Seroquel Prolong, 400 mg 60 pcs

Pharmacodynamics

Quetiapine is an atypical antipsychotic drug. Quetiapine and its active metabolite N-dezalkylquetiapine interact with brain neutrotransmitter receptors. Quetiapine and N-dezalkylquetiapine exhibit high affinity for serotonin receptor types 5NT₂ and dopamine receptor types D₁ and D₂ of the brain. Greater selectivity for serotonin receptors type 5NT₂ than for dopamine receptors type D₂ accounts for the major clinical antipsychotic properties of Seroquel Prolong and the low incidence of extrapyramidal side effects. In addition, N-dezalkylquetiapine exhibits a high affinity for the norepinephrine transporter. Quetiapine and N-dezalkylquetiapine have high affinity for histamine and α₁ adrenoreceptors and less affinity for α₂ adrenoreceptors and serotonin type 5NT₁ receptors. Quetiapine shows no appreciable affinity for cholinergic muscarinic and benzodiazepine receptors.

Quetiapine shows antipsychotic activity in standard tests.

The specific contribution of the metabolite N-dezalkylquetiapine to the pharmacological activity of quetiapine has not been established.

The results of a study of extrapyramidal symptoms (EPS) in animals revealed that quetiapine causes mild catalepsy at doses that effectively block type D₂ receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10 dopaminergic neurons compared to A9 nigrostriatal neurons involved in motor function.

Seroquel Prolong is well tolerated when taken at the recommended doses, including elderly patients.

In patients aged 66 to 89 years with dementia, taking Seroquel Prolong at doses of 50 to 300 mg/day decreases symptoms of depression.

The incidence of EPS and body weight in stable patients with schizophrenia does not increase with long-term therapy with Seroquel Prolong.

The DSM-IV (Diagnostic and Statistical Manual of Mental Disorders (4th ed.)) studies of major depressive disorder did not observe an increased risk of suicidal behavior and suicidal ideation when taking Seroquel Prolong compared to placebo.

Pharmacokinetics

Quetiapine is well absorbed from the GI tract. C_max of quetiapine and N-dezalkylquetiapine in plasma is reached approximately 6 h after administration of Seroquel Prolong. The equilibrium molar concentration of the active metabolite N-dezalkylquivetiapine is 35% of that of quetiapine.

The pharmacokinetics of quetiapine and N-desalkylquetiapine are linear and dose-dependent when taking Seroquel Prolong at doses up to 800 mg once daily.

When taking Seroquel Prolong once daily at a dose equivalent to the daily dose of Seroquel taken in 2 doses, similar AUCs were observed, but C_max was 13% lower. The AUC of the metabolite N-dezalkylquetiapine was 18% lower.

Studies of the effect of food intake on the bioavailability of quetiapine showed that eating a high-fat meal resulted in statistically significant increases in C_max and AUC for Seroquel Prolong of approximately 50 and 20%, respectively. Low-fat dietary intake had no significant effect on the C_max and AUC of quetiapine. It is recommended that Seroquel Prolong be taken once daily separately from meals.

Approximately 83% of quetiapine is bound to plasma proteins.

CYP3A4 has been found to be a key isoenzyme in the cytochrome P450-mediated metabolism of quetiapine. N-dezalkylquetiapine is formed with the participation of CYP3A4 isoenzyme.

Quetiapine and some of its metabolites (including N-dezalkylquetiapine) have weak inhibitory activity against cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4, but only at concentrations 5-50 times higher than those observed at commonly used effective doses of 300-800 mg/day.

Based on in vitro results, concomitant use of quetiapine with other drugs should not be expected to result in clinically significant inhibition of cytochrome P450-mediated metabolism of other drugs.

The T_1/2 of vetiapine and N-dezalkyl vetiapine is approximately 7 and 12 h, respectively. Approximately 73% of quetiapine is excreted in the urine and 21% in the feces. Quetiapine is actively metabolized in the liver, less than 5% of quetiapine is not metabolized and is excreted unchanged by the kidneys or in the feces.

There are no differences in pharmacokinetic parameters in men and women.

The average Cl of quetiapine in elderly patients is 30-50% less than in patients aged 18 to 65 years.

The mean plasma Cl of quetiapine is reduced by approximately 25% in patients with severe renal impairment (Cl creatinine2), but individual clearance rates are within the range of values found in healthy volunteers.

In patients with hepatic impairment (compensated alcoholic cirrhosis), the average plasma Cl of quetiapine is reduced by approximately 25%. Since quetiapine is extensively metabolized in the liver, patients with hepatic impairment may have increased plasma concentrations of quetiapine, which requires dose adjustments.

Indications

Schizophrenia, including:

Bipolar disorders, including:

Active ingredient

Composition

1 film-coated sustained release tablet contains:
active ingredient: quetiapine (as fumarate) 50, 150, 200, 300 and 400 mg,
excipients: lactose monohydrate; MCC; sodium citrate dihydrate; hypromellose; magnesium stearate.
coating composition: hypromellose; macrogol 400; E171 titanium dioxide; E172 red iron oxide dye (for 50 mg tablets), E172 yellow iron oxide dye (for 50, 200 and 300 mg tablets).

How to take, the dosage

Ingestion, swallowed whole (without splitting, chewing or breaking), once daily, separate from food.

Adults

The drug Seroquel Prolong should be taken at least 1 hour before meals.

The daily dose for the first 2 days of therapy is: 1st day – 300 mg, 2nd day – 600 mg. Recommended daily dose is 600 mg, but if necessary it can be increased to 800 mg/day. Depending on clinical effect and individual tolerance of a patient, the dose may vary from 400 to 800 mg/day. For maintenance therapy in schizophrenia, no dose adjustment is required after an exacerbation has subsided.

Seroquel Prolong should be taken before bedtime. The daily dose for the first 4 days of therapy is: 1st day – 50 mg, 2nd day – 100 mg, 3rd day – 200 mg, 4th day – 300 mg. Recommended daily dose is 300 mg. Depending on the clinical effect and patient’s individual tolerance, the dose can be increased up to 600 mg. The advantage of using Seroquel Prolong at a daily dose of 600 mg compared to 300 mg has not been identified. Seroquel Prolong at a dose greater than 300 mg should be prescribed by a physician experienced in the therapy of bipolar disorders.

. To prevent relapse of manic, depressive, and mixed episodes in bipolar disorders, patients with a positive response to treatment with Seroquel Prolong should continue therapy at the same daily dose as at the start of therapy. Seroquel Prolong should be taken before bedtime. Depending on the clinical effect and individual tolerance of the patient, the dose may vary from 300 to 800 mg/day. For maintenance therapy, it is recommended to use the minimum effective dose of Seroquel Prolong.

. For ease of administration, patients currently receiving split therapy with Seroquel may be switched to Seroquel Prolong once daily at a dose equivalent to the total daily dose of Seroquel. Dose adjustments may be necessary in individual cases.

In common with other neuroleptics, Seroquel Prolong should be used with caution in elderly patients, especially at the beginning of therapy. Selection of an effective dose of Seroquel Prolong may be slower in the elderly and the daily therapeutic dose is lower than in younger patients. The average plasma Cl of quetiapine is 30-50% lower in elderly patients compared to younger patients. In elderly patients, the starting dose of Seroquel Prolong is 50 mg/day. The dose may be increased by 50 mg daily until an effective dose is achieved, depending on the clinical response and tolerability of the drug in the individual patient.

Dose adjustment is not required for patients with renal impairment.

Quetiapine is extensively metabolized in the liver. Consequently, caution should be exercised when using Seroquel Prolong in patients with hepatic impairment, especially at the beginning of therapy. It is recommended to start therapy with Seroquel Prolong at a dose of 50 mg/day and increase the dose daily by 50 mg until an effective dose is achieved.

Interaction

Caution should be exercised when using Seroquel® Prolong with other CNS-acting drugs as well as with ethanol.

The main cytochrome P450 isoenzyme involved in the metabolism of quetiapine is CYP3A4. In studies in healthy volunteers, co-administration of vetiapine (in dose 25 mg) with ketoconazole, a CYP3A4 inhibitor, resulted in 5-8 times increase in AUC of vetiapine. Therefore, concomitant use of vetiapine and CYP3A4 isoenzyme inhibitors is contraindicated. It is not recommended to consume grapefruit juice during therapy with quetiapine.

In a pharmacokinetic study, the use of quetiapine in different doses before or simultaneously with carbamazepine resulted in a significant increase in quetiapine clearance and a corresponding decrease in AUC by an average of 13%, compared with quetiapine administration without carbamazepine. In some patients, the decrease in AUC was even more pronounced. Co-administration of quetiapine with phenytoin, another inducer of microsomal liver enzymes, was accompanied by an even more pronounced (about 450%) increase in clearance of quetiapine. Use of Seroquel® Prolong in combination with hepatic microsomal enzyme inducers such as carbamazepine and phenytoin reduces the plasma concentration of quetiapine and may decrease the effectiveness of therapy with Seroquel® Prolong.

The pharmacokinetics of quetiapine are not significantly altered by concomitant use with the antidepressants imipramine (CYP2D6 inhibitor) or fluoxetine (CYP3A4 and CYP2D6 inhibitor).

The pharmacokinetics of quetiapine are not significantly altered by concomitant use with the antipsychotic drugs risperidone or haloperidol. However, concomitant administration of quetiapine and thioridazine resulted in increased clearance of quetiapine by approximately 70%.

The pharmacokinetics of quetiapine are not significantly altered by concomitant use of cimetidine.

The clearance of lorazepam is decreased by approximately 20% when lorazepam is taken in a single dose of 2 mg with quetiapine at a dose of 250 mg 2 times/day.

The pharmacokinetics of lithium preparations are not altered by concomitant use with quetiapine.

There are no clinically significant changes in the pharmacokinetics of valproic acid and quetiapine when valproate seminatrium and quetiapine are used together.

Pharmacokinetic studies of the interaction of Seroquel® Prolong with drugs used in cardiovascular disease have not been conducted.

We should use caution when combining Ceroquel® Prolong with drugs that may cause electrolyte imbalance and QTc prolongation.

Quetiapine did not cause induction of hepatic enzyme systems involved in phenazone metabolism.

False positive screening tests for methadone and tricyclic antidepressants by enzyme immunoassay have been reported in patients taking quetiapine. Chromatographic testing is recommended to confirm screening results.

Special Instructions

Sleepiness and dizziness

Drowsiness and related symptoms, such as sedation, may occur during therapy with Seroquel®® Prolong. In clinical studies involving depressed patients with bipolar disorder and depressive episode, somnolence generally developed within the first 3 days of therapy. The severity of this side effect was mostly mild to moderate. If severe somnolence develops, patients with depression in the structure of bipolar disorder may require more frequent visits to the physician within 2 weeks from the onset of somnolence or until the severity of symptoms decreases. In some cases, it may be necessary to discontinue therapy with Seroquel® Prolong.

Prolong therapy with Seroquel® may cause orthostatic hypotension and dizziness, usually during dose titration at the start of therapy. Patients, especially the elderly, should use caution to avoid accidental injury (falls).

Patients with cardiovascular disease

Prolong should be administered with caution in patients with cardiovascular and cerebrovascular disease and other conditions predisposing to the development of arterial hypotension. Orthostatic hypotension may occur during treatment with Seroquel® Prolong, especially during dose titration at the beginning of therapy. If orthostatic hypotension occurs, dose reduction or slower titration may be required.

Dysphagia

Dysphagia and aspiration have been observed during therapy with Seroquel® Prolong. A cause-effect relationship of aspiration pneumonia to administration of Seroquel® Prolong has not been established. However, caution should be exercised when prescribing the drug in patients at risk of aspiration pneumonia.

Convulsive seizures

There is no difference in the incidence of seizures in patients taking quetiapine or placebo. However, as with therapy with other antipsychotic medications, caution is advised when treating patients with a history of seizures.

Extrapyramidal symptoms

An increased incidence of extrapyramidal symptoms in depressed adult patients with bipolar disorder when taking quetiapine for depressive episodes, compared with placebo. However, quetiapine therapy of patients with schizophrenia and mania in the structure of bipolar disorder showed no increase in the incidence of extrapyramidal symptoms compared with placebo.

Late dyskinesia

If symptoms of tardive dyskinesia develop, it is recommended that the dose of the drug be reduced or gradually withdrawn. Symptoms of tardive dyskinesia may worsen or even occur after discontinuation of the drug.

Malignant neuroleptic syndrome

With antipsychotic drugs, including quetiapine, MNS may develop, the clinical manifestations of which are hyperthermia, altered mental status, muscle rigidity, autonomic nervous system lability, increased CPK activity. In such cases, Seroquel® Prolong should be discontinued and appropriate treatment should be administered.

Extended neutropenia

In clinical trials of quetiapine, cases of marked neutropenia (neutrophil count of 9/l) have occasionally been reported. Most cases of severe neutropenia occurred several months after the start of quetiapine therapy. No dose-dependent effect was detected. Leukopenia and/or neutropenia resolved after discontinuation of quetiapine therapy. A possible risk factor for the occurrence of neutropenia is a previous low white blood cell count and a history of drug-induced neutropenia. In patients with a neutrophil count of 9/l, quetiapine should be discontinued. Patients should be monitored for possible symptoms of infection and neutrophil counts should be controlled (until they exceed 1.5 × 109/l).

Interaction with other medicinal products

The use of Seroquel ® Prolong in combination with potent liver enzyme system inducers, such as carbamazepine and phenytoin, reduces the plasma concentration of quetiapine and may decrease the effectiveness of therapy with Seroquel®® Prolong.

The administration of Seroquel® Prolong to patients receiving microsomal liver enzyme inducers is possible only if the expected benefit of therapy with Seroquel Prolong is not anticipated.sup>® Prolong exceeds the risk associated with hepatic enzyme inducer withdrawal. Changing the dose of microsomal enzyme inducers should be gradual. If necessary, they may be replaced with drugs that do not induce microsomal enzymes (e.g., valproic acid preparations).

Body weight

An increase in body weight has been noted during quetiapine administration. Clinical monitoring of patients is recommended in accordance with accepted standards of therapy.

Hyperglycemia

The development of hyperglycemia and/or development and exacerbation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, is possible during quetiapine administration. Regular monitoring of body weight and symptoms of hyperglycemia, such as polydipsia, polyuria, polyphagia and weakness, in patients receiving neuroleptics, including quetiapine, is recommended. Clinical monitoring of patients with diabetes mellitus and patients with risk factors for diabetes mellitus is recommended.

Lipid concentrations

At the time of quetiapine administration, triglyceride, total cholesterol and LDL cholesterol concentrations may increase, and HDL concentrations in blood may decrease.

Metabolic disorders

Body weight gain and elevated blood glucose and lipid concentrations in some patients may lead to a worsening of the metabolic profile, which requires appropriate monitoring.

Long QT interval

There has been no identified relationship between quetiapine administration and persistent increase in absolute QT interval value. However, prolongation of QT interval has been observed in overdose. Caution should be exercised when prescribing quetiapine, as well as other antipsychotic drugs, to patients with cardiovascular disease and with a history of QT interval prolongation. Caution is also required when prescribing quetiapine concomitantly with drugs that prolong the QT intervalc, with other neuroleptics, especially in elderly patients, in patients with congenital QT interval prolongation syndrome, with chronic heart failure, myocardial hypertrophy, hypokalemia or hypomagnesemia.

Acute reactions associated with withdrawal of the drug

The following acute reactions (withdrawal syndrome) may be observed during abrupt withdrawal of quetiapine – nausea, vomiting, insomnia, headache, dizziness and irritability. Therefore, withdrawal of the drug is recommended gradually over a period of at least 1-2 weeks.

Elderly patients with dementia

Seroquel® Prolong is not indicated for the treatment of psychosis associated with dementia. Some atypical neuroleptics in randomized placebo-controlled trials increased the risk of cerebrovascular complications by about 3-fold in patients with dementia. The mechanism of this increased risk is not understood. A similar risk of increased incidence of cerebrovascular complications cannot be ruled out for other antipsychotic medications or other patient groups. Seroquel® Prolong should be used with caution in patients at risk of stroke.

An analysis of the use of atypical neuroleptics for the treatment of psychosis associated with dementia in elderly patients found increased mortality in the group of patients treated with this group of drugs compared with the placebo group. Two 10-week placebo-controlled trials of quetiapine in a similar group of patients (n=710; mean age: 83 years; age range: 56-99 years) showed that mortality was 5.5% in the patient group receiving quetiapine and 3.2% in the placebo group. The causes of death noted in these patients were consistent with those expected in this population. No causal relationship was found between quetiapine treatment and the risk of increased mortality in older patients with dementia.

Venous thromboembolism

In cases of venous thromboembolism have been reported with neuroleptics. Risk factors should be evaluated before and during therapy with antipsychotics, including Seroquel® Prolong, and preventive measures should be taken.

Suicide/suicidal ideation or clinical deterioration

Depression is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicide-related events). This risk persists until the onset of significant remission. Due to the fact that it may take several weeks or more before a patient’s condition improves from the start of treatment, patients should be under close medical supervision until improvement occurs. Conventional clinical experience suggests that the risk of suicide may increase in the early stages of remission.

Other psychiatric disorders for which quetiapine is prescribed are also associated with an increased risk of suicidal events. In addition, such conditions may be comorbid with a depressive episode. Thus, the precautions used in therapy for patients with a depressive episode should also be taken when treating patients with other psychiatric disorders.

Patients with a history of suicidal events, as well as patients clearly expressing suicidal thoughts before initiating therapy, are at increased risk of suicidal intentions and suicide attempts. These patients require close monitoring during treatment. An FDA (Food and Drug Administration, USA) meta-analysis of placebo-controlled trials of antidepressants, summarizing data from approximately 4,400 children and adolescents and 7,700 adult patients with psychiatric disorders, found an increased risk of suicidal behavior on antidepressants compared to placebo in children, adolescents and adult patients under 25 years of age. This meta-analysis does not include studies that used quetiapine.

Patients receiving Seroquel® Prolong should be closely monitored, especially at the start of treatment and when dosing regimens are changed. Patients (and caregivers) should be warned to seek immediate medical attention if clinical deterioration, suicidal behavior/thoughts, and unusual behavior occur.

The rate of suicide-related events was 0.9% for both quetiapine (61/6270) and placebo (27/3047), according to short-term placebo-controlled studies for all indications and in all age groups.

In these studies in patients with schizophrenia, the risk of suicide-related events was 1.4% (3/212) for quetiapine and 1.6% (1/62) for placebo in patients aged 18-24 years; 0.8% (13/1663) for quetiapine and 1.1% (5/463) for patients older than 25 years; and 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under 18 years.

In patients with mania in bipolar disorder, the risk of suicidal events was 0% (0/67) for quetiapine and 0% (1/57) for placebo in patients aged 18-24 years; 1.2% (6/496) for quetiapine and 1.2% (6/503) for placebo in patients older than 25 years; 1% (2/193) for quetiapine and 0% (0/90) for placebo in patients under 18 years of age.

In depressed patients with bipolar disorder, the risk of suicidal events was 3% (7/233) for quetiapine and 0% (0/120) for placebo in patients aged 18-24 years; 1.8% (19/1616) for quetiapine and 1.8% (11/622) for placebo in patients over 25 years. There have been no studies involving depressed patients with bipolar disorder under 18 years of age.

In patients with a depressive episode, the risk of suicidal events was 2.1% (3/144) for quetiapine and 1.3% (1/75) for placebo in patients aged 18-24 years; 0.6% (11/1798) for quetiapine and 0.7% (7/1054) for placebo for patients > 25 years. There have been no studies involving patients with a depressive episode under 18 years of age.

Impact on driving and operating machinery

Seroquel® Prolong may cause drowsiness, so patients are not recommended to operate potentially hazardous machinery during treatment, including driving vehicles.

Contraindications

With caution:

Side effects

The most common side effects of Seroquel Prolong are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension, and dyspepsia.

The administration of Seroquel Prolong, as well as other antipsychotics, may be accompanied by weight gain, fainting, development of malignant neuroleptic syndrome, leukopenia, neutropenia and peripheral edema.

The frequency of adverse reactions is given as the following gradation: very frequently, ≥1/10; frequently, ≥1/100,

Overdose

A lethal outcome has been reported with 13.6 g of quetiapine in a patient participating in a clinical trial, as well as a lethal outcome after taking 6 g of quetiapine in a post-marketing study of the drug. At the same time, a case of quetiapine administered in a dose greater than 30 g without lethal outcome has been described. There are reports of extremely rare cases of quetiapine overdose resulting in prolonged QTc interval, death or coma. Patients with a history of severe cardiovascular disease may have an increased risk of overdose side effects.

The symptoms noted in overdose were mainly due to an increase in the known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia, and decreased BP.

Treatment: it is recommended to carry out measures aimed at maintaining respiratory and cardiovascular function, ensuring adequate oxygenation and ventilation. There is no specific antidote to quetiapine. In cases of severe intoxication it is necessary to remember about the possibility of overdose of several drugs.

In case of refractory arterial hypotension in quetiapine overdose, IV fluids and/or sympathomimetic drugs should be administered (norepinephrine and dopamine should not be given because stimulation of β-adrenoreceptors may cause increased BP reduction against blockade of α-adrenoreceptors by quetiapine).

Gastric lavage (after intubation if the patient is unconscious) and the use of activated charcoal and laxatives may facilitate excretion of unabsorbed quetiapine, but the effectiveness of these measures has not been studied. Close medical monitoring is required until the patient’s condition improves.

Pregnancy use

The safety and efficacy of quetiapine in pregnant women have not been established. As a consequence, Seroquel Prolong should only be used during pregnancy if the expected benefit to the woman justifies the potential risk to the fetus.

The extent of excretion of quetiapine with the woman’s milk is unknown. Women should avoid breastfeeding while taking Seroquel Prolong.

Similarities