450 intermediaries. Norquetiapine is mainly formed and transformed through CYP3A4.

quetiapine and some of its metabolites (including norquetiapine) are weak inhibitors of cytochrom P450 1A2, 2C9, 2C19, 2D6 and 3A4 In vitro. The inhibition of CYP In vitro is only 5 to 50 times higher than the dose of the specified dose in people 300 to 800 mg/day. Based on these in vitro results, the combination of quetiapine with other drugs may not significantly inhibit the metabolism of drugs combined through cytochrom P450 intermediaries. Animal studies show that quetiapine can cause the induction of cytochrom P450 enzymes. However, in a specific interactive study in psychotic patients, there is no increase in the activity of cytochrom P450 after using Quetiapine.

Elimination

Selling waste time of Cuetapine and Norquetiapine in the order of about 7 and 12 hours. About 73% of radioactive drugs are excreted in the urine and 21% in feces have less than 5% of the total amount of non -metabolic drugs.

The average dose ratio is calculated by the molecular concentration between free quetiapine and active metabolites in Norquetiapine plasma is

Special patient groups

Sex: The pharmacokinetics of the quet apine is no different but male and female.

Elderly: Quetanine's average clearance in the elderly is about 30-50% lower than in adults 18 - 65 years old.

Patients with renal impairment: The average clearance of quetiapine in blood in the undercarriage is about 25, in patients with severe renal impairment (creatinine clearance

Patients with liver failure: Average of quetiapine clearance in plasma decreases by about 25% in patients with liver failure (alcoholic cirrhosis in a stable state). Because Quetiapine is completely transferred by the liver, the plasma quetiapine concentration is higher than in patients with liver failure, and may need to adjust the dose for patients with liver failure.

Children:

Dynamic data is taken in 9 children aged 10 - 12 and 12 adolescents, stable treatment with 400 mg quetiapine twice a day. In a stable state, the dose - calculated according to the plasma concentration that has returned to the normal original substance, of Quetiapine in children and adolescents (10-17 years) is generally similar to the dose of adults, although CMAX in children is at the upper limit of CMAX in adults. AUC and CMAX of metabolites are active in Norquetiapine, in the order of about 62% and 49% in children (10-12 years old), and 28% and 14% according to adolescents (13 - 17 years old), higher than the value of adults.

There is no data of the liberated quetiapine in children and adolescents.

Please see more information about drugs in the instructions for the use of drugs attached.

Children

The unwanted reactions in the above adults should be considered in children and adolescents. The table below summarizes unwanted reactions that occur with higher frequency in children and adolescents (10-17 years old) compared to adults or unwanted reactions that do not occur in adults.

Table 2: ADRS in children and adolescents related to Quetiapine treatment occurs with higher frequency in children and minors compared to adults or unwanted effects that do not occur in adults.

The frequency of unwanted events is conventional as follows: Very common (≥ 1/10), common (≥ 1/100,

Be cautious when using

need to be very careful when taking the drug for patients in the following cases:

Because Megazon is indicated in the treatment of schizophrenia, bipolar disorders and treatment support for major depression in patients with major depression disorders (MDD), total anxiety disorders (GAD), safe data should be considered depending on the diagnosis in each patient and the dose is in use.

Effective and long -term safety in patients with serious depression disorders have not been evaluated in supportive treatment, but the effectiveness and long -term safety have been assessed in adult patients in single therapy.

Children:

It is not recommended to use quetiapine for children and minors under 18 years of age because there is no data to support the use of drugs for patients at this age.

How to change in thyroid function test is also recorded in children and adolescents.

Please see more information about drugs in the instructions for the use of drugs attached.

In addition, the long -term safety effects of Quetiapine therapy for growth and maturity are only studied for 26 weeks. It is unclear long -term effects on cognitive and behavioral development.

In the clinical studies that are controlled to the placebo using quetiapine for children and adolescents, Quetiapine is related to increased frequency of symptoms of extracurricular symptoms (EPS) compared to placebo in patients with schizophrenia, inductance due to bipolar disorders and depression due to bipolar disorders.

suicide/suicide thoughts or deteriorating clinical status:

Depression is associated with an increase in the risk of suicide, self -injury and suicide (events related to suicide). This risk persists until the remission is significantly reduced. Because there may not be improved in the first few weeks of treatment or longer, the patient should be carefully monitored until the disease is significantly improved. Clinical experience shows that the risk of suicide may increase in the early stage of disease recovery.

In addition, the doctor should consider risks that may occur suicide events after stopping the sudden quetiapine treatment, due to the known risk factors of the disease being treated.

Other mental illnesses that are indicated using quetiapine may also be associated with increased risk of suicidal events. In addition, these diseases can occur simultaneously with large frequencies.

Therefore, be careful when treating patients with other mental disorders like when treating patients with large depression.

Patients with a history of suicide -related events, or patients who are more likely to think of suicide before the beginning of treatment are recorded at risk of suicide or high suicide trying, and should be closely monitored during treatment. An analysis of clinical trials that are controlled with placebo with antidepressants in adult patients suffering from mental disorders show that in patients under the age of 25, there is an increase in the risk of suicide behavior in the group using antidepressants compared to the placebo group.

Combined with drug treatment, especially when starting treatment and when changing the dose, the most tightly monitoring of patients is that patients are at high risk. Patients (and patient caregivers) should be warned of the need to monitor all deteriorating clinical conditions, suicide behavior or thoughts or change in abnormal behaviors and finding medical support as soon as these symptoms appear.

In short -term clinical trials, with a placeborn in patients with major depression in bipolar disorders, an increase in the risk of suicidal events that have been recorded in adults (under 25 years old) treated with quetiapine compared to placebo patients (3.0% compared to 0%, in order). In clinical studies in patients with severe depression disorders, the frequency of suicidal events has been recorded in adult patients (under 25 years old) is 2.1% (3/44) in the treatment group with quetiapine and 1.3% (1/75) in the placebo use group.

Risk of metabolism:

Recorded the bad risks of metabolic including changes in weight, blood glucose (see the hypoglycemic ghkemp) and lipid that have been recorded in clinical studies, patient metabolic parameters should be assessed at the time of starting treatment and changes in these parameters should be controlled regularly during treatment. These parameters change worse need appropriate clinical control.

Symptoms of foreign tapes:

In clinical trials that are controlled with placebo, Quetiapine is related to an increase in frequency of extracurricular symptoms (EPS) compared to placebo in adult patients treating major depression in bipolar disorders and severe depression disorders as "undesirable effects and pharmacological properties".

using quetiapine can cause restlessness, manifested by subjective discomfort or restless restlessness and need to change the body position constantly accompanied by unable to sit or stand still. This symptom appears mainly during the first few weeks of treatment. In patients with these symptoms, it may be detrimental to the dose.

Late movement disorders:

If there are signs and symptoms of late movement disorders, should consider reducing the dose or stop using quetiapine. Symptoms of late movement disorders may be worse or even after treatment.

Sleep and dizziness:

Treatment with quetiapine can cause drowsiness and related symptoms, such as sedation (see "unwanted side effects"). In clinical studies on treatment of depression patients due to bipolar disorders and severe, drowsiness often appear in the first 3 days of treatment and mainly mild to moderate. Patients who experience severe sleepiness may need to be re -examined more often than 2 weeks from the symptoms of drowsiness or until this symptom is improved and may consider stopping treatment.

posture hypotension:

Quetiapine treatment is associated with hypotension and vertical and dizziness, which often appears during the dose adjustment phase. This may increase injury due to an accident (falling), especially in the elderly. Therefore, it is necessary to advise patients to be cautious until they get used to the unwanted effects of the drug.

Use cautious quetiapine in patients with a history of cardiovascular disease, cerebrovascular disease, or other diseases that cause hypotension. Consider reducing the dose or increasing the dose slowly if there is hypotension, especially in patients with cardiovascular disease.

convulsions:

In control clinical trials, there is no difference in the frequency of seizures between patients using quetiapine and placebo groups. There is no data on convulsions on patients with a history of convulsions. Similar to other anti -psychotic drugs, be cautious when used to treat patients with a history of convulsions.

malignant syndrome caused by sedatives:

Malignant syndrome caused by sedatives is related to the treatment of anti -psychotic drugs, including quetiapine (see the "unwanted effect" section). Clinical manifestations include overcrowding, mental changes, muscle spasms, unstable nervous systems and increased creatine phosphokinase. In this case, Quetiapine should be discontinued and appropriate treatment.

Severe neutropenia:

Serious leukopenia (neutrophils However, some cases occur in patients without risk factors available before. Quetiapine should be discontinued in patients with neutral leukemia

Consider the risk of neutropenia in patients with bacterial or fever manifestations, especially without clear risk factors, and must be appropriate clinical monitoring.

Recommend the patient to immediately report the appearance of signs and symptoms related to leukocytes or infections (for example, fever, weakness, indifference, or sore throat) at any time during Quetiapine treatment. These patients need to quickly check the number of leukemia and neutropenia, especially in the event of no risk factors.

Interactive drugs:

See more "interactions of other drugs with other drugs and other types of interactions".

weight:

Weight gain has been recorded in patients treated with Quetiapine, and should be monitored and controlled appropriately according to the instructions for using anti -psychotic drugs (see the "unwanted effect" and "pharmacological characteristics").

Hyperglycemia:

Recorded rare cases of hyperglycemia and/or occurring or severe diabetes sometimes associated with keto-acid infection or coma, including some deaths (see the "unwanted effect"). In some cases, the previous increase has been recognized as risk factors. The appropriate clinical monitoring mode is needed according to the instructions for the use of anti -psychotic drugs. Patients treated with any anti -psychotic drugs including Quetiapine should be monitored with signs and symptoms of hyperglycemia (such as thirst, multiple urethra, eating and fatigue) and patients with diabetes or there are risk factors for diabetes so they should be monitored periodically to avoid worsening in glucose control. Should monitor the weight periodically.

lipid:

Increase triglycerides, LDL and total cholesterol, and decrease HDL cholesterol has been recorded through clinical trials with quetiapine (see the "unwanted effect"). Lipid changes need to be appropriate clinical monitoring.

extends the QT range:

In clinical trials and use according to SPC, Quetiapine is not related to the continuous increase in the absolute QT range. The report after the drug is circulated on the market, the prolonged QT has been recorded when using Quetiapine at the treatment dose (see the "unwanted effect") and in the case of an overdose (see the "overdose" section). Like other anti -psychotic drugs, it is necessary to be cautious when prescribing Quetiapine for patients with cardiovascular disease or family history showing signs of prolonged QT. Caution should be careful when indicated quetiapine along with the drugs that extend the QT range, or use simultaneously with other sedatives, especially in the elderly, in patients with congenital QT syndrome, congestive heart failure, heart hypertrophy, potassium oral hypotension.

Myocarditis and myocarditis:

Myocarditis and myocarditis have been reported in clinical trials and after the drug is marketed, however, the causal relationship with Quetiapine has not been determined. Reassessment should be evaluated with quetiapine treatment in patients suspected of having myocarditis or myocarditis.

Cet Syndrome:

Symptoms of acute cessation such as nausea, vomiting, insomnia, headache, diarrhea, dizziness and stimulation may occur after a sudden stop of high -dose Quetiapine. Therefore, it is advisable to stop the drug slowly within a period of one to two weeks (see the "unwanted effect").

Elderly patients with mental disorders related to dementia:

Quetiapine has not been approved for the treatment of mental disorders related to intellectual decline.

In random clinical trials, controlled with placebo, the risk of brain vascular complications occurs 3 times higher than that of patients with dementia, which uses typical anti -psychotic drugs. The mechanism that increases this risk is not well understood. The increase in the risk of brain vascular complications is also not excluded for other anti -psychotic drugs or on other patients. Quetiapine should be used carefully for the group of subjects with risk factors.

In a meta-analysis, typical anti-psychotic drugs increase the risk of death in elderly patients with psychotic disorders associated with intellectual decline compared to the placebuild out of record. However, in the two Qetiapine studies with control with fake 10 weeks on the same group of patients (n = 710; average age: 83; age variables from 56-99), the frequency of death in patients treated with quetiapine is 5.5% compared to 3.2% in the fake group. The number of patients who die from many different causes in this test is consistent with the prediction. These data do not show the causal relationship between therapy and quetiapine and death in the elderly patients with intelligence.

Difficult to swallow:

Difficult to swallow has been reported to Quetiapine. Use a cautious apine stick in the lung patient due to inhalation.

constipation and intestinal obstruction:

Venous venous embolism (VTE):

Cases of venous embolism caused by thrombosis (VTE) have been reported when using anti -psychotic drugs. Because patients treated with anti -psychotic drugs often have risk factors for venous embolism due to thrombosis, it is necessary to identify all the venous embolism risk factors before and during treatment with quetiapine and take preventive measures.

pancreatitis:

Pancreatitis has been recorded in clinical trials and after the drug circulates on the market. In the reports after circulation on the market, not all cases are risky risk factors, many patients have known factors related to pancreatitis such as triglyceride, gallstones and drinking.

lactose:

Megazon tablets contain lactose. Patients with rare genetic galactose intolerance, lactase deficiency, or malposure of glucose-galactose should not use this drug.

Additional information:

Data on therapy in combination with quetiapine with divalproex or lithium in the treatment of acute impulsive attacks from average to heavy is limited, but this combination is often well tolerated (see the "unwanted effect" and "pharmacological characteristics"). Research data shows the efficiency of synergies after 3 weeks of therapy.

The effect of the drug on driving and operating machinery

Due to the main impact on the central nervous system, Quetiapine may affect the activities that need mental alertness. Therefore, it is necessary to advise patients not to drive or operate the machine until it is clearly determined.

Use drugs for women during pregnancy and lactation

fertility

No assessment of the effect of quetiapine on human fertility. The effects related to high prolactin concentration have been seen in mice, although this is not directly related to humans.

Pregnant women

The first three months of pregnancy

Published data in pregnant women with drugs (about 300-1000 results), including individual reports and some observation studies do not show an increase in the risk of defects due to treatment. However, based on all the available data, it is impossible to draw a clear conclusion. Animal studies show that there is reproductive toxicity. Therefore, quetiapine should only be used during pregnancy if proving the benefits superior to the risk.

The last three months of pregnancy

Babies who use anti -psychotic drugs (including quetiapine) during the last 3 months of pregnancy are at high risk of some harmful reactions, including symptoms of foreign tower and/or symptoms of cessation may vary in terms of level and time. There are some reports of agitation, abnormalities, weakness, tremor, drowsiness, respiratory failure, eating disorders. Therefore, should monitor babies carefully.

Women who are breastfeeding

Based on very few limited data from reported reports on the excretion of Quetiapne into breast milk, the excretion of Quetiapine at the dose does not seem commensurate. Due to the lack of raw data, the decision to use drugs in breastfeeding women needs to take into account the benefits of breastfeeding and mothers' therapeutic benefits.

Drug interaction

Quetiapine is mainly impacted on the central nervous system, so be careful when coordinating megazon with other drugs on other central nervous systems and alcohol.

Cytochrom P450 (CYP) 3A4 is the main enzyme responsible for the metabolism of quetiapine.

In a medical interactive study on a healthy volunteer, the simultaneous use of Quetiapine (dose of 25 mg) with ketoconazole, a CYP3A4 inhibitor, causes the AUC value of Quetiapine to increase 5-8 times higher than normal. So contraindicated use of quetiapine simultaneously with CYP3A4 inhibitors. In addition, it is also not recommended to use grapefruit juice during treatment with quetiapine.

In a multi -dose test to evaluate the dynamic of Quetiapine used before and during treatment with carbamazepine (considered as a liver enzyme induction), simultaneous use of quetiapine with carbamazepine significantly increases the liquidity of quetiapine. This increase in clearance reduces Quetiapine's systemic concentration (evaluated through AUC) on average 13% compared to when using Quetiapine alone; Although some patients may be larger. Due to this interaction, plasma concentration may be lower, and thus can affect Quetiapine's treatment effect. Simultaneous use of quetiapine with phenytoin (another liver enzyme induction) also increases the quetiapine clearance about 450%. In patients who are using liver enzyme induction drugs, the beginning of Quetiapine treatment should only be conducted after the doctor considers the benefits of quetiapine than stopping the use of liver enzyme induction drugs. It is important to stop the liver enzyme induction slowly, or if necessary, replace it with drugs that do not cause liver enzyme (such as sodium valproate) (see the "Causes of caution when taking the drug").

A 6 -week random study of lithium and quetiapine compared to placebo and quetiapine in adults are acute, a higher incidence of pagoda symptoms (especially tremor), drowsiness and weight gain observed in the group using lithium and quetiapine compared to the place of placebo and quetiapine.

pharmacokinetics of sodium valproate and quetiapine unchanged when used simultaneously. A rescue study on children and adolescents using Valproate, Quetiapine or both, the rate of leukopenia and neutropenia in the group using drugs combined higher than the single -treatment group.

Official studies on drug interaction with common cardiovascular drugs have not been conducted.

Be cautious when using Quetiapine simultaneously with drugs that cause electrolyte imbalance or extend QT.

Please see more information about drugs in the instructions for the use of drugs attached.