Laquel (Tablets) Instructions for Use

Marketing Authorization Holder

Pliva Hrvatska, d.o.o. (Croatia)

ATC Code

N05AH04 (Quetiapine)

Active Substance

Quetiapine (Rec.INN registered by WHO)

Dosage Forms

	Laquel	Combi-pack: film-coated tablets 25 mg: 6 pcs.; film-coated tablets 100 mg: 3 pcs.; film-coated tablets 200 mg: 1 pcs.
		Film-coated tablets, 25 mg: 60 pcs.
		Film-coated tablets, 100 mg: 60 pcs.
		Film-coated tablets, 200 mg: 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pink with a brownish tint, round, biconvex, with debossed inscriptions “QE” on one side and “25” on the other; on the cross-section – a homogeneous mass of white or almost white color.

Excipients : lactose monohydrate – 7.24 mg, microcrystalline cellulose – 8.776 mg, calcium hydrogen phosphate dihydrate – 4.2 mg, hypromellose – 2.4 mg, sodium starch glycolate – 4.2 mg, talc – 2.9 mg, colloidal silicon dioxide – 0.9 mg, magnesium stearate – 0.6 mg.

Film coating composition Opadry II pink 31F34566 – 1.8 mg (lactose monohydrate – 36%, hypromellose – 28%, titanium dioxide – 23.7%, macrogol 4000 – 10%, sunset yellow FCF aluminum lake – 1.3%, red iron oxide – 1%).

10 pcs. – blisters (6) – carton packs.

Film-coated tablets yellow with a brownish tint, round, biconvex, with debossed inscriptions “QE” on one side and “100” on the other; on the cross-section – a homogeneous mass of white or almost white color.

Excipients : lactose monohydrate – 28.96 mg, microcrystalline cellulose – 35.104 mg, calcium hydrogen phosphate dihydrate – 16.8 mg, hypromellose – 9.6 mg, sodium starch glycolate – 16.8 mg, talc – 11.6 mg, colloidal silicon dioxide – 3.6 mg, magnesium stearate – 2.4 mg.

Film coating composition Opadry II yellow 31F32561 – 7.2 mg (lactose monohydrate – 36%, hypromellose – 28%, titanium dioxide – 23.18%, macrogol 4000 – 10%, yellow iron oxide – 2.82%).

10 pcs. – blisters (6) – carton packs.

Film-coated tablets white, round, biconvex, with debossed inscriptions “QE” on one side and “200” on the other; on the cross-section – a homogeneous mass of white or almost white color.

Excipients : lactose monohydrate – 57.92 mg, microcrystalline cellulose – 70.208 mg, calcium hydrogen phosphate dihydrate – 33.6 mg, hypromellose – 19.2 mg, sodium starch glycolate – 33.6 mg, talc – 23.2 mg, colloidal silicon dioxide – 7.2 mg, magnesium stearate – 4.8 mg.

Film coating composition Opadry II white OY-L-28900 – 14.4 mg (lactose monohydrate – 36%, hypromellose – 28%, titanium dioxide – 26%, macrogol 4000 – 10%).

10 pcs. – blisters (6) – carton packs.

Combi-pack contains one blister of each dosage strength

Blisters (3) – carton packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic (neuroleptic) agent

Pharmacological Action

An atypical antipsychotic drug (neuroleptic) that interacts with various types of neurotransmitter receptors. It exhibits higher affinity for serotonin receptors (5-HT₂) than for dopamine receptors (D₁ and D₂) in the brain. It also has higher affinity for histamine and α₁-adrenergic receptors and lower affinity for α₂-adrenergic receptors. No significant affinity of quetiapine for muscarinic cholinergic receptors and benzodiazepine receptors has been found.

Quetiapine causes a selective reduction in the activity of mesolimbic A10 dopaminergic neurons compared to A9 nigrostriatal neurons involved in motor function. It does not cause a sustained increase in plasma prolactin concentration. Clinical studies have shown effectiveness against both positive and negative symptoms of schizophrenia.

The effect of quetiapine on 5-HT₂ and D₂ receptors lasts up to 12 hours after administration.

Pharmacokinetics

Absorption and Distribution

When taken orally, Quetiapine is well absorbed from the gastrointestinal tract. Food intake does not significantly affect the bioavailability of quetiapine. Approximately 83% of quetiapine is bound to plasma proteins.

Metabolism

It is actively metabolized in the liver. The main metabolites found in plasma do not have significant pharmacological activity. CYP3A4 has been identified as the key enzyme for cytochrome P450-mediated metabolism of quetiapine.

Quetiapine and some of its metabolites have weak inhibitory activity against cytochrome P450 enzymes 1A2, 2C9, 2C19, 2D6, and 3A4, but only at concentrations 10-50 times higher than those observed at the usual effective dose of 300-450 mg/day.

Excretion

T_1/2 is about 7 hours. Approximately 73% of the administered dose of quetiapine is excreted by the kidneys and 21% by the intestines, with less than 5% of quetiapine excreted unchanged by the kidneys or intestines.

Pharmacokinetics in Special Clinical Cases

The pharmacokinetics of quetiapine are linear, with no differences in pharmacokinetic parameters between men and women.

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

The average plasma clearance of quetiapine in patients with severe renal impairment and in patients with liver disease (stabilized alcoholic cirrhosis) is reduced by approximately 25% (CrCl less than 30 ml/min/1.73 m²), but individual clearance values are within the range corresponding to healthy individuals.

Indications

• Schizophrenia;
• Moderate to severe manic episodes in the structure of bipolar disorder. Does not prevent the development of manic and depressive episodes.

ICD codes

Dosage Regimen

Take orally twice a day, regardless of meals.

Treatment of schizophrenia

The daily dose for the first 4 days of therapy is: Day 1 – 50 mg, Day 2 – 100 mg, Day 3 – 200 mg, Day 4 – 300 mg.

Starting from day 4, the dose is individually adjusted to achieve an effective dose, usually 300-450 mg/day. Depending on the clinical effect and individual patient tolerance, the dose can range from 150 to 750 mg/day.

The maximum recommended daily dose is 750 mg.

Treatment of manic disorders

The daily dose for the first 4 days of therapy is: Day 1 – 100 mg, Day 2 – 200 mg, Day 3 – 300 mg, Day 4 – 400 mg. Further, by day 6 of therapy, the daily dose of the drug can be increased to 800 mg. The daily dose increase should not exceed 200 mg/day.

Depending on the clinical effect and individual tolerance, the dose can range from 200 to 800 mg/day. The usual effective dose is from 400 to 800 mg/day.

The maximum recommended daily dose is 800 mg/day.

In elderly patients the initial dose is 25 mg/day. The dose should be increased daily by 25-50 mg until an effective dose is reached, which is usually lower than in young patients.

In renal and/or hepatic impairment it is recommended to start therapy with a dose of 25 mg/day followed by a daily increase of 25-50 mg until an effective dose is reached.

Adverse Reactions

Definition of adverse reaction frequency: very common (>1/10), common (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare – (>1/10,000 and <1/1000), very rare (<1/10,000).

From the central nervous system: very common – dizziness, drowsiness, headache; common – syncope; uncommon – seizures; rare – tardive dyskinesia; with unknown frequency anxiety, hostility, agitation, insomnia, akathisia, tremor, depression, paresthesia occur.

From the cardiovascular system: common – tachycardia, orthostatic hypotension, cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis.

From the respiratory system: pharyngitis, rhinitis.

From the digestive system: common – dry mouth, constipation, dyspepsia; rare – jaundice, nausea, vomiting, abdominal pain; very rare – hepatitis.

From the hematopoietic system: common – leukopenia; uncommon – eosinophilia; very rare – neutropenia.

Laboratory parameters: common – increased activity of serum transaminases (ALT, AST); uncommon – increased GGT activity; increased serum concentrations of total cholesterol and triglycerides.

From the endocrine system: very rare – hyperglycemia, diabetes mellitus.

Allergic reactions: uncommon – hypersensitivity, angioedema, Stevens-Johnson syndrome, skin rash.

From the reproductive organs: rare – priapism.

Other: common – moderate asthenia, edema, weight gain; rare – back pain, chest pain, low-grade fever, myalgia, dry skin, blurred vision.

During treatment with quetiapine, a small dose-dependent decrease in the level of thyroid hormones is observed, in particular total and free T4. The maximum decrease in total and free T4 was recorded during the first 2-4 weeks of quetiapine therapy, with no further decrease in hormone levels during long-term treatment. There were no signs of clinically significant changes in the concentration of thyroid-stimulating hormone.

In almost all cases, the levels of total and free T4 returned to baseline after discontinuation of quetiapine therapy, regardless of the duration of treatment.

Quetiapine, like other antipsychotic drugs, can cause QT interval prolongation, but clinical studies have not revealed a relationship between quetiapine use and persistent QT interval prolongation.

Upon abrupt withdrawal of the drug, cases of withdrawal syndrome have been recorded, accompanied by nausea, vomiting; rarely – insomnia.

Contraindications

• Concomitant use of cytochrome P450 3A4 inhibitors (e.g., HIV protease inhibitors, azole antifungals, erythromycin, clarithromycin, nefazodone);
• Childhood (efficacy and safety not established);
• Pregnancy (efficacy and safety not established);
• Lactation period (efficacy and safety not established);
• Hypersensitivity to the components of the drug.

With caution the drug should be prescribed for arterial hypotension, heart failure, cardiac hypertrophy, cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, in elderly patients, with hepatic insufficiency, epilepsy, history of seizures, with concomitant use of drugs that prolong the QT interval, in patients with congenital QT interval prolongation or family predisposition to its prolongation, with hypocalcemia, hypomagnesemia, in the presence of risk factors for the development of venous thromboembolism.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation, because the efficacy and safety of its use during these periods have not been established.

Use in Hepatic Impairment

With caution the drug should be prescribed for hepatic insufficiency.

Use in Renal Impairment

In renal impairment it is recommended to start therapy with a dose of 25 mg/day followed by a daily increase of 25-50 mg until an effective dose is reached.

Pediatric Use

Contraindication: childhood (efficacy and safety not established).

Geriatric Use

In elderly patients the initial dose is 25 mg/day. The dose should be increased daily by 25-50 mg until an effective dose is reached, which is usually lower than in young patients.

Special Precautions

Orthostatic hypotension may be observed during the initial dose titration period. In this case, one should return to the previously taken dose. Special attention should be paid to patients with cardiovascular diseases, cerebrovascular diseases and other conditions predisposing to arterial hypotension.

Antipsychotic agents (neuroleptics), including Quetiapine, contribute to the development of thromboembolic complications in patients predisposed to thrombosis. Before starting therapy with quetiapine, it is necessary to identify all possible risk factors for the development of venous thromboembolism and take appropriate measures to prevent the development of thromboembolic complications.

No relationship has been identified between taking the drug as recommended and QT interval prolongation. However, QT interval prolongation was noted with drug overdose. Caution is required when prescribing quetiapine concomitantly with drugs that prolong the QTc interval, especially in the elderly, in patients with congenital long QT syndrome, heart failure, cardiac hypertrophy, hypocalcemia or hypomagnesemia, and in the presence of a family history of QT interval prolongation.

Should be used with caution in combination with other drugs that have a depressant effect on the central nervous system, as well as alcohol.

Caution is required when treating patients with a history of seizures.

During treatment with quetiapine, neuroleptic malignant syndrome (NMS) may develop, the clinical manifestations of which include hyperthermia, altered mental status, muscle rigidity, autonomic nervous system instability, and increased CPK levels. In such cases, discontinuation of the drug and appropriate treatment are necessary.

The possibility of developing tardive dyskinesia with long-term use of quetiapine should also be considered. In this case, the dose of the drug should be reduced or its discontinuation considered.

Upon abrupt withdrawal of high-dose treatment, the following acute reactions (withdrawal syndrome) may be observed: nausea, vomiting, rarely insomnia. Exacerbation of symptoms of mental illness and the appearance of involuntary movement disorders (akathisia, dystonia, dyskinesia) are also possible. Therefore, it is recommended to discontinue the drug gradually.

Laquel is not intended for the treatment of patients suffering from psychoses accompanying senile dementia.

There is evidence of an increased risk of cerebrovascular complications in patients with senile dementia while using atypical neuroleptics.

Caution should be exercised when prescribing Laquel to patients with risk factors for stroke.

The drug Laquel contains lactose, therefore it should not be prescribed to patients with lactase deficiency or glucose and galactose malabsorption disorders.

Effect on ability to drive vehicles and operate machinery

The drug may cause drowsiness, therefore, during the treatment period, patients are not recommended to drive vehicles or work with hazardous machinery.

Overdose

Symptoms drowsiness and excessive sedative effect, tachycardia and decreased blood pressure.

Treatment there is no specific antidote. In cases of serious intoxication – symptomatic treatment (maintaining respiratory function, cardiovascular system, ensuring adequate oxygenation and ventilation). Careful medical supervision and monitoring are necessary until the patient fully recovers.

Drug Interactions

CYP3A4 is the key enzyme involved in the metabolism of quetiapine. When co-administered with drugs that have a strong inhibitory effect on the CYP3A4 isoenzyme (azole antifungals and macrolide antibiotics), the plasma concentration of quetiapine can significantly increase. For example, when quetiapine and ketoconazole are co-administered, an increase in the AUC of quetiapine by 5-8 times has been shown. For this reason, such drug combinations are contraindicated. Also, during treatment with Laquel, it is not recommended to consume grapefruit juice.

When Laqvel is co-administered with drugs that induce the hepatic enzyme system, such as carbamazepine or phenytoin, the plasma concentration of quetiapine decreases. The risk and benefit of co-administering Laqvel and hepatic enzyme inducers (besides those mentioned above, barbiturates, rifampicin) should be carefully weighed. An increase in the dose of Laqvel may be required, which should be carried out gradually; the possibility of replacing Laqvel with a drug that does not induce hepatic microsomal enzymes (for example, with valproic acid) should also be considered.

The pharmacokinetics of lithium preparations are not altered when co-administered with Laqvel.

Concomitant administration of the antipsychotic drugs risperidone or haloperidol does not significantly affect the pharmacokinetics of quetiapine. However, concomitant administration of thioridazine leads to an approximately 70% increase in the clearance of quetiapine.

The pharmacokinetics of quetiapine are not significantly altered by the concomitant use of cimetidine, which is an inhibitor of cytochrome P450 isoenzymes, or when administered together with imipramine or fluoxetine.

When Laqvel and valproic acid preparations were co-administered, their pharmacokinetic parameters did not change significantly.

Drugs that depress the central nervous system, as well as ethanol, increase the risk of side effects.

Caution should be exercised when prescribing Laqvel in combination with drugs that prolong the QT interval (neuroleptics, antiarrhythmic drugs, halofantrine, mesoridazine, thioridazine, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, dolasetron, mefloquine, sertindole, cisapride), as well as with drugs that cause electrolyte imbalance (thiazide diuretics).

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.