Instructions Quetiksol film-coated tablets 25 mg blister No. 30
Composition
active ingredient: quetiapine;
1 film-coated tablet contains 25 mg, 100 mg or 200 mg of quetiapine fumarate equivalent to quetiapine;
excipients: microcrystalline cellulose; povidone K29-32; calcium hydrogen phosphate dihydrate; sodium starch glycolate (type A); lactose monohydrate; magnesium stearate;
for 25 mg: Opadry II Pink 33G34594 coating (hypromellose 6cP; titanium dioxide (E 171); lactose monohydrate; macrogol 3350; triacetin; iron oxide yellow (E 172); iron oxide red (E 172));
for 100 mg: Opadry II Yellow 33G32578 coating (hypromellose 6cP; titanium dioxide (E 171); lactose monohydrate; macrogol 3350; triacetin; iron oxide yellow (E 172));
for 200 mg: Opadry II White 33G28435 coating (hypromellose 6cP; titanium dioxide (E 171); lactose monohydrate; macrogol 3350; triacetin).
Dosage form
Film-coated tablets.
Main physicochemical properties:
film-coated tablets, 25 mg: light orange, round, biconvex, with the inscription Q on one side;
film-coated tablets, 100 mg: yellow, round, biconvex, with Q on one side;
Film-coated tablets, 200 mg: white, oval, biconvex, with the inscription Q on one side.
Pharmacotherapeutic group
Antipsychotic drugs.
ATX code N05A H04.
Pharmacological properties
Pharmacodynamics
Quetiapine is an atypical antipsychotic drug that interacts with different types of neurotransmitter receptors. Quetiapine has a higher affinity for serotonin receptors (5-HT2) than for dopamine receptors (D1 and D2) in the brain, has a high affinity for histamine and alpha1-adrenoceptors, but a lower affinity for alpha2-adrenoceptors. The effect of quetiapine on 5-HT2 and D2 receptors lasts up to 12 hours, which is confirmed by positron emission tomography data. Quetiapine has no affinity for M-cholinergic and benzodiazepine receptors. Quetiapine exhibits antipsychotic activity.
In the study of extrapyramidal symptoms, it was found that quetiapine causes only mild catalepsy at a dose that effectively blocks dopamine D2 receptors. Quetiapine causes a selective decrease in the activity of mesolimbic A10 dopaminergic neurons compared with A9 nigrostriatal motor neurons. The incidence of extrapyramidal symptoms when using quetiapine at a dose of 75–750 mg/day does not differ from that when using placebo or anticholinergic drugs.
Quetiapine does not cause an increase in serum prolactin levels.
Pharmacokinetics
Quetiapine is well absorbed and extensively metabolised after oral administration. Food intake has no significant effect on the bioavailability of quetiapine. Quetiapine is approximately 83% bound to plasma proteins. The peak molar concentration at steady state of the active metabolite N-desalkyl quetiapine is 35% of that observed for quetiapine. The elimination half-lives of quetiapine and N-desalkyl quetiapine are approximately 7 and 12 hours, respectively.
Quetiapine is effective when administered twice daily. Studies using positron emission tomography to assess the persistence of 5HT2 and D2 receptor occupancy for 12 hours after a dose of quetiapine also support this.
The pharmacokinetics of quetiapine and N-desalkyl quetiapine are linear within the recommended dose range. The kinetics of quetiapine do not differ between men and women.
The mean clearance of quetiapine in elderly patients is approximately 30-50% lower than in adults aged 18-65 years.
The mean plasma clearance of quetiapine was reduced by approximately 25% in patients with severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m2) and in patients with hepatic impairment (stable alcoholic cirrhosis), however, individual clearance values are within the range of those observed in healthy subjects. Less than 5% of the mean molar fraction of the dose of free quetiapine and the active plasma metabolite N-desalkyl quetiapine is excreted in the urine.
Quetiapine is extensively metabolized in the liver. Administration of radiolabeled quetiapine has shown that less than 5% of quetiapine is not metabolized and is excreted unchanged in the urine or feces. Approximately 73% of the radiolabel is excreted in the urine and 21% in the feces.
In vitro studies have shown that CYP3A4 is the major enzyme responsible for the cytochrome P450-mediated metabolism of quetiapine. N-desalkyl quetiapine is primarily formed and eliminated by CYP 3A4.
Quetiapine and several of its metabolites (including N-desalkyl quetiapine) have weak inhibitory activity against cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6 and 3A4 in vitro. Inhibition of CYP in vitro is only observed at concentrations approximately 5-50 times higher than those observed at doses of 300-800 mg/day in humans. Based on the in vitro results, co-administration of quetiapine with other drugs is not expected to result in clinically significant inhibition of the metabolism of another drug that is metabolized by cytochrome P450.
Indication
Treatment of schizophrenia. Treatment of manic episodes associated with bipolar disorder.
Contraindication
-Hypersensitivity to any of the components of the drug.
-Concurrent use of cytochrome P450 inhibitors, such as HIV protease inhibitors, azole antifungals, erythromycin, clarithromycin, and nefazodone.
Interaction with other medicinal products and other types of interactions
Given that quetiapine primarily acts on the central nervous system, Quetiapine should be used with caution in combination with other drugs with similar effects and with alcohol.
The pharmacokinetics of lithium were not altered when co-administered with Seroquel.
The pharmacokinetics of valproic acid and quetiapine were not altered to a clinically relevant extent when co-administered as valproate semisodium (also known as divalproex sodium (USAN)) and Quetiapine fumarate. Valproate semisodium is a stable complex compound consisting of sodium valproate and valproic acid in a 1:1 molar ratio.
The pharmacokinetics of quetiapine were not significantly altered after co-administration with the antipsychotics risperidone or haloperidol. However, co-administration of Quetiapine and thioridazine resulted in an increase in quetiapine clearance.
Quetiapine did not induce hepatic enzyme systems involved in the metabolism of antipyrine. However, in a multiple-dose study to evaluate the pharmacokinetics of quetiapine administered before and during treatment with carbamazepine (a hepatic enzyme inducer), concomitant administration of carbamazepine significantly increased quetiapine clearance. This increase in clearance reduced systemic exposure to quetiapine (as measured by AUC) to an average of 13% of that seen with quetiapine alone, although some patients had a greater effect. This interaction may result in decreased plasma concentrations, and therefore the need for an increase in the dose of Quetiapine should be considered for each patient based on clinical response. It should be noted that the maximum recommended dose of Quetiapine is 750 mg/day for the treatment of schizophrenia and 800 mg/day for the treatment of manic episodes associated with bipolar disorder. Long-term therapy with high doses should only be considered after careful assessment of the benefit-risk ratio for each individual patient.
Concomitant use of Quetiapine with phenytoin (another inducer of the microsomal enzyme) has been shown to increase the clearance of quetiapine. Patients taking Quetiapine concomitantly with phenytoin or other inducers of the hepatic enzyme (e.g. barbiturates, rifampicin, etc.) may require increased doses of Quetiapine to maintain control of psychotic symptoms. When phenytoin or carbamazepine or other inducers of the hepatic enzyme are withdrawn or when they are replaced by a non-inducer (e.g. sodium valproate), the dose of Quetiapine may need to be reduced.
CYP3A4 is a key enzyme involved in the cytochrome P450-mediated metabolism of quetiapine. The pharmacokinetics of quetiapine were not altered by co-administration with cimetidine, a known inhibitor of the P450 enzyme. The pharmacokinetics of quetiapine were not altered by co-administration with the antidepressants imipramine (a known CYP2D6 inhibitor) or fluoxetine (a known CYP3A4 and CYP2D6 inhibitor). However, caution should be exercised when co-administering Quetiapine with potent CYP3A4 inhibitors (such as azalea antifungals, macrolide antibiotics and protease inhibitors).
Application features
Cardiovascular diseases
Quetiapine should be used with caution in patients with established cardiovascular and cerebrovascular diseases or other conditions that may lead to hypotension.
Quetiapine may cause orthostatic hypotension, especially during initial dose titration, which is more common in elderly patients than in younger patients.
Quetiapine has not been associated with a sustained increase in the QTc interval. However, as with other antipsychotic drugs, caution should be exercised when prescribing quetiapine concomitantly with drugs that prolong the QTc interval, especially in the elderly.
Convulsions
Extrapyramidal symptoms and tardive dyskinesia
As with other antipsychotics, Quetiapine may cause tardive dyskinesia and extrapyramidal symptoms after long-term treatment. If signs and symptoms of tardive dyskinesia appear, consideration should be given to reducing the dose or discontinuing the drug.
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome may be associated with treatment with antipsychotics, including quetiapine. Clinical manifestations include hyperthermia, altered mental status, muscle rigidity, autonomic instability, and elevated creatine phosphokinase. In such cases, the drug should be discontinued and appropriate treatment initiated.
Severe neutropenia
Severe neutropenia (neutrophil count < 0.5 x 109/l) has been reported. Most cases of severe neutropenia have occurred within a few months of initiating quetiapine therapy. There is no apparent dose-related relationship. Possible risk factors for neutropenia include pre-existing low white blood cell count and a history of drug-induced neutropenia. Quetiapine should be discontinued in patients with neutrophil counts < 1.0 x 109/l. Patients should be monitored for signs of infection and neutrophil counts should be monitored (until they exceed 1.5 x 109/l).
Sudden discontinuation of the drug
Acute withdrawal symptoms such as nausea, vomiting and insomnia have been reported very rarely after abrupt discontinuation of high-dose antipsychotic treatment. Recurrence of psychotic symptoms and involuntary movement disorders (e.g. akathisia, dystonia and dyskinesia) have been reported. Therefore, gradual discontinuation over a period of at least one to two weeks is recommended.
Interactions
See also section “Interaction with other medicinal products and other types of interactions”.
Concomitant use of quetiapine with hepatic enzyme inducers such as carbamazepine may significantly reduce the systemic exposure of quetiapine. Higher doses of Quetiapine may be required when used concomitantly with a hepatic enzyme inducer, depending on clinical response to treatment.
When used concomitantly with drugs that are potent inhibitors of CYP3A4 (such as azalea antifungals, macrolide antibiotics and protease inhibitors), quetiapine plasma concentrations may be significantly higher than those observed in patients in clinical trials. Therefore, lower doses of Quetiapine should be used. Particular attention should be paid to elderly and debilitated patients. The risk-benefit ratio should be assessed individually for all patients.
Hyperglycemia
Cases of hyperglycemia or exacerbation of pre-existing diabetes mellitus have been reported during treatment with quetiapine. Appropriate clinical monitoring is recommended in patients with diabetes or those with risk factors for diabetes mellitus.
Elderly patients with dementia-related psychosis
Quetiapine is not approved for the treatment of psychosis associated with dementia.
In patients with dementia, an almost 3-fold increase in the risk of adverse cerebrovascular events has been observed with the use of some atypical antipsychotics. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics or for other patient populations. Quetiapine should be used with caution in patients with risk factors for stroke.
Effect on the liver
If jaundice develops, Quetixol should be discontinued.
Use during pregnancy or breastfeeding
The safety and efficacy of quetiapine in pregnant women have not been established. Therefore, Quetiapine should be used during pregnancy only if the expected benefit outweighs the potential risk.
The extent of excretion of quetiapine into breast milk is unknown. Therefore, women should be advised to discontinue breastfeeding while taking Quetiapine.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients are not recommended to drive or operate dangerous machinery, as Quetixol may cause drowsiness.
Method of administration and doses
Quetixol should be used by adults 2 times a day, regardless of meals.
Adults
For the treatment of schizophrenia
The total daily dose for the first 4 days of therapy is 50 mg (day 1), 100 mg
(day 2), 200 mg (day 3) and 300 mg (day 4).
From day 4 onwards, the dose should be titrated to the usual effective dose of 300-450 mg/day. Depending on clinical efficacy and individual tolerability, the dose may be adjusted within 150-750 mg/day.
For the treatment of manic episodes associated with bipolar disorder
For monotherapy or as an adjunct to mood stabilizer therapy, the total daily dose for the first four days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3), and 400 mg (day 4). Further increases to 800 mg/day on day 6 should be gradual, with dose increases of no more than 200 mg/day.
As with other antipsychotics, Quetiapine should be used with caution in elderly patients, especially at the beginning of treatment. Quetiapine should be initiated in elderly patients at a dose of 25 mg/day. The dose should be increased daily by 25-50 mg/day until an effective dose is reached, which is likely to be lower than for younger patients.
Liver and kidney dysfunction
In patients with impaired renal or hepatic function, oral clearance of quetiapine is reduced by approximately 25%. Quetiapine is extensively metabolized in the liver, therefore Quetiapine should be used with caution in patients with established hepatic insufficiency.
In patients with renal or hepatic insufficiency, treatment with Quetiapine should be initiated at a dose of 25 mg/day. The dose should be increased daily by 25-50 mg/day until an effective dose is reached.
Children
The safety and efficacy of the drug for the treatment of children (under 18 years of age) have not been studied, therefore the drug is not used in pediatric practice.
Overdose
Data on overdose with quetiapine are limited. The use of quetiapine in doses exceeding 20 g has been described; no fatalities have been recorded, and patients recovered without sequelae. Since the drug has been widely introduced into medical practice, there have been very rare reports of overdose with quetiapine resulting in death or coma, or QT prolongation.
Patients with cardiovascular disease may be at increased risk for the effects of overdose.
In general, the symptoms reported were due to an increase in the known pharmacological effects of the drug, such as drowsiness and sedation, tachycardia and hypotension.
There is no specific antidote for quetiapine. In case of severe intoxication, the need for multi-directional measures should be considered and intensive care procedures are recommended, including the restoration and maintenance of airway patency, ensuring adequate oxygenation and ventilation of the lungs, monitoring and support of the cardiovascular system.
Careful medical supervision and monitoring should continue until the patient recovers completely.
Adverse reactions
Nervous system: dizziness, drowsiness (may occur in the first two weeks of treatment and usually disappears with prolonged use), headache, extrapyramidal symptoms, loss of consciousness, convulsions, restless legs syndrome, dysarthria, dyskinesia.
On the part of the digestive system: dry mouth, constipation, dyspepsia, dysphagia.
From the blood and lymphatic system: leukopenia, eosinophilia, thrombocytopenia, neutropenia.
On the part of the organs of vision: blurred vision.
Cardiovascular system: cardiac arrhythmias, tachycardia, orthostatic hypotension (especially at the beginning of treatment).
Respiratory system: rhinitis.
Immune system disorders: hypersensitivity, anaphylactic reaction.
From the hepatobiliary system: hepatitis.
Reproductive system and breast disorders: priapism.
Metabolic: very rarely - exacerbation of diabetes mellitus.
Skin: Stevens-Johnson syndrome, angioedema.
General disorders: withdrawal symptoms (discontinuation of the drug), mild asthenia, weight gain (occurs mainly during the first weeks of treatment), peripheral edema, neuroleptic malignant syndrome.
Changes in laboratory parameters: increased serum transaminase levels (ALT, AST), decreased neutrophil count, increased blood glucose to hyperglycemic levels, increased gamma-GT levels, increased non-fasting serum triglyceride levels, increased total cholesterol, increased creatine phosphokinase levels.
Quetiapine treatment has been associated with a small dose-related decrease in thyroid hormone levels, particularly total T4 and free T4. The decrease in total and free T4 was maximal within the first two to four weeks of quetiapine treatment, with no further decrease during long-term treatment. In almost all cases, discontinuation of treatment resulted in recovery of total and free T4 levels, regardless of the duration of treatment. Smaller decreases in total T3 and circulating T3 were observed only at higher doses. Thyroxine-binding globulin (TBG) levels remained unchanged and generally no corresponding increases in thyroid-stimulating hormone (TSH) were observed.
Like other antipsychotics, Quetiapine may cause prolongation of the QTc interval.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 ºС.
Keep out of reach of children.
Packaging
10 tablets in a blister, 3 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Actavis Ltd./Actavis Ltd.
Location of the manufacturer and address of its place of business
BLB 016, Bulebel Industrial Estate, Zejtun ZTN 3000, Malta / BLB 016, Bulebel Industrial Estate, Zejtun ZTN 3000, Malta.
Applicant
CJSC “Farmlyga”, Republic of Lithuania/UAB “Farmlyga”, Republic of Lithuania.
Applicant's location
Meistru str. 9, Vilnius, LT-02189, Republic of Lithuania.
