Quetiapine

Pharmacological properties

quetiapine is an atypical antipsychotic drug. quetiapine and its active plasma metabolite norkvetiapine interact with many neurotransmitter receptors. quetiapine and norkvetiapine show an affinity for serotonin (5ht2) and dopamine d1 and d2 receptors in the brain. it is this combination of receptor antagonism with a greater selectivity for 5ht2 than for d2 receptors that is considered to be conducive to clinical antipsychotic effects and a low tendency to extrapyramidal side symptoms when using the drug ketylept retard compared to typical antipsychotic drugs.

Quetiapine has no affinity for the norepinephrine transporter and has a low affinity for 5HT serotonin₁A-receptors, while norkvetiapine has a high affinity for both substances. Inhibition by norkvetiapine, as well as a partial agonistic effect on 5HT₁A-receptors may contribute to the therapeutic efficacy of Ketilept Retard as an antidepressant. Quetiapine and norkvetiapine have a high affinity for histaminergic receptors and α₁-adrenoreceptors and moderate affinity for α₂-adrenoreceptors. Quetiapine also has a low affinity or no affinity for muscarinic receptors, while norkvetiapine has a moderate or high affinity for several subtypes of muscarinic receptors.

Pharmacodynamic effects. Quetiapine is active in tests for antipsychotic activity, such as conditioned reflex avoidance. It also blocks the action of dopamine agonists, which are measured either behaviorally or electrophysiologically, and increase the concentration of dopamine metabolites, the neurochemical index of inhibition of D₂receptors.

Pharmacokinetics

Absorption. Quetiapine is well absorbed after oral administration. C_max quetiapine and norkvetiapine in blood plasma is reached approximately 6 hours after taking the drug Ketilept Retard. Molar C_max in the equilibrium state of the active metabolite of norkvetiapine is 35% of those of quetiapine.

The pharmacokinetics of quetiapine and norkvetiapine is linear and proportional to doses up to 800 mg, inclusive, when applied once a day. When comparing the same total daily doses of Ketilept Retard, which was taken 1 time per day, and quetiapine immediate release (quetiapine fumarate immediate release), which was taken 2 times a day, the AUC was the same, but C_max in plasma was 13% lower in equilibrium. When comparing the drug Ketilept Retard with quetiapine, the immediate release of the AUC of the metabolite of norkvetiapine was lower by 18%.

In a study that examined the effect of food on the bioavailability of quetiapine, it was found that foods high in fat cause a statistically significant increase in C_max and AUC of the drug Ketilept Retard by about 50 and 20%, respectively. It cannot be ruled out that the effect of high-fat foods on the bioavailability of a drug may be higher. Light foods have no significant effect on C_max and AUC of quetiapine. Ketilept retard is recommended to be taken 1 time per day at least an hour before meals.

Distribution. Approximately 83% of quetiapine binds to plasma proteins.

Metabolism. Quetiapine is actively metabolized in the liver, the use of radioactively labeled quetiapine revealed that 5% of quetiapine is not metabolized and excreted unchanged in urine or feces.

T_½ quetiapine and norkvetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of the radioactive label is excreted in the urine and 21% in the feces.

In a person with urine, 5% of the total radioactivity of the average molar fraction of the dose of free quetiapine and the active metabolite of norkvetiapine is excreted.

Special populations

Floor. The pharmacokinetics of quetiapine in women and men is not different.

The elderly.The average clearance of quetiapine in the elderly is approximately 30–50% lower than in adults aged 18–65 years.

Impaired renal function. The average clearance of quetiapine in blood plasma in patients with severe impaired renal function (creatinine clearance of 30 ml / min / 1.73 m²) was reduced by about 25%, however, individual indicators of clearance are in the range characteristic of healthy individuals.

Impaired liver function. The average clearance of quetiapine in blood plasma is reduced by about 25% in patients with known impaired liver function (stable alcoholic cirrhosis). Since quetiapine is significantly metabolized in the liver, in patients with impaired liver function, an increase in its plasma level is expected. For these patients, a dose adjustment may be required.

Indications

Ketilept retard is indicated for the treatment of:

• schizophrenia, including the prevention of relapse in patients with a stable course of schizophrenia who received quetiapine maintenance therapy;
• bipolar disorder, in particular:
• for the treatment of moderate to severe manic episodes in bipolar disorder;
• for the treatment of severe depressive episodes in bipolar disorder;
• for the prevention of relapse in patients with bipolar disorder, in patients with manic or depressive episodes in which quetiapine is effective;
• as adjunctive therapy for severe depressive episodes in patients with severe depressive disorder (MAD) who have a suboptimal response to antidepressant monotherapy. Before starting therapy, the doctor must carefully study the safety profile of the drug Ketilept Retard.

Application

For each indication, there are different dosage regimens. you should make sure that the patient is prescribed a dosage corresponding to his condition.

Ketilept Retard should be used 1 time per day on an empty stomach. Tablets should be swallowed whole without breaking, chewing or crushing them.

For the treatment of schizophrenia and manic episodes from moderate to severe in bipolar disorder. Ketilept Retard should be used at least 1 hour before meals. The daily dose at the beginning of therapy is 300 mg on the 1st day and 600 mg on the 2nd day. The recommended daily dose is 600 mg, but if clinically justified, the dose can be increased to 800 mg / day. The dose should be adjusted within the range of effective doses: from 400 to 800 mg / day - depending on the clinical response and tolerance. For maintenance therapy for schizophrenia, there is no need for dose adjustment.

For the treatment of depressive episodes in bipolar disorder. Ketilept Retard should be used before bedtime. The total daily dose for the first four days of treatment is 50 mg (on the 1st day), 100 mg (on the 2nd day), 200 mg (on the 3rd day) and 300 mg (on the 4th day). The recommended daily dose is 300 mg. There is no additional advantage in the group of use of 600 mg compared with the group of 300 mg (see PHARMACOLOGICAL PROPERTIES). A dose of 600 mg may be effective for some patients. Doses of 300 mg should be prescribed by a doctor with experience in treating bipolar disorder. For some patients, in case of problems associated with intolerance to the drug, consider reducing the dose to a minimum of 200 mg.

For the prevention of relapse in bipolar disorder. To prevent the following manic, mixed, or depressive episodes of bipolar disorder, patients who have responded to the use of Ketilept Retard in the emergency treatment of bipolar disorder should continue to take Ketilept Retard in the same dose at bedtime. The dose of Ketilept Retard can be adjusted within the dose range from 300 to 800 mg / day, depending on the patient’s clinical response and tolerance. It is important that the lowest effective doses be used for maintenance therapy.

For concomitant treatment of severe depressive episodes with TDD. Ketilept Retard should be taken before bedtime. The daily dose at the beginning of therapy is 50 mg on the 1st and 2nd day and 150 mg on the 3rd and 4th day. In the course of short-term studies of concomitant therapy (with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine), the antidepressant effect was observed at doses of 150 and 300 mg / day and at a dose of 50 mg / day for one-time study . When using high doses of the drug, the risk of developing adverse reactions increases. Therefore, the doctor should make sure that the lowest effective dose, starting from 50 mg / day, is used for treatment. Increasing the dose from 150 to 300 mg / day should be based on an assessment of the patients condition.

Transfer from quetiapine in the dosage form of tablets with immediate release of the active substance. Patients who are treated with separate doses of quetiapine in the form of tablets with immediate release of the active substance can be transferred to Ketilept Retard in an equivalent total daily dose, which should be taken once a day. A dose titration period may be required to maintain a clinical response.

Elderly patients. Like other antipsychotics and antidepressants, Ketilept Retard should be used with caution in elderly patients, especially at the beginning of treatment and during the dose selection period. There may be a need for a slower dose titration of Ketilept Retard, and the daily therapeutic dose may be lower than that used in younger patients. The average plasma clearance of quetiapine was reduced by 30–50% in the elderly compared with younger patients. Treatment of elderly patients should begin with a dose of 50 mg / day. The dose can be increased gradually by 50 mg / day until an effective dose is achieved depending on the clinical response and tolerability of treatment. Elderly patients with depressive episodes with TDD should start taking 50 mg / day on day 1-3, increasing the dose to 100 mg / day on day 4 and 150 mg / day on day 8. The lowest effective dose should be applied, starting at 50 mg / day. If, based on the assessment of the patients condition, it is necessary to increase the dose to 300 mg / day, this should not be done earlier than after 22 days of treatment.

In patients over the age of 65 with depressive episodes in bipolar disorder, safety and efficacy have not been investigated.

Impaired renal function. Dose adjustment is not necessary for patients with impaired renal function.

Impaired liver function. Quetiapine is actively metabolized in the liver. Therefore, the drug Ketilept Retard should be used with caution in patients with impaired liver function, especially during the initial period of dose selection. Treatment of patients with impaired liver function should begin with a dose of 50 mg / day. The dose can be increased in increments of 50 mg / day until an effective dose is achieved, depending on the patients clinical response and tolerance to therapy.

Children. Ketilept Retard is not recommended for use in children due to the lack of data supporting its use in this age group.

Contraindications

Hypersensitivity to the active substance or to any component of the drug. simultaneous use of cytochrome p450 3a4 inhibitors, such as HIV protease inhibitors, azole antifungal drugs, erythromycin, clarithromycin and nefazodone, is contraindicated.

Side effects

When taking quetiapine, the following adverse reactions were most often reported: drowsiness, dizziness, dry mouth, headache, withdrawal symptoms (in case of discontinuation of the drug), increased plasma tg levels, increased total cholesterol (especially LDL cholesterol), decreased levels of HDL cholesterol, weight gain, decreased hemoglobin levels and extrapyramidal symptoms.

Like taking other antipsychotics, the use of quetiapine was accompanied by an increase in body weight, syncope, malignant antipsychotic syndrome, leukopenia and peripheral edema.

On the part of the blood and lymphatic system: a decrease in hemoglobin²³, a decrease in the number of neutrophils, an increase in the level of eosinophils²⁸leukopenia^{1, 29}thrombocytopenia¹⁴, anemia, agranulocytosis²⁷neutropenia¹.

From the immune system: hypersensitivity (including allergic skin reactions); anaphylactic reaction⁶.

Endocrine system: hyperprolactinemia¹⁶a decrease in total T₄²⁵decrease in free T₄²⁵a decrease in total T₃²⁵increased levels of TSH²⁵decrease in free T₃²⁵hypothyroidism²²Inadequate secretion of ADH.

On the part of metabolism and nutrition: increased levels of TG in blood plasma^{11, 31}an increase in total cholesterol (especially LDL cholesterol)^{12, 31}, decreased HDL cholesterol^{18, 31}weight gain^{9, 31}, increased appetite, increased blood glucose to hyperglycemia^{7, 31}hyponatremia²⁰, diabetes^{1, 5, 6}metabolic syndrome³⁰.

From the psyche: unusual dreams and nightmares, suicidal thoughts and suicidal behavior²¹, somnambulism and related phenomena, such as talking in a dream, as well as eating disorders.

From the nervous system: dizziness^{4, 17}drowsiness^{2, 17}headache, extrapyramidal symptoms^{1, 22}, dysarthria, cramps¹, restless legs syndrome, tardive dyskinesia^{1, 6}fainting^{4, 17}.

From the cardiovascular system: tachycardia⁴palpitation²⁴Q-T interval prolongation^{1, 13, 19}bradycardia³³; orthostatic hypotension^{4, 17}; venous thromboembolism¹.

From the side of the organ of vision: blurred vision.

From the urinary system: urinary retention.

Respiratory, thoracic and mediastinal disorders: dyspnea²⁴rhinitis.

From the digestive system: dry mouth; constipation, dyspepsia, vomiting²⁶; dysphagia⁸pancreatitis¹intestinal obstruction / ileus.

From the hepatobiliary system: increased levels of AlAT³Asat³, gamma-glutamyltranspeptidases (gamma-HT³), in blood plasma; jaundice⁶hepatitis.

On the part of the skin and subcutaneous tissue: angioedema⁶, Stevens-Johnson syndrome⁶, toxic epidermal necrolysis, erythema multiforme.

From the musculoskeletal system and connective tissue: rhabdomyolysis.

Pregnancy, the postpartum period and perinatal conditions: drug withdrawal syndrome in newborns³², neonatal withdrawal.

From the reproductive system and mammary glands: sexual dysfunction; priapism, galactorrhea, edema of the mammary glands, menstrual irregularities.

General disorders and reactions at the injection site: withdrawal symptoms (discontinuation)^{1, 10}, mild asthenia, peripheral edema, irritability, pyrexia; malignant antipsychotic syndrome¹hypothermia.

Changes in laboratory parameters: increased levels of CPK in the blood¹⁵.

¹See SPECIAL INSTRUCTIONS.

²Drowsiness may occur during the first 2 weeks of treatment and usually disappears with prolonged use of quetiapine.

³Asymptomatic increase (deviation from the norm 3 × the upper limit of the norm) of transaminases (AlAT, AsAT) or gamma-HT levels was observed in some patients with quetiapine. This increase was usually reversible with continued treatment with quetiapine.

⁴Like other antipsychotic drugs that block α₁-adrenergic receptors, quetiapine can often cause orthostatic hypotension, which is accompanied by dizziness, tachycardia, in some patients, fainting, especially during the initial dose selection (see SPECIAL INSTRUCTIONS).

⁵Exacerbation of existing diabetes has been reported very rarely.

⁶The frequency of these adverse reactions was determined only on the basis of post-marketing data on the use of quetiapine, with the use of quetiaprine in a dosage form with a quick release.

⁷Fasting blood glucose ≥126 mg / dl (≥7.0 mmol / L) or after-meal glucose ≥200 mg / dl (≥11.1 mmol / L) in at least one case.

⁸An increase in the frequency of dysphagia with quetiapine compared with placebo was observed only in clinical trials of bipolar depression.

⁹An increase in body weight of 7% compared to the original. It occurs mainly during the first weeks of therapy in adults.

¹⁰The withdrawal symptoms that were most commonly observed during short-term placebo-controlled clinical trials of monotherapy: insomnia, nausea, headache, diarrhea, vomiting, dizziness, and irritability. The frequency of these reactions decreased significantly after a week of discontinuation of treatment.

¹¹TG levels of ≥200 mg / dL (≥2,258 mmol / L) (patients aged ≥18 years) or ≥150 mg / dL (≥1,694 mmol / L) (patients aged 18 years) in at least one case.

¹²Cholesterol levels ≥240 mg / dL (≥6.2064 mmol / L) (patients aged ≥18 years) or ≥200 mg / dL (≥5.172 mmol / L) (patients aged 18 years) in at least one case.

An increase in LDL cholesterol ≥30 mg / dL (≥0.769 mmol / L) was observed very often.

The average value among patients with this increase was 41.7 mg / dl (1.07 mmol / L).

¹³See text below as indicated in the paragraphs below.

¹⁴Platelets ≤100 · 10⁹/ l in at least one case.

¹⁵According to reports of clinical studies of adverse reactions, an increase in the level of CPK in the blood is not associated with malignant antipsychotic syndrome.

¹⁶Prolactin level (patients aged 18 years) at any time: 20 mcg / L (869.56 pmol / L) - in men; 30 μg / L (1304.34 pcmol / L) - in women.

¹⁷May cause a fall.

¹⁸HDL cholesterol at any time: 40 mg / dL (1.025 mmol / L) - in men; 50 mg / dl (1.282 mmol / L) - in women.

¹⁹The duration of the Q – T interval is from 450 to ≥450 ms with an increase of ≥30 ms. In placebo-controlled studies of quetiapine, the mean change and the number of patients with clinically significant deviations are similar in the quetiapine and placebo groups.

²⁰Deviation from 132 to ≤132 mmol / L with at least one examination.

²¹Cases of suicidal thoughts and suicidal behavior were noted during quetiapine therapy or immediately after discontinuation of treatment (see SPECIAL INSTRUCTIONS and PHARMACOLOGICAL PROPERTIES).

²²See PHARMACOLOGICAL PROPERTIES.

²³A decrease in hemoglobin to ≤13 g / dl (8.07 mmol / L) in men, ≤12 g / dl (7.45 mmol / L) in women with at least one examination was observed in 11% of patients treated with quetiapine , in all studies, including open ones. In patients, the average maximum decrease in hemoglobin at any time was 1.50 g / dl.

²⁴These phenomena often occurred against the background of tachycardia, dizziness, orthostatic hypotension, and / or major cardiac / respiratory diseases.

²⁵Total T deviation₄free T₄total T₃ and free T₃ was 0.8 pmol / L and the TSH deviation was 5 mIU / L.

²⁶Consistent with increased incidence of vomiting in elderly patients (≥65 years).

²⁷The deviation of the level of neutrophils from ≥1.5 · 10⁹/ l to 0.5 · 10⁹/ l at any time during treatment.

²⁸The deviation of the eosinophil level was 1 · 10⁹ cells / l.

²⁹The deviation of the level of leukocytes was ≤3 · 10⁹ cells / l.

³⁰According to reports of metabolic syndrome from all clinical studies of quetiapine.

³¹During clinical studies, some patients noted an increase in metabolic factors that adversely affect body weight, blood glucose and lipids.

³²See Use during Pregnancy and Breastfeeding.

³³May be associated with hypotension and / or fainting. The frequency of occurrence is based on reports of an adverse reaction of bradycardia and related phenomena, which were noted in all clinical studies of quetiapine.

Cases of prolonged Q – T interval, ventricular arrhythmias, sudden unclear lethal outcome, cardiac arrest, and torsade de pointes type arrhythmias were recorded with the use of antipsychotic drugs and are considered specific for this class of drugs.

Children.The above adverse reactions noted in adults also occur in children.

Adverse reactions were observed during clinical trials of the use of quetiapine in children.

The table below provides adverse reactions that had a high incidence in this age group of patients or which were not observed in adult patients.

Adverse reactions are located depending on their frequency of occurrence in the following categories: very often (≥1 / 10); often (≥1 / 100 to 1/10); infrequently (≥1 / 1000 to 1/100); rarely (≥1 / 10,000 to 1/1000) and very rarely (1/10 000).

¹Prolactin levels (18 year old patients) at any time: 20 mcg / L (869.56 pmol / L) in male patients; 26 μg / L (1130.428 pcmol / L) - in female patients. Mene