Seroquel Prolong, 300 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.

Higher selectivity for 5NT₂ type serotonin receptors than for D₂ type dopamine receptors, 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.

About 83% of quetiapine is bound to plasma proteins.

CYP3A4 has been found to be a key isoenzyme in the cytochrome P450-mediated metabolism of vetiapine. 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 relapse prevention in stable patients; bipolar disorders, including:

Active ingredient

Composition

1 film-coated sustained release tablet contains:

the active ingredient:

Quetiapine (as fumarate) 300 mg,

auxiliary substances:

Lactose monohydrate;

MCC;

Sodium citrate dihydrate;

Hypromellose;

Magnesium stearate,

composition of the shell:

Hypromellose; macrogol 400; E171 titanium dioxide; E172 iron oxide yellow dye

How to take, the dosage

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

Adults

The treatment of schizophrenia, moderate and severe manic episodes in the structure of bipolar disorder

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

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.

The treatment of episodes of depression in the structure of bipolar disorder

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 individual tolerance of a patient, the dose can be increased up to 600 mg. The advantage of using Seroquel® Prolong in daily dose of 600 mg compared to 300 mg was not stated. Seroquel® Prolong at a dose greater than 300 mg should be prescribed by a physician experienced in the therapy of bipolar disorders.

Prevention of recurrence of bipolar disorder in patients with prior effective quetiapine therapy for manic or depressive episodes in the structure of bipolar disorder

. To prevent recurrence of manic, depressive, and mixed episodes in bipolar disorder, 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.

Transfer from Seroquel to Seroquel Prolong

For ease of administration, patients currently receiving fractional 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.

Elderly patients

As with other neuroleptic agents, Seroquel Prolong should be used with caution in elderly patients, especially at the beginning of therapy. Adjustment of the 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.

Patients with renal impairment

Dose adjustment is not required for patients with renal impairment.

Patients with hepatic insufficiency

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 combining Seroquel Prolong with other CNS-acting drugs and with alcohol.

The cytochrome P450 (CYP) 3A4 isoenzyme is the main isoenzyme responsible for the metabolism of quetiapine through the cytochrome P450 system. In studies in healthy volunteers, co-administration of quetiapine (in dose 25 mg) with ketoconazole, a CYP3A4 inhibitor, resulted in 5-8 times higher AUC of quetiapine.

Hence, co-administration of vetiapine and CYP3A4 cytochrome 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 administration resulted in a significant increase in Cl of quetiapine and a corresponding decrease in AUC, an average of 13%, compared with quetiapine administration without carbamazepine. In some patients, the decrease in AUC was even more pronounced. This interaction was accompanied by a decrease in plasma concentration of quetiapine and may have reduced the effectiveness of therapy with Seroquel® Prolong. Co-administration of quetiapine with phenytoin, another inducer of microsomal liver system, was accompanied by an even more pronounced (by about 450%) increase in clearance of quetiapine. The use of Seroquel® Prolong in patients receiving liver enzyme system inducers is possible only if the expected benefit of therapy with Seroquel® Prolong exceeds the risk associated with withdrawal of the liver enzyme inducer drug. Changing the dose of microsomal enzyme inducers should be gradual. If necessary, they may be replaced by drugs that do not induce microsomal enzymes (for example, valproic acid preparations).

The pharmacokinetics of quetiapine were not significantly changed by concomitant use of the antidepressant imipramine (CYP2D6 inhibitor) or fluoxetine (CYP3A4 and CYP2D6 inhibitor).

The pharmacokinetics of quetiapine is not significantly changed by concomitant use with antipsychotic drugs – risperidone or haloperidol. However, concomitant administration of quetiapine and thioridazine resulted in an increase in the Cl of quetiapine by approximately 70%.

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

Lorazepam clearance is decreased by approximately 20% when 2 mg of lorazepam is taken once with Clavetiapine at a dose of 250 mg twice daily.

The pharmacokinetics of lithium preparations are not altered by concomitant use of quetiapine. No clinically significant changes in the pharmacokinetics of valproic acid and quetiapine have been observed when valproate seminatrium and quetiapine are used together.

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

Cautions must be taken 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

Drowsiness and associated symptoms such as sedation may occur during therapy with Seroquel Prolong. In clinical studies involving depressed patients with bipolar disorder, somnolence generally developed within the first three 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.

Patients with cardiovascular disease

Patients with cardiovascular and cerebrovascular disease and other conditions predisposing to hypotension should be cautious when using Seroquel Prolong. 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 and aspiration have been observed during therapy with Seroquel Prolong. A causal relationship of aspiration pneumonia with administration of Seroquel Prolong has not been established. However, caution should be exercised when administering the drug to 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 antipsychotics, caution is advised when treating patients with a history of seizures.

Extrapyramidal symptoms

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

Late dyskinesia

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

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome may develop while taking antipsychotic drugs, including quetiapine. Clinical manifestations of the syndrome include hyperthermia, altered mental status, muscle rigidity, autonomic nervous system lability, and increased creatine phosphokinase activity. In such cases, Seroquel Prolong should be discontinued and appropriate treatment should be given.

Severe neutropenia

In clinical trials of quetiapine, cases of severe neutropenia (neutrophil count of 9/l) have rarely 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. The patient should be monitored for possible symptoms of infection and neutrophil counts should be controlled (until the level exceeds 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 decreases the plasma concentration of quetiapine and may decrease the effectiveness of therapy with Seroquel Prolong.

The administration of Seroquel Prolong to patients receiving liver enzyme system inducers is possible only if the expected benefit of therapy with Seroquel Prolong exceeds the risk associated with withdrawal of the liver enzyme inducer drug. Changes in the dose of microsomal enzyme inducers should be gradual. If necessary, they may be replaced by drugs that do not induce microsomal enzymes (for example, valproic acid preparations).

Hyperglycemia

The development of hyperglycemia or exacerbation of diabetes mellitus is possible against the background of quetiapine administration, in patients with a history of diabetes mellitus. Clinical monitoring of patients with diabetes mellitus and patients with risk factors for diabetes mellitus is recommended.

Lipid concentrations

Quetiapine administration may increase triglyceride and cholesterol concentrations and decrease HDL concentrations.

Long QT interval

There is 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 previously observed prolongation of the QT interval. Caution should also be exercised when prescribing quetiapine concomitantly with QT interval prolongersc, other neuroleptics, especially in the elderly, patients with congenital QT interval prolongation syndrome, 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, it is recommended that the drug be withdrawn gradually, over a period of at least one or two 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 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 excluded for other antipsychotic drugs or other patient groups. Seroquel Prolong should be used with caution in patients at risk of stroke.

A review 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 lethal outcomes observed 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.

Suicidal ideation/suicidal thoughts 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 intent and suicide attempts and should be carefully monitored during treatment.

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

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; 1.4% (2/147) for quetiapine and 1.3% (1/75) for placebo in patients under 18 years of age.

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 (see “Special Indications”).

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.

Seroquel Prolong may cause drowsiness, so patients should not operate machinery that are hazardous 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

Symptoms. A fatal outcome has been reported when 13.6 g of quetiapine was taken in a patient in a clinical trial and a fatal outcome after taking 6 g of quetiapine in a post-marketing study of the drug. At the same time, there has been a non-fatal case of quetiapine administered in doses greater than 30 g.

There have been reports of extremely rare cases of quetiapine overdose resulting in prolonged QTs interval, death or coma.

In patients with a history of severe cardiovascular disease, the risk of side effects may increase with overdose.

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

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

Continuous medical monitoring should continue 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