Pharmacological properties of the drug Ketilept
Pharmacodynamics. Quetiapine is an atypical antipsychotic drug that has an antagonistic effect on brain neurotransmitter receptors. Quetiapine has an affinity for serotonin (5HT1A and 5HT2), dopamine (D1 and D2), histamine (H1) and adrenergic (α1 and α2) receptors; higher affinity for 5HT2 receptors than for D1 and D2 receptors. Quetiapine also has a high affinity for histaminergic (H1) and α1-adrenergic receptors and a lower affinity for α2 receptors, while having no noticeable affinity for muscarinic cholinergic or benzodiazepine receptors. The mechanism of action of quetiapine, like other antipsychotic drugs, is unknown. Drowsiness during the action of quetiapine can be explained by its high affinity for histamine (H1) receptors. Similarly, orthostatic hypotension during quetiapine administration may be explained by its high affinity for α1-adrenergic receptors. Pharmacokinetics . After oral administration, quetiapine is rapidly absorbed into the gastrointestinal tract. The maximum concentration in blood plasma is observed after 1.5 hours. Food intake affects the bioavailability of quetiapine. Quetiapine is widely distributed in the body; its apparent volume is 10±4 l/kg. At therapeutic concentrations, 83% of the drug binds to blood plasma proteins. Clinical studies have shown that quetiapine is effective when used twice a day. Although the half-life of quetiapine is almost 7 hours, positron emission tomography data show that 5HT2 and D2 receptor occupancy is maintained for up to 12 hours after a single dose of quetiapine. Quetiapine is significantly metabolized in the liver; the main routes of its biotransformation are sulfonic oxidation and oxidation. In vitro , it has been shown that the main enzyme in the cytochrome P450-mediated metabolism of quetiapine is CYP 3A4. The main metabolites that are formed in the body do not have important pharmacological activity. After oral administration of a single dose of 14C-labeled quetiapine, ≤5% of the ingested amount is excreted unchanged; this indicates the deep metabolism of quetiapine. Approximately 73% of the radioactivity is excreted in urine and 21% in feces. The pharmacokinetics of quetiapine are linear over the therapeutic dose range and are not significantly affected by gender or race. The average clearance of quetiapine in elderly patients is approximately 30–50% lower than in adult patients aged 18–65 years. In severe renal failure (creatinine clearance ≤30 ml/min/1.73 m2) and liver failure (alcoholic cirrhosis), the average clearance of quetiapine is reduced by approximately 25%.
Ketilept tablets p/o 25 mg No. 10x3
Name
Ketilept tablet p/o 25 mg per bl. in pack №10x3
Description
White or off-white, round, biconvex, film-coated tablets, engraved with a stylized letter E on one side and the number 201 on the other side, with little or no odor.
Main active ingredient
Quetiapine
Release form
10 tablets in a blister made of PVC/PVDC/aluminum foil. 3 or 6 blisters are packed in a cardboard box along with instructions for medical use for patients.
Dosage
25 mg per bl. in pack №10x3
special instructions
When planning a diet, patients with lactose intolerance should take into account that each tablet of Ketilept 25 mg, 100 mg, 150 mg, 200 mg and 300 mg contains 4 mg, 16 mg, 24 mg, 32 mg, and 48 mg of lactose, respectively. If you have an intolerance to certain sugars, ask your doctor for advice before using this medicine.
Indications for use
Bipolar depression: a condition characterized by depressed mood, lack of energy, guilt, loss of appetite, or insomnia. Mania: a condition in which the patient feels overly "high", agitated, enthusiastic, inappropriately active, or incorrectly assessing the situation, including aggression and disruptive (destructive) behavior. Schizophrenia: a disorder characterized by hallucinations (where the patient hears or feels things that do not exist, believes in the reality of things that do not exist, or is overly suspicious, anxious, nervous, depressed, guilty, and confused. Your doctor may continue to prescribe Ketilept even if your condition improves, to prevent a recurrence of your symptoms. It may help if you tell a relative or close friend that you are suffering from these symptoms and ask them to read this leaflet. Ask them to tell you if your symptoms may get worse or if they notice changes in your behavior.
Directions for use and doses
Always take this medication exactly as directed by your doctor. If you are unsure, be sure to consult your doctor or pharmacist. Dosage regimen The procedure for taking Ketilept is determined by your doctor. Your doctor will prescribe you an appropriate starting dose, which may be increased later. Different dosage regimens are recommended for different indications. If you are prescribed the usually recommended dose, you may be prescribed 150 mg to 800 mg per day, depending on your condition and individual treatment needs. Directions for use: Take the tablets either once a day, before bed, or twice a day, depending on your disease. Swallow Ketilept tablets whole, without chewing, with water. Ketilept can be taken regardless of meals. Do not drink grapefruit juice while taking Ketilept as it may change the effectiveness of this drug. Do not stop taking Ketilept tablets until your doctor stops this drug, even if you feel better. Children and adolescents under 18 years of age Ketilept film-coated tablets should not be administered to children and adolescents under 18 years of age. Liver dysfunction If you have impaired liver function, your doctor may change the dose of the drug. Elderly patients If you are an elderly person, your doctor may change the dose of the drug. If you take too many Ketilept tablets If you take more Ketilept than prescribed, contact your doctor or the nearest hospital as soon as possible. Take these instructions and any remaining tablets with you to show your doctor. Symptoms of overdose: drowsiness, dizziness, and changes in heart rate are usually observed. If you forget to take one or more doses of Ketilept If you miss a dose, take it as soon as you remember. Do not take the missed dose at the same time or close to the next dose. After this, continue taking the drug in the regimen and doses prescribed by your doctor. Do not take a double dose to make up for a missed dose. If you stop taking Ketilept tablets Do not stop taking Ketilept, even if you feel better, until your doctor stops the drug. If you suddenly stop taking Ketilept, symptoms such as nausea, vomiting, insomnia, dizziness, headache, diarrhea or irritability may return; Your symptoms may also return. Your doctor may advise you to gradually reduce your dose before stopping the drug. If you have any further questions about the use of this medicine, ask your doctor or pharmacist.
Use during pregnancy and lactation
Pregnancy If you are pregnant, breastfeeding, think you are pregnant, or are planning to become pregnant, tell your doctor. You should not take Ketilept during pregnancy without first consulting your doctor. Newborns whose mothers took Ketilept during the third trimester of pregnancy (the last three months of pregnancy) may experience the following symptoms: trembling, muscle stiffness and/or weakness, drowsiness, agitation, breathing problems and difficulty feeding. If your child develops any of these symptoms, you should consult your doctor. Breastfeeding You should not take Ketilept if you are breastfeeding. Before taking any medications, consult your doctor.
Precautionary measures
Check with your doctor or pharmacist before starting to take Ketilept if: you or members of your family have or have had heart disease (for example, a significant increase in heart rate, a condition known as QT prolongation, or are using any medications that affect your heart rate; you have low blood pressure; you have had a stroke, especially if you are older; you or members of your family have had thrombosis (blood clots in the blood vessels), as these medicines can cause blood clots to form in the blood vessels You have a diseased liver You have ever had an epileptic seizure You have diabetes or have risk factors for diabetes (a family history of diabetes or high blood sugar during pregnancy) If this is the case, your doctor may Check your blood sugar levels while using Ketilept if you have developed pancreatitis (inflammation of the pancreas) or have risk factors for pancreatitis, such as gallstones or elevated triglycerides (a certain type of fat in your blood); You know that you have previously had a low white blood cell count, either due or not due to taking other medications; You are an older person with dementia (brain loss). If this is the case, you should not take Ketilept as the group of drugs that Ketilept belongs to may increase the risk of stroke or, in some cases, the risk of death in older patients with dementia; You have ever stopped breathing for a short time during a normal night's sleep (sleep apnea) and are taking medications that slow down the activity of the brain ("depressants"); You have now or in the past been unable to empty your bladder completely (urinary retention) if you have an enlarged prostate gland, a bowel obstruction or increased intraocular pressure. These conditions are usually caused by drugs called "anticholinergics." These drugs affect the function of nerve cells and are used to treat certain diseases. If you are referred to hospital, tell the medical staff that you are taking Ketilept. Tell your doctor immediately if you experience any of the following conditions while taking Ketilept: a combination of fever, severe muscle stiffness, sweating, and confusion (a condition called neuroleptic malignant syndrome). In this case, you will need immediate medical attention; uncontrolled movements, primarily of the face and tongue; dizziness or feeling very sleepy. In older patients, this may lead to falls; seizures; prolonged, painful erection (priapism). Such conditions can be caused by these types of drugs. Tell your doctor as soon as possible if you experience the following conditions during treatment with Ketilept: simultaneous development of fever, flu-like illness, sore throat or any other infection, as this may be due to a decrease in the number of white blood cells and require discontinuation of the drug Ketilept and/or treatment prescriptions; constipation with persistent abdominal pain or constipation that does not respond to treatment, as this can lead to the development of intestinal obstruction. Suicidal thoughts and worsening depression If you suffer from depression and/or anxiety, you may have thoughts of harming yourself. This condition may be more pronounced at the beginning of treatment with antidepressants, since these drugs do not begin to work immediately, usually taking two to three weeks, or maybe more, before they begin to act. You may be more likely to have these thoughts if: you have previously had thoughts of suicide or harming yourself; You are a young adult. Clinical trial results have identified an increased risk of suicidal behavior in adult patients younger than 25 years of age with psychiatric illness. If you have thoughts of suicide or harming yourself, contact your healthcare provider or go to the hospital immediately. It may help if you tell a relative or close friend that you are suffering from these symptoms and ask them to read this leaflet. Ask them to tell you if your symptoms may worsen or if they notice changes in your behavior. Weight gain Patients taking Ketilept have experienced an increase in body weight. You and your doctor should monitor your weight regularly. Children and adolescents under 18 years of age In children and adolescents, the safety and effectiveness of Ketilept have not been established. Ketilept is not intended for the treatment of children and adolescents under 18 years of age.
Interaction with other drugs
Tell your doctor or pharmacist about any medicines you are taking, have recently taken, or might take, including those taken without a prescription. Do not take Ketilept if you are taking the following medicines: certain medicines to treat HIV infection; drugs (azoles) for the treatment of fungal infections; erythromycin or clarithromycin (to treat infections); Nefadozone (for the treatment of depression). Tell your doctor if you are taking the following medicines: medicines used to treat epilepsy (phenytoin, carbamazepine); drugs for the treatment of high blood pressure; barbiturates (to treat insomnia); thioridazine or lithium (an antipsychotic); drugs that affect the heart, such as drugs that can change electrolyte balance (low potassium or magnesium levels), such as diuretics or certain antibiotics (drugs to treat infections); medications that may cause constipation; drugs called anticholinergics, which affect the function of the nervous system to treat certain diseases. Check with your doctor before stopping any medicine. Taking Ketilept tablets with food, drinks and alcohol Ketilept can be taken regardless of meals. While taking Ketilept, be careful with drinking alcoholic beverages, as combined use of alcohol with Ketilept may cause drowsiness. Do not drink grapefruit juice while taking Ketilept as it may change the effectiveness of this drug. Effect of Ketilept on drug tests If you have drug levels measured in your urine, using Ketilept may give a false positive result for methadone or tricyclic antidepressants (TCAs), even if you have not taken them. The test results should be confirmed with a more specific test.
Contraindications
If you are allergic to quetiapine or any of the other ingredients of this medicine listed in the section “What Quetiapine contains”. If you are taking one of the following drugs: HIV protease inhibitors to treat an infection AIDS drugs containing azole (to treat fungal infections) erythromycin, clarithromycin (antibiotics to treat infections) nefazodone (a drug to treat depression). Do not take this drug if the above information applies to you. If you are unsure, ask your doctor or pharmacist for advice.
Compound
Quetiapine fumarate, quetiapine Excipients: microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl starch (type A), povidone, magnesium stearate, colloidal anhydrous silicon dioxide. Shell composition: hypromellose, titanium dioxide, lactose monohydrate, macrogol 4000, triacetin (triacetylglycerol), iron oxide yellow, iron oxide red.
Side effect
Like all medicines, this drug can cause side effects, although not everyone gets them. Very common side effects (affects more than 1 in 10 patients): Dizziness (may cause falls), headache, dry mouth. Drowsiness (this may go away with continued use of Ketilept tablets) (may lead to falls). Increase in body weight. Withdrawal symptoms (symptoms that develop when you stop taking Ketilept) include nausea, vomiting, insomnia, dizziness, headache, irritability and diarrhea. You should stop taking Ketilept gradually over 1-2 weeks. Abnormal muscle movements, including difficulty initiating muscle movement, trembling, restlessness, or muscle stiffness without pain. Changes in the content of certain fats in the blood (triglycerides and total cholesterol). Common side effects (occur in 1-10 out of 100 patients): Fast heartbeat. Feeling of a strong, rapid heartbeat or skipped heartbeats. Constipation, indigestion. Weakness (can lead to falls). Swelling of the arms and legs. Low blood pressure when standing up, which can lead to dizziness or fainting (may lead to falls). Increased blood sugar levels. Deterioration of visual acuity. Nightmares and abnormal dreams. Increased feeling of hunger. Feeling irritable. Speech disorders. Suicidal thoughts and worsening depression. Immediately inform your doctor or go to the hospital! Dyspnea. Vomiting (mainly in elderly patients). Fever. Changes in the level of thyroid hormone in the blood. A decrease in the number of certain types of blood cells. Increased activity of liver enzymes (based on blood test results). Increased levels of the hormone prolactin (in rare cases, can cause swelling of the mammary glands, unexpected release of breast milk in men and women, and menstrual irregularities). Uncommon side effects (occur in 1-10 out of 1000 patients): Seizures. Allergic reactions with the appearance of spots on the skin that rise above the surface of the skin, swelling of the skin, swelling around the mouth. Unpleasant motor restlessness in the lower extremities (an irresistible need to move the extremities). Difficulty swallowing. Uncontrolled movements, mainly of the face and tongue. Sexual dysfunction. Diabetes. Abnormal conduction of electrical impulses in the heart (prolongation of the QT interval on the ECG). A slower than normal heart rate that may develop early in treatment, which can lead to low blood pressure and fainting. Difficulty passing urine. Fainting (may lead to falling). Stuffy nose. Decreased red blood cell count. Reducing sodium levels in the blood. Worsening of existing diabetes mellitus. Rare side effects (affect 1 to 10 in 10,000 patients): Fever, accompanied by sweating, muscle stiffness, severe drowsiness, and fainting (a condition called neuroleptic malignant syndrome). Yellow discoloration of the skin and sclera of the eyes (jaundice). Inflammation of the liver (hepatitis). Prolonged, painful erection (priapism). Swelling of the mammary glands with sudden release of milk in men and women. Menstrual irregularities. The appearance of blood clots in the veins, mainly of the lower extremities (symptoms include swelling, pain and redness of the extremity), which can travel through the blood vessels to the lungs, causing chest pain and difficulty breathing. If you notice any of these symptoms, contact your doctor immediately. Walking, talking or eating while sleeping. Decreased temperature (hypothermia). Inflammation of the pancreas, causing severe pain in the abdomen and back. A condition called metabolic syndrome, in which you may develop three or more of the following changes: increased fat tissue around your belly, low levels of good cholesterol (HDL), increased levels of triglycerides (fats) in the blood, high blood pressure and increased blood sugar levels. The simultaneous development of a fever, flu-like condition, sore throat, or any other infection, accompanied by a very low white blood cell count (a condition called agranulocytosis). Intestinal obstruction. Increased levels of creatine phosphokinase (a substance found in muscles). Very rare side effects (less than 1 in 10,000 patients): Severe skin rash, blisters/vesicles or red spots on the skin. A severe allergic reaction (anaphylaxis) that may cause difficulty breathing or shock. Rapidly developing swelling of the skin, usually around the eyes, lips or throat (angioedema). A serious condition with the appearance of blisters on the skin, mouth, around the eyes and genitals (Stevens Johnson syndrome). Abnormal production of a hormone that controls urine volume. Breakdown of muscle fibers and muscle pain (rhabdomyolysis). Frequency unknown (frequency cannot be determined from available data): Rash with irregularly shaped red dots on the skin (erythema multiforme). A serious, sudden allergic reaction with symptoms such as fever, blistering, and peeling of the skin (toxic epidermal necrolysis). Newborns whose mothers took Ketilept during pregnancy may develop withdrawal symptoms. The class of drugs that quetiapine belongs to can cause heart rhythm problems that can be serious and in some cases even fatal. The following side effects are only detected if blood has been tested: Changes in the levels of certain fats in the blood (increased levels of lipids - triglycerides and total cholesterol). Changes in blood sugar levels. Changes in the level of thyroid hormone in the blood. Increased liver enzyme levels. A decrease in the number of certain types of blood cells (such as white and red blood cells). Increased levels of creatine phosphokinase (a component of muscle). Decreased sodium levels in the blood. Increased prolactin levels (in rare cases, can cause swelling of the mammary glands, unexpected release of breast milk in men and women, and menstrual irregularities). Your doctor may order regular blood test monitoring. Additional side effects in children and teenagers Children and teenagers may experience the same side effects as adults. The following side effects have been observed more frequently in children and adolescents: Very common (affects more than 1 in 10 patients): Increased levels of the hormone prolactin in the blood: In rare cases, this may cause swelling of the mammary glands, unexpected release of breast milk in boys and girls. Menstrual irregularities (absence or irregular menstruation). Increased appetite. Vomit. Abnormal muscle movements, including difficulty initiating muscle movement, trembling, restlessness, or muscle stiffness without pain. Increased blood pressure. Common (occurs in 1-10 out of 100 patients): Feeling weak, fainting (can lead to falling). Stuffy nose. Irritability. Reporting side effects If you notice any of the listed side effects, including those not mentioned in this leaflet, please contact your doctor or pharmacist. By reporting side effects, you can help get more information about the safety of this medicine.
Storage conditions
Store at a temperature not exceeding 25°C. Keep out of the reach of children!
Use of the drug Ketilept
Ketilept should be taken 2 times a day with meals or regardless of meals. Adults. The total daily dose in the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4). Starting from the 4th day, the usual effective daily dose of Ketilept is 300 mg. Depending on the clinical response and tolerability of each patient, the dose can be adjusted between 150 and 750 mg/day. The safety of daily doses of 800 mg has not been assessed in clinical studies. For the treatment of acute manic episodes in bipolar disorders: the total daily dose in the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4). th day). From the 6th day, it is possible to increase the dose by no more than 200 mg/day until the maximum is reached (800 mg/day). Depending on the clinical response and tolerability of each patient, the dose can be adjusted ranging from 200 to 800 mg/day. The usual effective dose ranges from 400 to 800 mg/day. Elderly patients. Like other antipsychotic drugs, Ketilept should be used with caution in elderly patients, especially at the beginning of treatment. Elderly patients are recommended to first prescribe the drug at a dose of 25 mg/day, and then increase the dose by 25–50 mg/day until an effective dose is reached, which is usually lower than in young patients. In clinical studies, oral clearance of quetiapine may be reduced by 30–50% in patients aged ≥65 years, which may require dose adjustments. As in elderly patients, slow dose titration and reduced doses are recommended in debilitated patients or those susceptible to hypotensive reactions. Children and teenagers. The effectiveness and safety of quetiapine in children and adolescents has not been established. In case of renal dysfunction. Despite a 25% decrease in the clearance of quetiapine after oral administration of the drug in patients with severe renal failure (creatinine clearance 10–30 ml/min/1.73 m2), clinical studies have shown that in patients with normal renal function and patients with kidney diseases, plasma levels of the drug did not differ after taking equal doses of quetiapine. Therefore, there is no need to change the dose of Ketilept. Liver dysfunction. Quetiapine is significantly metabolized in the liver; its clearance in patients with liver disease is 25% lower than in patients with normal liver function. Therefore, if liver dysfunction is diagnosed, especially at the beginning of the course of treatment, it may be necessary to change the dose of the drug. It is recommended to start treatment with 25 mg of the drug per day, then increase the dose by 25–50 mg every day until an effective dose is reached, depending on the patient’s clinical response and individual tolerance. Maintenance therapy. Despite the lack of sufficient data on the possible duration of treatment with quetiapine in patients with schizophrenia, the effectiveness of maintenance therapy with other antipsychotic drugs has been established. Therefore, it is recommended to continue taking Ketilept to such patients; To maintain remission, it is advisable to use the lowest dose. Patients should be periodically assessed to determine the need for maintenance therapy. Resumption of an interrupted course of treatment in patients previously treated with quetiapine. If it is necessary to restart treatment with Ketilept in patients who have previously interrupted quetiapine therapy, the following is recommended: when resuming therapy less than 1 week after discontinuation of Ketilept, the drug can be continued at the dose used for maintenance therapy. When resuming therapy in patients who have not received Ketilept for 1 week, the rules for initial dose selection should be followed and the effective dose should be determined based on the patient’s clinical response. Transition from therapy with other antipsychotic drugs. There are no data on the specifics of switching from other antipsychotic drugs to quetiapine, as well as on the combined use of quetiapine with other antipsychotic drugs. Although some people with schizophrenia can be stopped immediately from the antipsychotic they are taking, most patients need to be tapered off gradually. In all cases where switching from one drug to another requires the simultaneous use of 2 antipsychotic drugs, this period of combined use should be reduced if possible. When transferring patients with schizophrenia from long-acting antipsychotic drugs to Ketilept, its use should be started at the time of the next scheduled dose. The need for continued therapy with a drug intended to treat the extrapyramidal side effects of a previous long-acting antipsychotic should be periodically assessed.
Ketilept, 300 mg, film-coated tablets, 60 pcs.
Inside
, regardless of food intake.
For adults.
Acute and chronic psychoses, including schizophrenia:
the drug is prescribed 2 times a day. The total daily dose in the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4).
Starting from the 4th day, the usual effective daily dose of Ketilept® is from 300 to 450 mg/day.
Depending on the clinical effect and tolerability in each patient, the dose can be selected (varied) from 150 to 750 mg/day. The maximum recommended daily dose is 750 mg.
For the treatment of acute manic episodes in bipolar disorder:
the drug is prescribed 2 times a day. The total daily dose in the first 4 days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4).
Further selection of the dose up to 800 mg/day by the 6th day is possible with an increase of no more than 200 mg/day. Depending on the clinical response and tolerability of each patient, the dose can be adjusted to range from 200 to 800 mg/day. The usual effective dose ranges from 400 to 800 mg/day. The maximum recommended daily dose is 800 mg/day.
For the treatment of depressive episodes in bipolar disorder:
Ketilept® is prescribed once a day at night. The daily dose in the first 4 days of therapy is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3), 300 mg (day 4). The recommended dose is 300 mg/day. The maximum recommended daily dose is 600 mg/day.
Elderly patients.
The recommended starting dose is 25 mg per day, and then the dose should be increased by 25-50 mg per day until an effective dose is reached, which is usually lower than in younger patients. Likewise, more cautious dose selection and reduced dosages are recommended for patients who are debilitated or predisposed to hypotensive reactions.
Children and teenagers.
The effectiveness and safety of quetiapine in children and adolescents has not been established.
Kidney and liver failure.
It is recommended to initiate therapy with 25 mg/day, then increase the dose daily by 25–50 mg until an effective dose is achieved, depending on the patient's clinical response and individual tolerance.
Maintenance therapy.
To maintain remission, it is advisable to use the lowest dose. Patients should be periodically assessed to determine the need for maintenance therapy.
Resumption of an interrupted course of treatment in patients previously treated with quetiapine
. When resuming therapy less than 1 week after discontinuation of the drug Ketilept®, the drug can be continued at a dose adequate for maintenance therapy. When resuming therapy in patients who have not received Ketilept® for more than 1 week, the rules for initial dose selection should be followed and the effective dose should be set based on the patient’s clinical response.
Side effects of the drug Ketilept
The most common side effects: drowsiness, dizziness, dry mouth, asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia. As with therapy with other antipsychotic drugs, loss of consciousness, neuroleptic malignant syndrome, leukopenia, neutropenia and peripheral edema were observed while taking quetiapine. Side effects classified by body system occurred: very often (1/10); often (≤1/10 and 1/100); sometimes (≤1/100 and 1/1000); rare (≤1/1000); very rare (≤1/10,000). Blood and lymph system: often - leukopenia; sometimes - eosinophilia; very rarely - neutropenia. Immune system disorders: sometimes - hypersensitivity reactions. Metabolism: often - increase in body weight, increase in serum transaminases (ALAT, AST); very rarely - hyperglycemia, diabetes mellitus. Dysfunction of the nervous system: very often - dizziness, drowsiness; often - loss of consciousness; sometimes - epileptic seizures. Cardiac dysfunction: often - tachycardia. Vascular disorders: often - orthostatic hypotension. Impaired breathing and functions of the thoracic cavity and mediastinum : often - rhinitis. Gastrointestinal dysfunction: often - dry mouth, constipation, dyspepsia. Dysfunction of the reproductive organs and mammary glands: rarely - priapism. General disorders and tissue condition at the injection site: often - mild asthenia, peripheral edema; rarely - neuroleptic malignant syndrome. Laboratory tests : sometimes - increased levels of gamma GT5, triglycerides after meals, increased total cholesterol. Treatment with Ketilept was associated with a small dose-dependent decrease in thyroid hormone levels, namely total T4 and free T4. The maximum decrease in total and free T43 was recorded during the first 2–4 weeks of quetiapine therapy, without further decrease in hormone levels during prolonged treatment. In almost all cases, cessation of treatment resulted in a restoration of total T4 and free T4 levels, regardless of the duration of treatment. A slight decrease in total T3 was observed only at high doses. The level of thyroxine-binding globulin did not change and, accordingly, no increase in TSH levels was observed. No signs of hypothyroidism were observed while taking Ketilept. Like other antipsychotics, quetiapine may cause QTc prolongation. Reactions to sudden drug withdrawal have also been described.
KETILEPT
Side effects
The most common side effects of quetiapine are drowsiness, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.
According to summary data from clinical studies, the number of patients who stopped taking the drug due to side effects was approximately the same in the groups receiving placebo and quetiapine. As with other antipsychotics, syncope, neuroleptic malignant syndrome, leukopenia, neutropenia and peripheral edema have been reported during use of quetiapine.
Adverse events observed with the administration of quetiapine and classified by body system are listed below in this order: very common (> 1/10); frequent (<1/10 and >1/100); uncommon (<1/100 and >1/1000); rare (<1/1000); very rare (<1/10,000).
Blood and lymph system
Common: leukopenia3. Uncommon: eosinophilia. Very rare: neutropenia3.
Immune system disorders
Uncommon: hypersensitivity.
Metabolism and nutrition
Frequent: increase in body weight4, increase in serum transaminases (ALT, AST)5. Very rare: hyperglycemia1,7, diabetes mellitus1,7.
Nervous system dysfunction
Very common: dizziness1,6, drowsiness2. Frequent: headache, anxiety, psychomotor agitation, tremor, fainting1,6. Uncommon: epileptic seizures1.
Cardiac dysfunction
Frequent: tachycardia1,6.
Vascular disorders
Common: orthostatic hypotension1,
6.
Disorders of breathing and functions of the thoracic cavity and mediastinum
Frequent: rhinitis, pharyngitis.
Gastrointestinal tract dysfunctions
Common: dry mouth, constipation, diarrhea, dyspepsia, abdominal pain.
Disorders of the functions of the reproductive organs and mammary glands
Rare: priapism.
General disorders and tissue condition at the injection site
Frequent: mild asthenia, peripheral edema. Rare: neuroleptic malignant syndrome1.
Laboratory research
Uncommon: increased gamma GT5 levels, increased postprandial triglyceride levels, increased total cholesterol.
Others
Lower back pain, chest pain, low-grade fever, myalgia, dry skin, decreased visual acuity.
(1) See section "Special instructions and precautions for use."
(2) Drowsiness may occur, especially during the first two weeks of treatment, which usually resolves with continued use of Ketilept®.
(3) There were no cases of sustained severe neutropenia or agranulocytosis in controlled clinical studies of quetiapine. During the observation period after registration of the drug, leukopenia and/or neutropenia resolved after discontinuation of quetiapine administration. Possible risk factors for leukopenia and/or neutropenia include a pre-existing low white blood cell count and a history of drug-induced leukopenia and/or neutropenia.
(4) Increase in body weight is mainly observed in the first weeks of treatment.
(5) Some patients have experienced asymptomatic increases in serum transaminases (ALT, AST) or gamma-GT during quetiapine administration. These increases usually resolved with continued administration of quetiapine.
(6) Like other antipsychotics with alpha-1-blocking activity, Ketilept® may cause orthostatic hypotension with dizziness, tachycardia and (in some patients) syncope, especially during the initial dosage period. See section 4.4 "Special instructions and precautions for use."
(7) In very rare cases, hyperglycemia and worsening of pre-existing diabetes have been reported while taking quetiapine.
Quetiapine has been associated with a low-dose induced decrease in thyroid hormone levels (T4 and free T4). The maximum reduction occurred during the first two to four weeks of taking quetiapine, but no further reduction occurred with a long course of treatment. In almost all cases, discontinuation of quetiapine resulted in restoration of T4 and free T4 levels, regardless of the duration of treatment.
Less significant reductions in T3 and reverse T3 were observed only at higher doses of quetiapine. Levels of TSH and TSH (thyroxine-binding globulin) remained unchanged.
No clinically significant hypothyroidism was detected.
Like other antipsychotics, quetiapine may cause QTc prolongation, but this effect was not consistent in clinical trials.
Reactions to sudden drug withdrawal have been described (see Special Instructions).
Special instructions for the use of the drug Ketilept
Ketilept should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions that lead to hypotension. Ketilept may cause orthostatic hypotension, especially during the initial dose adjustment period; this is more common in older patients than in younger patients. Like other antipsychotic drugs, Ketilept is prescribed with caution to patients who have a history of epileptic seizures; under these conditions, the drug can significantly reduce the seizure threshold (for example, in Alzheimer's disease or in people aged 65 years). Ketilept, like other antipsychotics, can cause tardive dyskinesia with prolonged use. If signs and symptoms of tardive dyskinesia occur, dose reduction or discontinuation of Ketilept should be considered. Neuroleptic malignant syndrome is a potentially dangerous condition that occurs very rarely during treatment with antipsychotic drugs. Its clinical manifestations include increased temperature, changes in mental state, muscle rigidity, instability of autonomic functions (fluctuations in heart rate and blood pressure, sweating, arrhythmia), as well as increased CPK levels. In such cases, Ketilept should be discontinued and appropriate therapy should be prescribed. Acute withdrawal symptoms, including nausea, vomiting, and insomnia, are very rarely described after abrupt cessation of high-dose antipsychotic medications. Relapses of symptoms of psychosis and the appearance of disorders associated with involuntary movements (akathisia, dystonia and dyskinesia) are possible. Therefore, if it is necessary to stop taking the drug, a gradual dose reduction is recommended. When preparing a diet for patients with lactose intolerance, it should be taken into account that film-coated tablets contain lactose, respectively 4.42; 17.05 and 34.1 mg. This drug should not be used in patients with hereditary galactose intolerance, hereditary lactase deficiency, or glucose-galactose malabsorption syndrome. The ability to influence reaction speed when driving vehicles or working with other mechanisms. Due to its effect on the central nervous system, Ketilept may reduce the level of attention of patients. Therefore, in the first stages of treatment, for an individually determined period of time, the patient should be prohibited from driving motor vehicles or dangerous mechanisms. In the future, the degree of restrictions should be set for each patient individually.
Instructions for use KETILEPT®
Since quetiapine has several indications for use, its safety profile should be considered in relation to each patient's diagnosis and dosage of the drug.
Children and adolescents aged 10 to 18 years
Quetiapine is not recommended for children and adolescents under 18 years of age due to the lack of data supporting the use of quetiapine in this age group. In clinical studies with quetiapine, it was found that in addition to the known safety profile established in adults (see section Side effects), some side effects occurred with a higher frequency in children and adolescents compared to adult patients (increased appetite, increased prolactin levels serum, vomiting, rhinitis and syncope), and some side effects have variable significance in children and adolescents (eg, extrapyramidal symptoms and irritability), and one side effect has not previously been observed in clinical trials in adults (increased blood pressure).
Changes in thyroid function test results have also been observed in children and adolescents.
In addition, studies examining the effects of long-term use of quetiapine on growth and development did not exceed 26 weeks. The effect of long-term use of quetiapine on cognitive function and behavior is also unknown.
In placebo-controlled studies in children and adolescents with schizophrenia or manic bipolar disorder, quetiapine was shown to increase the incidence of extrapyramidal symptoms (EPS) compared with placebo (see Adverse Reactions section).
Suicide, suicidal ideation, or worsening clinical condition
Depression in bipolar disorder is associated with an increased risk of suicidal ideation, self-harm, and suicide risk. This risk persists until significant remission occurs. Since improvement may not occur during the first weeks, and possibly for a longer period, patients should be carefully monitored until improvement occurs. Clinical experience also suggests that suicide risk may increase early in the course of improvement.
In addition, clinicians should consider the possible risk of suicide following sudden discontinuation of quetiapine due to known risk factors for the disease being treated with quetiapine.
Other psychiatric disorders for which quetiapine is prescribed may also increase the risk of suicide. Moreover, these disorders may be comorbid with a major depressive episode. Therefore, the same precautions should be taken when treating patients with other psychiatric disorders as when treating patients with a major depressive episode.
Patients with a history of suicidal ideation or behavior, as well as those with significant suicidal ideation before treatment, are at increased risk for suicidal ideation and suicide attempts and should therefore be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders found an increased risk of suicidal behavior when comparing groups of patients receiving antidepressants compared with placebo in patients aged <25 years.
In the early stages of treatment, as well as after changing the dose of the drug, patients, especially those at risk, should be closely monitored.
Patients (and caregivers) should be warned to monitor for clinical worsening, suicidal behavior or ideation, or unusual changes in behavior, and to seek medical attention if these symptoms occur.
In shorter-term, placebo-controlled clinical trials of patients with major depressive episode due to bipolar disorder, an increased risk of suicide-related events was observed in young adult patients <25 years of age receiving quetiapine compared with those receiving placebo (3.0% vs 0). % respectively).
Misuse and Abuse
There have been reports of misuse or abuse. Caution should be exercised when prescribing quetiapine to patients with a history of alcoholism or drug abuse.
Risk of developing metabolic disorders
Based on the observed risk of worsening the metabolic profile in clinical studies, including changes in body weight, changes in lipids and blood glucose (hyperglycemia), metabolic parameters should be monitored at the start of treatment, and changes in these parameters should be monitored regularly as treatment progresses. Deterioration of these parameters should be adjusted based on clinical need (see section Side effects).
Extrapyramidal symptoms
In placebo-controlled clinical trials in adult patients, an increased incidence of extrapyramidal symptoms (EPS) was found compared with placebo in patients treated for major depressive episodes in bipolar disorders (see sections Side effects and Pharmacological effects).
The use of quetiapine has been associated with the development of akathisia with a subjectively unpleasant or depressing restlessness, a need to move, often accompanied by an inability to stand or sit quietly. These symptoms are more likely to develop during the first weeks of treatment. In patients with these symptoms, increasing the dose may harm them.
Tardive dyskinesia
If signs and symptoms of tardive dyskinesia develop, dose reduction or discontinuation of Ketilept® should be considered. Symptoms of tardive dyskinesia may worsen or appear for the first time when treatment is stopped (see Side effects section).
Drowsiness and dizziness
An association has been found between the use of quetiapine and drowsiness or related symptoms (eg, sedation) (see Adverse Reactions section). In clinical studies involving patients with bipolar depression, these symptoms developed during the first three days of treatment, and their intensity was generally mild or moderate. Patients with bipolar disorder who develop severe, severe sleepiness may need more frequent contact with their doctor for at least 2 weeks after the onset of sleepiness.
Orthostatic hypotension
Quetiapine may cause orthostatic hypotension and associated dizziness (see section Side effects), especially at the initial stage of dose selection; it occurs more often in older patients than in younger patients. This may increase the risk of accidental falls, especially in older patients, compared to younger ones. For patients with cardiovascular disease, a dose reduction or slower individual dose titration is recommended. Therefore, patients are advised to exercise caution before determining the effect of the drug on their body.
Cardiovascular diseases
Ketilept® should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or other conditions predisposing to hypotension. Quetiapine may cause orthostatic hypotension, especially during the initial dose titration period, so a dose reduction or slower dose titration should be considered. Slower dose titration is recommended in patients with cardiovascular disease.
Sleep apnea syndrome
Sleep apnea syndrome has been observed in patients receiving quetiapine. Quetiapine should be administered with caution to patients taking other medicinal products that inhibit the central nervous system and who currently have or have had a history of sleep apnea (eg, weight gain/obesity, male patients).
Epileptic seizures
In controlled clinical trials, no differences were found in the frequency of epileptic seizures in patients receiving quetiapine or placebo. There are no data on the frequency of seizures in patients with a history of seizures. As with other antipsychotic drugs, caution should be exercised when treating patients with a history of epileptic seizures (see Side Effects section).
Neuroleptic malignant syndrome (NMS)
Neuroleptic malignant syndrome can occur during treatment with antipsychotic drugs, including quetiapine (see section Side effects). Its clinical manifestations include fever, changes in mental status, muscle rigidity, instability of autonomic functions (inconsistent heart rate and blood pressure, sweating, arrhythmia), as well as increased levels of creatine phosphokinase. In such cases, Ketilpet® should be discontinued and appropriate drug therapy should be prescribed.
Severe neutropenia and agranulocytosis
Severe neutropenia (neutrophil count <0.5 x 109/L) was observed in clinical studies with quetiapine. Most cases of severe neutropenia developed within several months of starting treatment with quetiapine. There is no obvious dose dependence of this effect. Based on post-marketing experience, some cases have been fatal. Possible risk factors for the development of neutropenia include a history of low white blood cell count or neutropenia caused by other drugs. If the neutrophil count decreases to <1.0 x 109/L, quetiapine should be discontinued. Patients should be monitored for signs and symptoms of infection and neutrophil levels monitored until they exceed 1.5 x 109/L (see Side Effects and Pharmacological Actions).
The possibility of developing neutropenia should be considered in patients with infection or fever, especially in the absence of predisposing factors, which requires appropriate treatment. Patients should be informed to report signs/symptoms of agranulocyotosis/infection (fever, weakness, lethargy, or sore throat). In such patients, it is necessary to immediately determine the number of leukocytes and the absolute number of neutrophils, especially in the absence of predisposing factors.
Anticholinergic (muscarinergic effects)
Norquetiapine, the active metabolite of quetiapine, has moderate to strong affinity for various muscarinic receptor subtypes. This predetermines the possibility of developing anticholinergic side effects when using quetiapine in recommended doses, when used together with other drugs that have anticholinergic properties, as well as in overdose. Quetiapine should be used with caution in patients concomitantly receiving other drugs with anticholinergic properties. Quetiapine should also be prescribed with caution to patients who have or have previously had urinary retention, clinically significant prostatic hypertrophy, intestinal obstruction or similar conditions, increased intraocular pressure or angle-closure glaucoma (see sections Drug interactions, Side effects, Overdose and Pharmacological effects).
Interactions
(see also section Drug interactions)
The use of quetiapine concomitantly with a strong hepatic enzyme inducer, such as carbamazepine or phenytoin, significantly reduces the plasma concentrations of quetiapine, which may affect the effectiveness of treatment with this drug. In patients receiving a liver enzyme inducer, treatment with Quetiapine should only be initiated if the physician determines that the benefits of quetiapine outweigh the risk of discontinuing the liver enzyme inducer. It is important that any change in inducer dosage be gradual and, if necessary, replaced with a non-inducer drug such as sodium valproate.
Body mass
Weight gain has been observed in patients receiving quetiapine; changes in body weight should be monitored and adjusted as a clinically important change, in accordance with available guidelines for the use of antipsychotic drugs (see sections Side effects and Pharmacological effects).
Hyperglycemia
Hyperglycemia or exacerbation of pre-existing diabetes, sometimes accompanied by the development of ketoacidosis or coma, sometimes fatal, have been described in rare cases (see section Side effects). In some cases, this was preceded by an increase in body weight, which can be considered as a predisposing factor. Appropriate clinical monitoring is recommended in accordance with available guidelines for the use of antipsychotic drugs. Patients receiving antipsychotic drugs, including quetiapine, should be monitored for the development of signs and symptoms of hyperglycemia (polydipsia, polyuria, polyphagia and weakness), and patients with diabetes, as well as patients at risk of developing diabetes mellitus, should be regularly monitored for worsening glycemic control. control.
Lipids
Increases in triglycerides, LDL and total cholesterol, as well as decreases in HDL cholesterol, were observed in clinical studies with quetiapine (see Side Effects section). Changes in lipid levels should be monitored and corrected as clinically significant.
QT prolongation
In clinical trials in which the drug was used in accordance with the instructions for medical use, the use of quetiapine was not associated with persistent prolongation of the QT interval. However, in post-registration studies, prolongation of the QT interval was observed in therapeutic doses (see section Side effects) and in overdose (see section Overdose). Just as when prescribing other antipsychotic drugs, caution should be exercised when prescribing quetiapine to patients with cardiovascular diseases, when combining quetiapine with drugs that increase the QT interval (including other antipsychotic drugs), especially in elderly patients, patients with congenital long QT syndrome, heart failure, cardiac hypertrophy, hypokalemia, hypomagnesemia and in patients with a family history of QT interval prolongation.
Cardiomyopathy and myocarditis
In clinical studies and with the use of quetiapine in the post-registration period, there have been reports of the development of cardiomyopathy and myocarditis, however, a causal relationship with quetiapine has not been established. The appropriateness of treatment with quetiapine in patients with cardiomyopathy and myocarditis should be analyzed.
Sudden withdrawal reactions
Acute withdrawal symptoms, including insomnia, nausea, vomiting, headache, diarrhea, dizziness, and irritability, have been described after abrupt discontinuation of high-dose antipsychotic medications. Therefore, if it is necessary to stop taking the drug, it is recommended to gradually reduce the dose over one to two weeks (see section Side effects).
Elderly patients with dementia-related psychosis
Quetiapine is not approved for use in patients with psychosis associated with dementia.
An approximately 3-fold increase in the risk of adverse cerebrovascular events was observed in randomized placebo-controlled trials in populations with dementia with the use of some atypical antipsychotics. The mechanism for this increased risk is unknown. An increased risk cannot be excluded also with the use of other antipsychotics or in other patient populations. In placebo-controlled studies using quetiapine, the incidence of cerebrovascular adverse events per 100 patient-years in the quetiapine group was not greater than that in the placebo group. Quetiapine should be used with caution in patients with risk factors for stroke.
A meta-analysis of atypical antipsychotics found that older patients with dementia-related psychosis had an increased risk of death compared with placebo.
However, in two 10-week placebo-controlled studies of quetiapine in the same patient population (n=710; mean age 85 years, range 56-99 years), mortality in the quetiapine group was 5.5% versus 3.2% in the placebo group. In these studies, patients died from many causes that would be expected in this population. These data do not allow us to establish a causal relationship between quetiapine use and death in elderly patients with dementia.
Dysphagia
Dysphagia (see Side Effects section) and aspiration have been observed during treatment with quetiapine. Ketilept® should be used with caution in patients at risk of developing aspiration pneumonia.
Constipation and intestinal obstruction
Constipation is a risk factor for intestinal obstruction. There have been reports of constipation and intestinal obstruction while taking quetiapine (see section Side effects). Deaths have been reported in patients at increased risk of intestinal obstruction, including those concomitantly receiving drugs that inhibit intestinal motility, who did not inform the doctor about the development of constipation. Patients with intestinal obstruction require close monitoring and emergency medical attention.
Venous thromboembolism
Cases of venous thromboembolism (VTE) have been observed during treatment with antipsychotic drugs. Due to the fact that patients receiving antipsychotic drugs had acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Ketilept® and preventive measures should be taken.
Pancreatitis
Pancreatitis has been observed both in clinical studies and in post-marketing experience. Despite the fact that in the post-registration period, risk factors were not identified in all cases, many patients had factors against which pancreatitis could develop:
- increased triglyceride levels (see section Special instructions), gallstones and alcohol consumption.
Additional Information
There are limited data on the use of quetiapine in combination with divalproex or lithium for moderate to severe episodes of mania. However, combination therapy was well tolerated (see sections Side effects and Pharmacological effects). These data revealed an additive effect at week 3.
Ketilept® contains lactose monohydrate
Since Ketilept® contains lactose monohydrate, this drug should not be prescribed to patients with rare hereditary disorders of galactose tolerance, hereditary lactose deficiency or glucose-galactose malabsorption syndrome.
Preclinical safety studies
In a series of in vitro
and
in vivo
no signs of genotoxicity were detected. The following abnormalities have not yet been confirmed in long-term clinical trials in laboratory animals at exposure levels achievable in clinical settings:
- Pigment deposition in the thyroid gland was observed in rats. In marmoset monkeys, follicular cell hypertrophy of the thyroid gland, a decrease in plasma T3 levels, a decrease in hemoglobin levels and the number of erythrocytes and leukocytes were found. Cases of lens opacities and cataracts have been reported in dogs.
Given all these data, the benefit of quetiapine treatment must be weighed against the safety risk to the patient.
Impact on the ability to drive vehicles and operate machinery
Due to its effect on the central nervous system, Ketilept® may reduce the level of wakefulness of patients. Therefore, in the first stages of treatment, for an individually determined period of time, patients should be advised to refrain from driving vehicles and working with dangerous mechanisms. In the future, the degree of restrictions should be set for each patient individually.
Drug interactions Ketilept
Ketilept should be prescribed with extreme caution in combination with other drugs that act on the central nervous system. The combined use of Ketilept with phenytoin leads to increased clearance of quetiapine from plasma when administered orally, since phenytoin induces cytochrome P450 isoenzyme 3A4. Due to the combination of quetiapine (250 mg 3 times a day) and phenytoin (100 mg 2 times a day), the average clearance of quetiapine after oral administration increased 5 times. To correct symptoms of schizophrenia in patients receiving concomitant quetiapine and phenytoin, an increase in the dose of Quetylept or other hepatic enzyme inducers (for example, carbamazepan, barbiturates, rifampicin or glucocorticoids) may be required. In these cases, caution should be exercised when differentiating from phenytoin and/or switching to valproate, which does not have enzyme-inducing properties. Carbamazepine When combined with carbamazepine, the clearance of quetiapine was significantly increased. As a result of this interaction, the concentration of Ketilept in the blood plasma may decrease and there is a need to use the drug in higher doses. It should be noted that for the treatment of schizophrenia, the maximum recommended daily dose of Ketilept is 750 mg. Long-term use of higher doses is possible only after a careful assessment of the benefit/risk ratio for a particular patient. Combination use with ketoconazole (200 mg/day for 4 days), a strong inhibitor of the cytochrome P450 3A enzyme, after oral administration reduced the clearance of quetiapine by 84%, as a result of which the concentration of quetiapine in the blood plasma increased by an average of 235%. Therefore, caution should be exercised during the simultaneous use of Ketilept and ketoconazole and other cytochrome P450 inhibitors, azole antifungals and macrolide antibiotics (for example, itraconazole, fluconazole and erythromycin); necessary appropriate reduction in the dose of quetiapine. Regular daily use of cimetidine (400 mg 3 times daily for 4 days) resulted in up to a 20% reduction in the average clearance of quetiapine (150 mg 3 times daily) after oral administration. When using Ketilept with cimetidine simultaneously, there is no need to change the dose of Ketilept. Thioridazine (200 mg twice daily) increased the clearance of quetiapine (300 mg twice daily) by 65% after oral administration. The combined use of quetiapine (300 mg 2 times a day) with antipsychotics such as haloperidol (7.5 mg 2 times a day) or risperidone (3 mg 2 times a day) did not change the equilibrium pharmacokinetic parameters of quetiapine. Concomitant use of quetiapine (300 mg twice daily) with the antidepressant and CYP3A4 and CYP2D6 inhibitor fluoxetine (60 mg once daily) or the CYP2D6 inhibitor imipramine (75 mg twice daily) did not change the equilibrium pharmacokinetic parameters quetiapine. Effect of Ketilept on other drugs. Repeated daily administration of quetiapine (up to 750 mg/day in 3 divided doses) does not cause clinically significant changes in the clearance of antipyrine or its metabolites. This indicates that quetiapine does not have an inhibitory effect on liver enzymes that are involved in the cytochrome P450-mediated metabolism of antipyrine. The combined use of quetiapine (250 mg 3 times a day) with lithium did not affect the pharmacokinetic parameters of lithium at steady state. The mean oral clearance of lorazepam (single dose 2 mg) was reduced by 20% while taking quetiapine (250 mg three times daily). Smoking does not affect the plasma clearance of quetiapine. Clinical studies have shown that quetiapine potentiates the effects of alcohol in patients with psychosis. Therefore, you should refrain from drinking alcohol during the course of treatment with Ketilept.
Ketilept®
Particular caution is required when prescribing Ketilept® in combination with other drugs acting on the central nervous system.
The results of an in vitro study showed that quetiapine and 9 of its metabolites in vivo are weak inhibitors of metabolic processes mediated by cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6 and 3A4). CYP3A4 is the main enzyme responsible for P-450-mediated metabolism of quetiapine.
Effect of other drugs on Ketilept®
Phenytoin
The combination of the drug Ketilept® with phenytoin leads to an increase in plasma clearance of quetiapine, because Phenytoin induces cytochrome P450 isoenzyme 3A4. The combination of quetiapine (250 mg three times daily) and phenytoin (100 mg twice daily) increased the mean clearance of quetiapine after oral administration by 5 times.
To correct symptoms of schizophrenia in patients receiving concomitant quetiapine and phenytoin, increased doses of Ketilept® or other liver enzyme inducers (for example, carbamazepine, barbiturates, rifampicin or glucocorticoids) may be required. In these cases, caution is required when discontinuing phenytoin and/or switching to valproate, which does not have enzyme-inducing properties.
Carbamazepine
Co-administration with carbamazepine significantly increased the clearance of quetiapine, which reduced the systemic exposure of quetiapine. Due to this interaction, higher doses of Ketilept® may be required.
P450 3A inhibitors
Co-administration with ketoconazole (200 mg per day for 4 days), a strong inhibitor of the cytochrome P450 3 enzyme, reduced the clearance of quetiapine after oral administration by 84%, resulting in an average increase in quetiapine plasma concentrations of 235%. Therefore, caution is required when combining Ketilept® with ketoconazole and other cytochrome P450 inhibitors, azole antifungals and macrolide antibiotics (for example, itraconazole, fluconazole and erythromycin); a corresponding reduction in the dose of quetiapine is necessary.
Cimetidine
Regular daily administration of cimetidine (400 mg three times daily for 4 days), which is a nonspecific enzyme inhibitor, resulted in a 20% reduction in the mean plasma clearance of quetiapine (150 mg three times daily) after oral administration. When using Ketilept® with cimetidine simultaneously, there is no need to change the dose of Ketilept®.
Thioridazine
Thioridazine (200 mg twice daily) increased the plasma clearance of quetiapine (300 mg twice daily) by 65% after oral administration.
Risperidone and haloperidol
The combination of quetiapine (300 mg twice daily) with the antipsychotic drug haloperidol (7.5 mg twice daily) or risperidone (3 mg twice daily) did not change the steady-state pharmacokinetics of quetiapine.
Fluoxetine and imipramine
The combination of quetiapine (300 mg twice daily) with the antidepressant and CYP3A4 and CYP2D6 inhibitor fluoxetine (60 mg once daily) or the known CYP2D6 inhibitor imipramine (75 mg twice daily) did not change the steady-state pharmacokinetics of quetiapine.
Effect of Ketilept® on other drugs
Antipyrine
Repeated daily administration of quetiapine (up to 750 mg per day with three doses) did not cause clinically significant changes in the clearance of antipyrine or its metabolites. This indicates that quetiapine does not have a significant inhibitory effect on liver enzymes involved in cytochrome P450-mediated metabolism of antipyrine.
Lithium
The combination of quetiapine (250 mg three times daily) with lithium did not affect any of the pharmacokinetic parameters of lithium at steady state.
Lorazepam
The mean oral clearance of lorazepam (single dose 2 mg) was reduced by 20% while taking quetiapine (250 mg three times daily).
Smoking
did not affect the clearance of quetiapine from blood plasma.
Clinical studies have shown that quetiapine potentiates the cognitive and motor effects of alcohol
in patients with psychosis. Therefore, you should not drink alcohol during treatment with Ketilept®.
Ketilept overdose, symptoms and treatment
There is very little evidence of quetiapine overdose in clinical studies. Most of the reported symptoms were due to an increase in the known pharmacological effects of the drug, such as drowsiness, sedation, tachycardia and hypotension. There is no specific antidote for Ketilept. In case of severe intoxication, the possibility of the patient taking several drugs simultaneously should always be considered. Intensive care is recommended, including clearing the patient's airway, ensuring adequate oxygenation and ventilation, and monitoring and maintaining cardiovascular function. Enhanced medical surveillance and monitoring should continue until the patient recovers completely.
