Active ingredients: Quetiapine
Seroquel 50 mg, 150 mg, 200 mg, 300 mg, 400 mg prolonged release tablets
Seroquel package inserts are available for pack sizes:- Seroquel 50 mg, 150 mg, 200 mg, 300 mg, 400 mg prolonged release tablets
- SEROQUEL 25 mg FILM-COATED TABLETS, SEROQUEL 100 mg FILM-COATED TABLETS, SEROQUEL 150 mg FILM-COATED TABLETS, SEROQUEL 200mg FILM-COATED TABLETS, SEROQUEL 300 mg FILM-COATED TABLETS
Why is Seroquel used? What is it for?
Seroquel prolonged-release tablets contain a substance called quetiapine. This substance belongs to a group of medicines called antipsychotics. Seroquel prolonged-release tablets can be used to treat a variety of diseases, such as the following:
- Bipolar depression and major depressive episodes associated with major depressive disorder: You may feel sad, or depressed, with guilt, without energy, without appetite, or with difficulty falling asleep.
- Mania: You may feel very excited, euphoric, agitated, enthusiastic or hyperactive or have poor judgment, including states of aggression or upset.
- Schizophrenia: one has the sensation of hearing or feeling things that are not present in reality, one becomes convinced of things that do not correspond to the truth or one feels unusually suspicious, anxious, confused, guilty, tense or depressed.
When Seroquel prolonged-release tablets are taken to treat major depressive episodes associated with major depressive disorder, it should be used in addition to another medicine indicated to treat this disease.
Seroquel prolonged-release tablets are also taken for the prevention of relapses in bipolar disorder (manic, mixed or depressive episodes).
Your doctor may continue to prescribe Seroquel prolonged-release tablets even if you feel better.
Contraindications When Seroquel should not be used
Do not take Seroquel prolonged-release tablets:
- if you are allergic (hypersensitive) to quetiapine or any of the other ingredients of Seroquel prolonged-release tablets
if you are taking any of the following medicines:
- some medicines for the HIV virus
- azole medications (for infections caused by fungi)
- erythromycin or clarithromycin (for infections)
- nefazodone (for depression).
Do not take Seroquel prolonged-release tablets if it falls into any of the categories described above.
If you are not sure, talk to your doctor or pharmacist before taking Seroquel prolonged-release tablets.
Precautions for use What you need to know before taking Seroquel
Before taking your medicine, tell your doctor if:
- You or someone else in your family have or have ever had heart problems, for example heart rhythm disturbances, or if you are taking any medicines that can affect the way your heart beats.
- Your blood pressure is low.
- He has had a stroke, especially if he is elderly.
- Suffering from liver problems.
- He suffered from convulsions (seizures).
- Have diabetes or are at risk of developing diabetes.In this case, your doctor may check your blood sugar levels while you are taking Seroquel prolonged-release tablets.
- You know that you have had low levels of white blood cells in the past (whether or not caused by other medicines).
- You are an elderly person with dementia (loss of certain brain functions). In this case, Seroquel prolonged-release tablets should not be taken, because this class of medicines, to which Seroquel prolonged-release tablets belongs, may increase the risk of stroke, or in some cases the risk of death, in elderly patients with dementia.
- You or someone else in your family have a history of blood clot related disorders, as medicines of this type can promote blood clot formation.
Tell your doctor immediately if you experience the following symptoms:
- Fever associated with severe muscle stiffness, sweating or low level of consciousness (a disease called 'neuroleptic malignant syndrome'). Immediate medical attention may be required.
- Uncontrollable movements, mainly of the face or tongue.
- Dizziness or an intense feeling of sleepiness. This can increase the risk of accidental injury (falls) in elderly patients.
- Convulsions (seizures)
- Persistent and painful erection (Priapism)
The following conditions can be caused by the type of medicine you are taking. Tell your doctor as soon as possible if you experience:
- fever, flu-like symptoms, sore throat or any other infection, as these may be the result of a very low white blood cell count, which may require Seroquel to be stopped and / or treatment given.
- Constipation along with persistent abdominal pain or constipation that has not responded to treatment, as they could lead to more serious intestinal blockage.
Thoughts of suicide and worsening of depression
If you are depressed, you may sometimes feel the need to harm or kill yourself. These feelings may be more intense at the start of treatment, as these medicines take time to work, usually about two weeks but sometimes even longer. These thoughts may intensify even if you suddenly stop taking the medicine. You are more likely to have these kinds of sensations if you have previously had thoughts of harming or killing yourself or if you are a young adult. Information from clinical trials has indeed shown an increased risk of suicidal thoughts and / or suicidal behavior in young adults with depression under the age of 25.
If you become aware that you have thoughts of harming or suicidal, contact your doctor or go to the hospital immediately. You may find it helpful to tell a relative or close friend that you have depression and have them read this leaflet. You may ask them to warn you if they think your depressive state is getting worse or if they are worried about some changes in your behavior.
Weight gain has been reported in patients taking Seroquel prolonged-release tablets. Your body weight needs to be checked regularly by both you and your doctor.
Interactions Which drugs or foods may change the effect of Seroquel
Taking Seroquel prolonged-release tablets with other medicines
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines - as they may interfere with the action of the medicine you are taking - including non-prescription and herbal products.
Do not take Seroquel prolonged-release tablets if you are taking any of the following medicines:
- Some medicines for the HIV virus.
- Azole drugs (for infections caused by fungi)
- Erythromycin or clarithromycin (for infections).
- Nefazodone (for depression).
Tell your doctor if you are taking any of the following medicines:
- Medicines for epilepsy (such as phenytoin or carbamazepine)
- Medicines for high blood pressure.
- Barbiturates (for sleep disorders).
- Thioridazine (another antipsychotic medicine).
- Medicines that affect the heartbeat, for example medicines that can cause electrolyte imbalance (low levels of potassium or magnesium) such as diuretics (pills that increase urine production) or some antibiotics (medicines to treat infections).
- Medicines that can cause constipation.
Before you stop taking any medicine, talk to your doctor.
Taking Seroquel prolonged-release tablets with food and drink
- The effect of Seroquel prolonged-release tablets may be influenced by food, and you should therefore take the tablets at least one hour before a meal or before going to sleep.
- Pay attention to the amount of alcohol you consume. This is important because the combined effect of Seroquel prolonged-release tablets and alcohol may promote sleepiness.
- Do not drink grapefruit juice while you are taking Seroquel prolonged-release tablets, as it can affect the way the medicine works.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, planning to become pregnant or breast-feeding, please inform your doctor before taking Seroquel prolonged-release tablets. You should not take Seroquel prolonged-release tablets during pregnancy without first discussing it with your doctor. Seroquel prolonged-release tablets should not be taken while breastfeeding.
The following symptoms, which may represent withdrawal, have been observed in neonates of mothers who have taken conventional or atypical antipsychotics, including Seroquel film-coated tablets, during the last trimester (last three months of pregnancy): tremor, stiffness and / o muscle weakness, sleepiness, agitation, breathing problems and difficulty in eating. If your child shows any of these symptoms, contact your doctor.
Driving and using machines
The tablets can make you drowsy. Do not drive or use any tools or machinery until you know what effect the tablets have on you.
Important information about some of the ingredients of Seroquel prolonged-release tablets
Seroquel prolonged-release tablets contain lactose, a type of sugar. If you have been advised by your doctor that you have an intolerance to some sugars, talk to your doctor before taking this medicine.
Effect on urine screening tests.
If you need to have a urine screening test, taking quetiapine could lead to false positive results for methadone or certain medications for depression, called tricyclic antidepressants, when certain testing methods are used even if you are not. taking methadone or tricyclic antidepressants, if this happens more specific tests should be done.
Dose, Method and Time of Administration How to use Seroquel: Posology
Always take Seroquel prolonged-release tablets exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. Your doctor will decide which starting dose is most appropriate for you. The maintenance dose (daily dose) will depend on the type of disease and your individual needs, but is usually between 150 mg and 800 mg.
- You must take the tablets once a day.
- The tablets must not be divided, chewed or crushed.
- You should swallow the tablets whole, with a sip of water.
- Take the tablets between meals (at least one hour before a meal or at bedtime, your doctor will tell you when).
- Do not drink grapefruit juice while you are taking Seroquel prolonged-release tablets, as it can affect the way the medicine works.
- Do not stop taking the tablets even if you feel better, unless your doctor tells you that you can.
Liver problems
If you have liver problems, your doctor may start treatment with a lower dose and increase it slowly.
Senior citizens
If you are elderly, your doctor may start treatment with a lower dose and increase it slowly.
Children and adolescents under 18 years of age
Seroquel prolonged-release tablets should not be used in children and adolescents under 18 years of age.
Overdose What to do if you have taken too much Seroquel
If you take more Seroquel prolonged-release tablets than prescribed by your doctor, you may feel sleepy, feel dizzy and experience an abnormal heartbeat. Contact your doctor or the nearest hospital immediately, taking the pack of Seroquel prolonged-release tablets with you.
If you forget to take Seroquel prolonged-release tablets
If you forget to take a dose, take it as soon as you remember it. If it is almost time for your next dose, wait for the scheduled time. Do not take a double dose to make up for a forgotten dose.
If you stop taking Seroquel prolonged-release tablets
If you suddenly stop taking Seroquel prolonged-release tablets you may have difficulty sleeping (insomnia), feel nauseous, or experience headache, diarrhea, vomiting, dizziness or irritability. Your doctor may suggest that you gradually reduce the dose before stopping treatment.
If you have any further questions on the use of Seroquel prolonged-release tablets, ask your doctor or pharmacist.
Side Effects What are the side effects of Seroquel
Like all medicines, Seroquel prolonged-release tablets can cause side effects, although not everybody gets them. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Very common (affects more than 1 in 10 people):
- Dizziness (which can lead to falls), headache, dry mouth.
- Feeling sleepy (which disappears over time as you continue treatment with Seroquel prolonged-release tablets) (which can lead to falls).
- Withdrawal symptoms (symptoms that appear when you stop taking Seroquel prolonged-release tablets), which include not being able to sleep (insomnia), feeling sick (nausea), headache, diarrhea, being sick (vomiting), dizziness and irritability. A gradual withdrawal of the drug is recommended, over a period of at least 1 or 2 weeks.
- Weight gain.
- Abnormal muscle movements, which include difficulty in starting a muscle movement, tremor, a feeling of restlessness or muscle stiffness without pain.
Common (affects less than 1 in 10 people):
- Rapid heartbeat
- Feeling that the heart is racing, beating fast or a feeling of missing beats.
- Blocked nose.
- Constipation, upset stomach (indigestion).
- Feeling weak, fainting (which can lead to falls).
- Swelling of the arms or legs.
- Low blood pressure when standing up. This can cause dizziness or fainting (which can cause falls).
- Increased blood sugar levels.
- Blurred vision.
- Abnormal dreams and nightmares.
- Increased feeling of hunger.
- Irritability.
- Disturbances in conversation and speech.
- Thoughts of suicide and worsening of depression.
- Dyspnea.
- Vomiting (especially in elderly patients).
- Fever.
Uncommon (affects less than 1 in 100 people):
- Convulsions or seizures.
- Allergic reactions including skin bruising (bruising), swelling of the skin and the area around the mouth.
- Unpleasant sensation in the legs (also called restless legs syndrome).
- Difficulty swallowing.
- Uncontrollable movements, mainly of the face or tongue.
- Sexual dysfunctions.
- QT interval prolongation (on electrocardiogram).
- A slowing of the normal heart rate may occur when treatment is started and may be associated with low blood pressure and fainting.
- Worsening of pre-existing diabetes.
- Difficulty urinating.
Rare (affects less than 1 in 1000 people):
- High body temperature (fever) associated with sweating, muscle stiffness, increased feeling of numbness or fainting (a disease called 'neuroleptic malignant syndrome').
- Yellowing of the skin and eyes (jaundice).
- Inflammation of the liver (hepatitis).
- Prolonged and painful erection (priapism).
- Swelling of the breasts and unexpected production of milk from the mammary gland (galactorrhea).
- Menstrual disturbances.
- Blood clots in the veins, especially in the legs (symptoms include swelling, pain and redness in the legs), which can travel through blood vessels to the lungs, causing chest pain and difficulty in breathing. If you notice any of these symptoms, contact your doctor immediately.
- Sleepwalking and other related events (such as sleep talking and sleep related eating disorders).
- Decrease in body temperature (Hypothermia).
- Inflammation of the pancreas.
- Combination of fever, flu-like symptoms, sore throat or any other infection with a very low white blood cell count, a condition referred to as agranulocytosis
- Intestinal obstruction.
Very rare (affects less than 1 in 10,000 people):
- Severe rash, blisters or red patches on the skin (Stevens-Johnson syndrome).
- Severe allergic reaction (called anaphylaxis) which can cause difficulty in breathing or shock.
- Rapid swelling of the skin, usually in the area around the eyes, lips and throat (angioedema).
- Inappropriate secretion of antidiuretic hormone (which controls urine volume).
- Damage to muscle fibers and muscle pain (rhabdomyolysis).
Frequency not known:
- Neonatal withdrawal syndrome. Withdrawal symptoms could occur in newborn babies of mothers who took Seroquel during pregnancy.
- Extrapyramidal symptoms (see section Pregnancy and lactation).
The class of medicines to which Seroquel prolonged-release tablets belongs can cause heart rhythm problems, which can even be serious and in some cases fatal.
Some side effects are only visible after taking a blood test. These include changes in the amount of certain fats (triglycerides and total cholesterol) or sugars present in the blood, changes in blood levels of thyroid hormones, increases in liver enzymes, decreases in the number of certain types of blood cells (eg leukocytes, neutrophils, platelets), decreases in the amount of red blood cells and hemoglobin, increases in serum creatine phosphokinase (a substance found in muscle), decreases in the amount of sodium in the blood, and increases in the amount of blood "prolactin hormone present in the blood. Increases in the levels of the hormone prolactin can, in rare cases, have the following consequences:
- Breast enlargement and unexpected production of milk from the mammary gland in both men and women.
- Absence or irregularity of the menstrual cycle in women.
Your doctor will then order blood tests from time to time.
Children and adolescents
The same side effects seen in adults can also occur in children and adolescents. The following side effects have only been reported in children and adolescents:
Very common (affects more than 1 in 10 people):
- Increased blood pressure.
The following side effects were reported more frequently in children and adolescents:
Very common (affects more than 1 in 10 people):
- Increased blood levels of a hormone called prolactin.
These increases in the amount of prolactin can in rare cases result in the following conditions:
- Breast enlargement and unexpected production of milk from the mammary gland in boys and girls
- Absence or irregularity of the menstrual cycle in girls
- Increased appetite
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on safety. of this medicine.
Expiry and Retention
- Keep out of the reach and sight of children.
- Do not use Seroquel prolonged-release tablets after the expiry date which is stated on the carton after the abbreviation EXP. The expiry date refers to the last day of the month.
- Seroquel prolonged-release tablets do not require special storage conditions.
- Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What Seroquel prolonged-release tablets contain
- The active ingredient is quetiapine. Seroquel prolonged-release tablets contain 50 mg, 150 mg, 200 mg, 300 mg or 400 mg of quetiapine (as quetiapine fumarate).
- The excipients are:
Tablet core: microcrystalline cellulose, sodium citrate, lactose monohydrate, magnesium stearate, hypromellose.
Tablet coating: hypromellose, macrogol, titanium dioxide (E171).The 50 mg, 200 mg and 300 mg tablets also contain yellow iron oxide (E172) and the 50 mg tablets contain red iron oxide (E172).
What Seroquel prolonged-release tablets look like and contents of the pack
All prolonged-release tablets are oval shaped and engraved with XR and strength. The 50 mg tablets are peach colored; the 150 mg tablets are white; the 200 mg tablets are yellow; 300 mg tablets are light yellow and 400 mg tablets are white The pack of 60 tablets is registered for all strengths.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
SEROQUEL PROLONGED RELEASE TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Seroquel 50 mg contains 50 mg of quetiapine (as quetiapine fumarate).
Excipient: 119 mg of lactose (anhydrous) per tablet.
Seroquel 150 mg contains 150 mg of quetiapine (as quetiapine fumarate).
Excipient: 71 mg of lactose (anhydrous) per tablet.
Seroquel 200 mg contains 200 mg of quetiapine (as quetiapine fumarate).
Excipient: 50 mg of lactose (anhydrous) per tablet.
Seroquel 300 mg contains 300 mg quetiapine (as quetiapine fumarate).
Excipient: 47 mg of lactose (anhydrous) per tablet.
Seroquel 400 mg contains 400 mg of quetiapine (as quetiapine fumarate).
Excipient: 15 mg of lactose (anhydrous) per tablet.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Prolonged-release tablets
Seroquel 50 mg peach-colored tablets engraved with "XR 50" on one side.
Seroquel 150 mg white tablets engraved with "XR 150" on one side.
Seroquel 200 mg yellow tablets engraved with "XR 200" on one side.
Seroquel 300 mg light yellow tablets engraved with "XR 300" on one side.
Seroquel 400 mg white tablets engraved with "XR 400" on one side.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Seroquel prolonged-release tablets are indicated for:
• treatment of schizophrenia
• treatment of bipolar disorder:
• For the treatment of moderate to severe manic episodes in bipolar disorder
• For the treatment of major depressive episodes in bipolar disorder
• For the prevention of recurrence of manic or depressive episodes in patients with bipolar disorder who have previously responded to quetiapine treatment.
• Add-on treatment of major depressive episodes in patients with Major Depressive Disorder (MDD) with suboptimal response to antidepressant monotherapy (see section 5.1). Before starting treatment, the physician should consider the safety profile of SEROQUEL prolonged-release tablets (see section 4.4).
04.2 Posology and method of administration
There are different dosing schedules for each indication. It must therefore be ensured that patients receive clear information on the most appropriate dosage for their condition.
Seroquel prolonged-release tablets should be administered once daily, between meals. The tablets should be swallowed whole, and not divided, chewed or crushed.
Adults
For the treatment of schizophrenia and moderate to severe manic episodes associated with bipolar disorder
Seroquel prolonged-release tablets should be administered at least one hour before meals. The daily dose at the start of therapy is 300 mg on day 1 and 600 mg on day 2. The recommended daily dose is 600 mg; however, if justified by the clinical condition, the dosage can be increased to 800 mg per day. The dose should be adjusted within an effective dose range of 400 mg to 800 mg per day, depending on the patient's clinical response and tolerability. No dose adjustment is required for maintenance therapy of schizophrenia.
For the treatment of major depressive episodes in bipolar disorder
Seroquel prolonged-release tablets should be administered in the evening before bedtime. The total daily dose for the first four days of therapy is 50 mg (Day 1), 100 mg (Day 2), 200 mg (Day 3) and 300 mg (Day 4). The recommended daily dose is 300 mg. In clinical studies, no additional benefit was observed in the 600 mg group compared to the 300 mg group (see section 5.1). Individual patients may benefit from the administration of a dose of 600 mg. Doses greater than 300 mg should be administered by physicians experienced in the treatment of bipolar disorder. In individual patients, in the event of tolerability problems, clinical studies have indicated that a dose reduction to a minimum of 200 mg may be considered.
For the prevention of relapses in bipolar disorder
To prevent recurrence of manic, mixed or depressive episodes in bipolar disorder, patients who have responded to Seroquel prolonged-release tablets for acute treatment of bipolar disorder should continue taking Seroquel prolonged-release tablets at the same dose as the night before. to go to bed. The dose of Seroquel prolonged-release tablets can be varied according to individual clinical response and tolerability within a range of 300-800 mg / day. It is important to use the lowest effective dose for maintenance therapy.
For the adjunctive treatment of major depressive episodes associated with DCS
Seroquel prolonged-release tablets should be administered at bedtime. At initiation of therapy, the daily dose is 50 mg on Days 1 and 2, and 150 mg on Days 3 and 4. The antidepressant effect has been observed at doses of 150 and 300 mg / day in short-term clinical trials. term as add-on therapy (in combination with amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline and venlafaxine - see section 5.1) and at a dose of 50 mg / day in short-term clinical studies conducted as monotherapy. At higher doses the risk of occurrence of adverse events increases. The physician should therefore ensure that the lowest effective dose for treatment is used, starting with 50 mg / day. Any increase in dosage from 150 to 300 mg / day must be made on the basis of the individual patient's assessment.
Switching from Seroquel immediate-release tablets
To ensure a more convenient mode of administration, patients currently treated with divided doses of Seroquel immediate-release tablets can be switched to Seroquel prolonged-release tablets at the equivalent total daily dose taken once daily. Individual dosage adjustments may be required.
Senior citizens
As with other antipsychotics and antidepressants, Seroquel prolonged-release tablets should be administered with caution in the elderly, particularly during the initial dosing period. Progressive dose escalation of Seroquel prolonged-release tablets may need to be slower and the daily therapeutic dose may need to be lower than in young patients. In elderly patients, the mean plasma clearance of quetiapine was reduced by 30%. -50% compared to younger patients. The starting dose for elderly patients is 50 mg / day. The dose may be increased in increments of 50 mg / day to an effective dose, depending on the clinical response and the tolerability of the individual patient.
In elderly patients with major depressive episodes associated with MDD, the starting dose should be 50 mg / day on Days 1-3, increasing to 100 mg / day on Day 4 and 150 mg / day on Day 8. The minimum effective dose, starting with 50 mg / day. If a dose increase to 300 mg / day is required based on individual patient assessment, this increase should be done no earlier than Day 22 of treatment.
Efficacy and safety have not been evaluated in patients over 65 years of age with depressive episodes associated with bipolar disorder.
Pediatric population
Seroquel prolonged-release tablets should not be used in children and adolescents below 18 years of age due to a lack of data to support its use in this age group. Currently available data from placebo-controlled clinical trials are described in sections 4.4, 4.8, 5.1 and 5.2.
Impaired renal function
No dosage adjustment is necessary in patients with impaired renal function.
Impaired liver function
Quetiapine is extensively metabolised by the liver. Therefore, Seroquel prolonged-release tablets should be used with caution in patients with known hepatic impairment, particularly during the initial stages of treatment. The starting dose of quetiapine in patients with hepatic impairment should be 50 mg / day. The dose may be increased in daily increments of 50 mg / day to the effective dose, depending on the clinical response and tolerability of the individual patient.
04.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1
Concomitant administration of cytochrome P450 3A4 inhibitors, such as HIV protease inhibitors, azole antifungal agents, erythromycin, clarithromycin and nefazodone, is contraindicated (see section 4.5).
04.4 Special warnings and appropriate precautions for use
As Seroquel prolonged-release tablets are approved for several indications, the safety profile of the drug with respect to the individual patient's diagnosis and the dose to be administered must be considered.
Long-term efficacy and safety in patients with MDD have not been evaluated as add-on treatment; however, long-term efficacy and safety have been evaluated in adult patients receiving monotherapy (see section 5.1).
Pediatric population
Quetiapine should not be used in children and adolescents below 18 years of age due to a lack of data to support its use in this age group. Clinical studies with quetiapine have shown that, in addition to the known safety profile observed in adults (see section 4.8), some adverse events occur with a higher frequency in children and adolescents than in adults (increased appetite, increased serum prolactin, vomiting, rhinitis and syncope) or may have different implications for children and adolescents (extrapyramidal symptoms and irritability), while one of these had never been previously reported in studies conducted in adults (increased blood pressure). and abnormalities in thyroid function tests have also been observed in adolescents.
Furthermore, in terms of safety, the long-term implications of quetiapine treatment on growth and maturation have not been analyzed beyond 26 weeks. The long-term implications for cognitive and behavioral development are unknown.
In placebo-controlled clinical trials in children and adolescent patients, quetiapine was associated with an "increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia, bipolar mania and bipolar depression (see section 4.8).
Suicide / suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission. As this improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement is achieved. From general clinical experience it has been observed that the risk of suicide may increase in the early stages of improvement.
In addition, the physician should consider the potential risk of suicide-related events following abrupt discontinuation of quetiapine treatment due to known risk factors for the disease in question.
Other psychiatric disorders for which quetiapine is prescribed may also be associated with an increased risk of suicide-related events. In addition, these pathologies may exist in co-morbidities with major depressive episodes. The same precautions followed for the treatment of patients with major depressive episodes should therefore be adopted when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those who exhibit a significant degree of suicidal ideation prior to initiation of treatment are at an increased risk of suicidal ideation or attempted suicide, and should therefore be subjected to close surveillance during treatment. A meta-analysis of placebo-controlled clinical trials with antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with the use of antidepressants compared to placebo in patients less than 25 years of age.
Careful monitoring of patients, particularly those at high risk, should be performed during therapy, especially in the initial stages of treatment and following dose changes. Patients (and caregivers) should be advised of the need to monitor for any clinical worsening, suicidal behavior or thoughts and unusual changes in behavior, and to seek immediate medical attention if such symptoms occur.
In shorter-term placebo-controlled clinical trials in patients with major depressive episodes associated with bipolar disorder, an increased risk of suicide-related events was observed in young adult patients (less than 25 years of age) treated with quetiapine compared to patients treated with placebo (3.0% vs 0%, respectively). In clinical trials in patients with MDD, the incidence of suicide-related events in young adult patients (less than 25 years of age) was 2.1% (3/144) for quetiapine and all. , 3% (1/75) for placebo.
Metabolic risk
Given the risk of worsening of the metabolic profile, including changes in body weight, blood glucose (see hyperglycaemia) and lipids, which has been found in clinical trials, patients' metabolic parameters should be evaluated at the start of the course. treatment and changes in these parameters should be checked regularly during treatment. Worsening of these parameters should be managed as clinically appropriate (see also section 4.8).
Extrapyramidal symptoms :
In placebo-controlled clinical trials in adult patients treated for major depressive episodes related to bipolar disorder and major depressive disorder, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo (see sections 4.8 and 5.1). .
The use of quetiapine has been associated with the development of akathisia, characterized by a subjectively unpleasant or disturbing feeling of agitation and the need to move, often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who experience these symptoms, increasing the dose could be harmful.
Tardive dyskinesia :
Dosage reduction or discontinuation of quetiapine therapy should be considered if signs and symptoms of tardive dyskinesia occur. Symptoms of tardive dyskinesia may worsen or even arise after discontinuation of treatment (see section 4.8).
Somnolence and dizziness :
Quetiapine treatment has been associated with somnolence and related symptoms, such as sedation (see section 4.8).In clinical trials for the treatment of patients with bipolar depression and major depressive disorder, the onset of this event generally occurs within the first 3 days of treatment and is mainly mild to moderate in intensity. Patients experiencing severe sleepiness. , may require more frequent checks for a minimum period of 2 weeks after the onset of drowsiness, or until symptoms improve, and discontinuation of treatment should be considered.
Orthostatic hypotension:
Quetiapine treatment has been associated with orthostatic hypotension and related dizziness (see section 4.8) which, similar to somnolence, usually occur during the initial dose-titration phase. This can increase the occurrence of accidental injuries (falls), especially in the elderly population. Therefore, patients should be advised to exercise caution until they become aware of their individual sensitivity to the drug.
Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or other conditions predisposing to hypotension.
Dosage reduction or more gradual titration should be considered if orthostatic hypotension occurs, especially in patients with underlying cardiovascular disease.
Seizures :
Controlled clinical trials have shown no differences in the incidence of seizures in patients treated with quetiapine or placebo. There are no data available on the incidence of seizures in patients with a history of seizures. As with other antipsychotics, caution is recommended when treating patients with a history of seizures (see section 4.8).
Neuroleptic malignant syndrome :
Neuroleptic malignant syndrome has been associated with treatment with antipsychotic drugs, including quetiapine (see section 4.8). Clinical manifestations include hyperthermia, altered mental status, muscle stiffness, autonomic nervous system instability and increased creatinine phosphokinase. If such manifestations occur, quetiapine treatment should be discontinued and appropriate medical therapy instituted.
Severe neutropenia and agranulocytosis :
Cases of severe neutropenia (neutrophil white blood cell count (WBC) and a "history of iatrogenic neutropenia" have been reported in clinical trials with quetiapine. However, some cases have occurred in patients with no pre-existing risk factors. quetiapine should be discontinued in patients with a neutrophil count for signs and symptoms of infection and the neutrophil count should be regularly monitored (until it exceeds 1.5x109 / L) (see section 5.1).
Neutropenia should be considered in patients with infection or fever, particularly in the absence of clear predisposing factors, and should be managed as clinically appropriate.
Patients should be advised to immediately report the appearance of signs / symptoms consistent with agranulocytosis or infection (eg fever, weakness, lethargy, or sore throat) at any time during Seroquel therapy. Such patients should have a timely white blood cell count and absolute neutrophil count (ANC), especially in the absence of predisposing factors.
Interactions :
See also section 4.5.
Concomitant use of quetiapine with potent hepatic enzyme inducers such as carbamazepine or phenytoin substantially reduces the plasma concentrations of quetiapine, possibly affecting the efficacy of therapy. In patients treated with hepatic enzyme inducers, quetiapine treatment can only be initiated if the physician considers that the benefits of therapy outweigh the risks of discontinuing hepatic enzyme inducers. It is important that any change in inducer is gradual and, if necessary, replaced by a non-inducer drug (eg sodium valproate).
Body weight
Body weight gain has been reported in patients treated with quetiapine; patients should be monitored and treated as clinically appropriate according to the guidelines of the antipsychotic used (see sections 4.8 and 5.1).
Hyperglycemia :
Hyperglycaemia and / or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma have been reported rarely, including some cases with fatal outcome (see section 4.8). In some cases, a previous increase in body weight could be a predisposing factor. Therefore, appropriate clinical monitoring is advisable according to the guidelines of the antipsychotic used. Patients treated with any antipsychotic drug, including quetiapine, should be monitored for possible signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia and weakness) , while patients with diabetes mellitus or diabetes mellitus risk factors should be monitored regularly for possible worsening of glucose control Weight should be monitored regularly.
Lipids :
Increases in triglycerides and LDL and total cholesterol and decreases in HDL cholesterol have been observed in clinical studies with quetiapine (see section 4.8). Changes in lipids must be managed in a clinically appropriate manner.
Prolongation of the QT interval :
Quetiapine was not associated with persistent increases in absolute QT interval in clinical studies and during use according to the instructions in the Summary of Product Characteristics (SmPC). In post-marketing experience, QT interval prolongation has been observed with quetiapine at therapeutic doses (see section 4.8) and in overdose (see section 4.9). As with other antipsychotics, caution is required when prescribing quetiapine to patients with cardiovascular disease or a family history of QT prolongation. Caution should be exercised when prescribing quetiapine with drugs known to prolong the QT interval, or with concomitant neuroleptics, especially in elderly subjects, in patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalaemia or hypomagnesaemia (see section 4.5).
Cardiomyopathy and myocarditis
Cases of cardiomyopathy and myocarditis have been reported in clinical trials and in post-marketing experience; however, a causal relationship with quetiapine has not been established. Quetiapine treatment should be re-evaluated in patients suspected of having cardiomyopathy or myocarditis.
Discontinuation of treatment :
After abrupt discontinuation of quetiapine treatment, acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability have been reported. A "gradual discontinuation," over a period of at least 1-2 weeks is recommended (see section 4.8).
Elderly patients with dementia-related psychosis :
The use of quetiapine is not authorized for the treatment of psychosis related to dementia.
An approximately 3-fold increased risk of cerebrovascular events was observed in randomized placebo-controlled clinical trials in a population of dementia patients treated with some atypical antipsychotics. The mechanism of this increased risk is unknown. An increased risk for other antipsychotics or other patient populations cannot be excluded. Quetiapine should be used with caution in patients with stroke risk factors.
An increased risk of death compared to placebo in elderly patients with dementia-related psychosis was reported in a meta-analysis performed on atypical antipsychotic drugs. However, in two placebo-controlled, 10-week clinical trials with quetiapine in the same patient population (n = 710; mean age 83 years; range: 56-99 years), the incidence of mortality in quetiapine-treated patients was 5.5% versus 3.2% in the placebo group. Patients in these studies died from various causes consistent with expectations for this population. These data did not establish a causal relationship between treatment with quetiapine and death in elderly patients with dementia.
Dysphagia
Dysphagia has been reported with quetiapine (see section 4.8). Quetiapine should be used with caution in patients at risk of pneumoniaab ingestis.
Constipation and intestinal obstruction
Constipation is a risk factor for intestinal obstruction. Constipation and intestinal obstruction have been reported with quetiapine (see section 4.8 Undesirable effects). Fatal cases are included in patients who have an increased risk of intestinal obstruction, including those being treated with multiple concomitant therapies that reduce intestinal motility and / or those who may not report symptoms of constipation Patients with intestinal obstruction / ileus should undergo close monitoring and urgent care.
Venous thromboembolism (VTE)
Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, it is necessary to identify all possible risk factors for VTE before and during treatment with VTE. quetiapine and take appropriate preventive measures Pancreatitis
Pancreatitis has been reported in clinical trials and during post-marketing experience. Among post-marketing reports, while not all cases could identify risk factors, many patients had factors that are known to be associated with pancreatitis. , such as increased triglycerides (see section 4.4), gallstones, and alcohol consumption.
Additional information
There are limited data on the use of quetiapine in combination with sodium or lithium valproate in acute moderate to severe manic episodes; however, the combination therapy was well tolerated (see sections 4.8 and 5.1). Data showed an effect. additive in the third week.
Lactose :
Seroquel prolonged-release tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
04.5 Interactions with other medicinal products and other forms of interaction
Since quetiapine has its main activity on the central nervous system, quetiapine should be administered with caution in combination with other centrally active drugs and with alcohol.
(CYP) 3A4 is the major enzyme of the cytochrome P450 system responsible for the metabolism of quetiapine. In an interaction study in healthy volunteers, co-administration of quetiapine (dosage of 25 mg) with ketoconazole, a CYP3A4 inhibitor, caused a 5-8-fold increase in quetiapine AUC. For this reason, use. concomitant quetiapine with CYP3A4 inhibitors is contraindicated. It is also recommended not to take quetiapine with grapefruit juice.
In a study in patients treated with multiple doses to evaluate the pharmacokinetics of quetiapine, administered before and during treatment with carbamazepine (known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced systemic quetiapine exposure (as assessed by AUC) by an average of 13% compared to administration of quetiapine alone, although a more marked effect was observed in some patients. As a consequence of this interaction, concentrations may occur. plasma levels, which may interfere with the efficacy of quetiapine therapy. Co-administration of quetiapine and phenytoin (another inducer of the microsomal enzyme system) resulted in a marked increase in quetiapine clearance of approximately 450%. In patients being treated with hepatic enzyme inducers, quetiapine treatment can only be initiated if the physician considers that the benefits of quetiapine outweigh the risk of discontinuing hepatic enzyme inducers. It is important that any changes in these inducers occur gradually and, if necessary, be replaced by a non-inducer (e.g. sodium valproate) (see section 4.4).
Co-administration of antidepressants based on imipramine (a known inhibitor of CYP2D6) or fluoxetine (a known inhibitor of CYP3A4 and CYP2D6) does not significantly alter the pharmacokinetic profile of quetiapine.
Co-administration of the antipsychotics risperidone or haloperidol does not significantly alter the pharmacokinetics of quetiapine. Concomitant use of quetiapine and thioridazine causes an increase in the clearance of quetiapine by approximately 70%.
Co-administration of cimetidine does not alter the pharmacokinetic profile of quetiapine.
The pharmacokinetics of lithium are not affected by concomitant administration of quetiapine.
A " higher incidence of extrapyramidal related events (particularly tremor, somnolence and weight gain) in the lithium add-on group compared to the placebo add-on group (see section 5.1).
Concomitant administration of sodium valproate and quetiapine does not have a clinically relevant influence on the pharmacokinetics of the two products. In a retrospective study of children / adolescents who received valproate, quetiapine, or both, a high incidence of leukopenia and neutropenia was found in the combination therapy group compared to the monotherapy groups.
No formal interaction studies have been performed with the most commonly used cardiovascular drugs.
Caution should be exercised when quetiapine is administered concomitantly with drugs known to cause electrolyte imbalances or prolongation of the QT interval.
There have been reports of false positive results of enzyme immunoassays for methadone and tricyclic antidepressants in patients who have taken quetiapine. It is recommended that dubious results of enzyme immunoassays be confirmed by appropriate chromatographic technique.
04.6 Pregnancy and lactation
Pregnancy
First quarter
The moderate amount of published data from exposed pregnancies (between 300-1000 pregnancy outcomes), including individual reports and some observational studies do not suggest an increased risk of malformations due to treatment. However, based on all available data, no definitive conclusion can be drawn. Animal studies have shown reproductive toxicity (see section 5.3). Therefore, quetiapine should only be used during pregnancy if the benefits justify the potential risks.
Third quarter
Infants exposed to antipsychotic treatment (including quetiapine) during the third trimester of pregnancy are at risk of experiencing adverse reactions, including extrapyramidal symptoms and / or withdrawal symptoms which may vary in severity and duration after birth. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress or nutritional disturbances have been reported. Consequently, newborns should be carefully monitored.
Feeding time
Based on a very limited amount of data from published reports on "excretion of quetiapine in human breast milk, the degree of quetiapine excretion at therapeutic doses does not appear to be constant. Given the lack of robust data, a decision must be made whether to discontinue" breastfeeding or discontinue Seroquel prolonged-release tablets taking into account the benefit of breastfeeding for the baby and the benefit of therapy for the mother.
Fertility
Effects of quetiapine on human fertility have not been evaluated. Effects related to elevated prolactin levels were found in rats, although they are not directly relevant to humans (see section 5.3 Preclinical data).
04.7 Effects on ability to drive and use machines
Due to its primary central nervous system effects, quetiapine may interfere with activities requiring mental alertness. Therefore, patients should be advised not to drive or operate machinery until their individual susceptibility to this effect is known.
04.8 Undesirable effects
The most commonly observed adverse drug reactions (ADRs) with quetiapine (≥10%) are somnolence, dizziness, headache, dry mouth, withdrawal symptoms (discontinuation), increases in serum triglycerides, increases in total cholesterol (predominantly cholesterol LDL), decreases in HDL cholesterol, weight gain, decreased hemoglobin and extrapyramidal symptoms.
The incidence of ADRs associated with quetiapine therapy is reported in the following table (Table 1) according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group; 1995).
Table 1: ADRs associated with quetiapine therapy
The frequencies of adverse events are classified according to the following convention: very common (≥1 / 10), common (≥1 / 100,
1 See section 4.4.
2 Somnolence may occur, usually during the first two weeks of treatment, which usually resolves with continued administration of quetiapine.
3 Asymptomatic (shift from normal to ≥3X ULN at any time) elevations in serum transaminases (ALT, AST) or gamma-GT have been observed in some patients treated with quetiapine. These elevations were generally reversible with continued quetiapine therapy.
4 As with other antipsychotics with alpha1 adrenergic blocking activity, quetiapine may commonly induce orthostatic hypotension, associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial titration phase (see section 4.4).
5 The frequency calculation for these ADRs derives exclusively from post-marketing data.
6 Fasting blood glucose ≥126 mg / dL (≥7.0 mmol / L) or non-fasting blood glucose ≥200 mg / dL (≥11.1 mmol / L) on at least one "occasion.
7 An increase in the rate of dysphagia with quetiapine compared with placebo was only observed in clinical trials in bipolar depression.
8. Based on> 7% weight gain from baseline weight. It occurs predominantly during the first few weeks of treatment in adults.
9 The following withdrawal symptoms were observed more frequently in acute, placebo-controlled monotherapy clinical trials evaluating withdrawal symptoms: insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability. The incidence of these reactions decreased significantly 1 week after stopping the drug.
10 Triglycerides ≥200 mg / dL (≥2.258 mmol / L) (patients aged ≥18 years) or ≥150 mg / dL (≥1.694 mmol / L) (patients aged
11 Cholesterol ≥240 mg / dL (≥6.2064 mmol / L) (patients aged ≥18 years) or ≥200 mg / dL (≥5.172 mmol / L) (patients aged
12 See text below.
13 Platelets ≤100 x 109 / L on at least one "occasion.
14 Based on clinical trial reports of adverse events related to creatine phosphokinase elevation not associated with neuroleptic malignant syndrome.
15 Prolactin levels (patients> 18 years of age):> 20 mcg / L (> 869.56 pmol / L) male; > 30 mcg / L (> 1304.34 pmol / L) females, at any time of observation.
16 They can cause falls.
17 HDL cholesterol:
18 Incidence of patients with QTc passed from
19 Change from> 132 mmol / L to ≤132 mmol / L in at least one case.
20 Cases of suicidal ideation and suicidal behaviors have been reported during quetiapine therapy or early after treatment discontinuation (see sections 4.4 and 5.1).
21 See paragraph 5.1.
22 The decrease in hemoglobin to values ≤13 g / dL (8.07 mmol / L) in males and ≤12 g / dL (7.45 mmol / L) in females occurred on at least one "occasion in" 11 % of patients treated with quetiapine in all clinical studies, including open label extensions. In these patients, the mean maximum decrease in hemoglobin at any time was -1.50 g / dL.
23 These reports have often occurred with tachycardia, dizziness, orthostatic hypotension and / or concomitant cardiorespiratory disease.
24 Based on deviation from normal baseline to potentially clinically important values at any later time in all clinical trials. Changes in total T4, free T4, total T3 and free T3 are defined as 5 mUI / L at any time.
25 Based on the increased rate of vomiting in elderly patients (> 65 years of age).
26 Changes in baseline neutrophils from ≥1.5x109 / L a
27 Based on deviation from normal baseline to potentially clinically important values at any time after baseline across all clinical trials. Changes in eosinophils are defined as> 1x109 cells / L at any time.
28 Based on deviation from normal baseline to potentially clinically important values at any time after baseline across all clinical trials. Changes in white blood cells are defined as ≤3x109 cells / L at any time.
29 Based on reports of metabolic syndrome in all clinical trials with quetiapine.
30 In clinical studies, worsening of more than one of the metabolic factors such as weight, blood glucose and lipids has been observed in some patients (see section 4.4).
31 See section 4.6.
32 They may occur at or near treatment initiation and may be associated with hypotension and / or syncope. The frequency is based on reported adverse events of bradycardia and related events in all clinical trials with quetiapine.
Cases of QT prolongation, ventricular arrhythmia, sudden unexplained death, cardiac arrest and torsades de pointes have been reported following the use of neuroleptics and are considered to be effects of this class of drugs.
Pediatric population
The same ADRs described above for adults should be considered for children and adolescents. The table below summarizes ADRs that occur more frequently in children and adolescents (aged 10-17 years) than in the adult population or ADRs that have not been identified in the adult population.
Table 2: ADRs associated with quetiapine therapy in children and adolescents that occur with a higher frequency than adults or have not been identified in the adult population
The frequencies of adverse events are classified according to the following convention: very common (> 1/10), common (> 1/100, 1 / 1,000, 1 / 10,000,
1. Prolactin levels (patients aged 20 mcg / L (> 869.56 pmol / L) in males;> 26 mcg / L (> 1130.428 pmol / L) in females at any time of observation. 1% of patients reported an increase in prolactin levels> 100 mcg / L.
2. Based on exceeding clinically significant thresholds (adapted from National Institute of Health criteria) or increases> 20 mmHg in systolic blood pressure or> 10 mmHg in diastolic blood pressure at any time of observation in two acute clinical studies (3- 6 weeks) placebo-controlled in children and adolescents.
3. Note: The frequency is similar to that seen in adult patients, but irritability may be associated with different clinical implications in children and adolescents than in adults.
4. See paragraph 5.1.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
04.9 Overdose
Symptoms
In general, the reported signs and symptoms are attributable to an enhancement of the known pharmacological effects of the drug, such as eg. somnolence and sedation, tachycardia and hypotension.
Overdose can lead to QT interval prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and / or agitation, coma and death. Patients with pre-existing severe cardiovascular disease may be more at risk of developing overdose effects (see section 4.4 Orthostatic hypotension).
Treatment of overdose
There is no specific antidote for quetiapine. In cases with more severe manifestations, the possibility of the involvement of different drugs should be considered, and therefore intensive care procedures are recommended, including the establishment and maintenance of a patent airway to support adequate oxygenation and ventilation. monitoring and support of cardiovascular function.
According to the published literature, patients with delirium and agitation and a clear anticholinergic syndrome can be treated with 1-2 mg of physostigmine (under continuous ECG monitoring). Use of this drug is not recommended as standard treatment due to the potential negative effect of physostigmine on heart conductance. Physostigmine can be used in the absence of ECG aberrations. Do not use physostigmine in case of arrhythmias, any degree of heart block or enlargement of the QRS complex.
Although prevention of absorption in overdose has not been evaluated, gastric lavage may be considered in cases of severe intoxication, possibly within one hour of ingestion. Administration of activated charcoal should also be considered.
In cases of quetiapine overdose, refractory hypotension should be treated with appropriate measures such as intravenous fluids and / or sympathomimetic agents. Epinephrine and dopamine should be avoided, as beta stimulation can worsen hypotension during the onset of blockade. alpha induced by quetiapine.
Careful medical supervision and appropriate monitoring must be ensured until the patient is cured.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antipsychotics; diazepines, oxazepines and thiazepines.
ATC code: N05A H04.
Mechanism of action :
Quetiapine is an atypical antipsychotic drug. Quetiapine and the active metabolite found in human plasma, norquetiapine, interact with a broad spectrum of neurotransmitter receptors. Quetiapine and norquetiapine have an "affinity for brain serotonergic (5HT2) and dopamine D1 and D2 receptors. The combination of a receptor antagonism with greater selectivity for 5HT2 receptors over D2 receptors is believed to contribute to clinical antipsychotic properties and reduced propensity of Seroquel to induce extrapyramidal undesirable effects (EPS) compared to typical antipsychotics. Quetiapine and norquetiapine have no "appreciable affinity for benzodiazepine receptors, while they possess" high affinity for histaminergic and alpha 1 adrenergic receptors, a " Moderate affinity for alpha 2 adrenergic receptors and a "moderate to high affinity for several muscarinic receptors. NET inhibition and partial agonist action at 5HT1A sites by norquetiapine may contribute to the therapeutic efficacy of Seroquel XR. as an antidepressant drug.
Pharmacodynamic effects :
Quetiapine was found to be active in antipsychotic activity assessment tests, such as the conditional avoidance test. It is also capable of blocking the action of dopaminergic agonists, as assessed from both a behavioral and electrophysiological point of view, and increases concentration. of dopamine metabolites considered neurochemical markers of D2 receptor blocking activity.
In preclinical tests for the prediction of extrapyramidal symptoms (EPS), quetiapine was different from typical antipsychotics, presenting an atypical profile. Chronic administration of quetiapine does not cause supersensitivity of dopaminergic D2 receptors. Quetiapine induces only weak catalepsy at doses effective for blocking dopamine D2 receptors. After chronic administration, quetiapine demonstrates selectivity for the limbic system by blocking the depolarization of the mesolimbic area without effect on the nigrostriatal area where dopaminergic neurons are present. Quetiapine, after acute and chronic administration, shows a minimal propensity for dystonic manifestations in haloperidol-sensitized or drug-free Cebus monkeys (see section 4.8).
Clinical efficacy :
Schizophrenia
The efficacy of Seroquel prolonged-release tablets in the treatment of schizophrenia was demonstrated in a 6-week placebo-controlled clinical study conducted in patients who met DSM-IV criteria for the diagnosis of schizophrenia, and in one Active-controlled clinical trial on switching from immediate-release Seroquel to prolonged-release Seroquel tablets in clinically stable outpatient schizophrenic patients.
The primary outcome variable in the placebo-controlled study was the change in PANSS total score from baseline to final assessment. Administration of Seroquel prolonged-release tablets 400 mg / day, 600 mg / day and 800 mg / day was associated with statistically significant improvements in psychotic symptoms compared to placebo. The magnitude of effect of the 600 mg and 800 mg doses was greater than that of the 400 mg dose.
In a 6-week active-controlled clinical trial comparing switching from one drug to another, the primary outcome variable was the proportion of patients who experienced lack of efficacy, i.e. discontinued. study treatment for lack of therapeutic efficacy or for which the total score on the PANSS scale was higher by 20% or more in the visits following randomization. In patients stabilized on Seroquel immediate-release tablets at doses between 400 mg and 800 mg, efficacy was maintained when subjects were switched to an equivalent daily dose of Seroquel prolonged-release tablets administered once daily.
In a long-term study in stable schizophrenic patients treated with Seroquel prolonged-release tablets for 16 weeks, Seroquel prolonged-release tablets were more effective than placebo in preventing relapse. The estimated risk of relapse after 6 months of treatment was 14.3% for the Seroquel prolonged-release tablets treatment group compared to 68.2% for placebo. The mean dose was 669 mg. There were no further safety concerns regarding treatment with Seroquel prolonged-release tablets for up to 9 months (median 7 months). In particular, there was no increase in reports of EPS-related adverse events and weight gain in association with prolonged treatment with Seroquel prolonged-release tablets.
Bipolar disorder
In the treatment of moderate to severe manic episodes in two clinical trials conducted as monotherapy, Seroquel demonstrated superior efficacy to placebo in reducing manic symptoms at 3 and 12 weeks.The efficacy of Seroquel prolonged-release tablets was further substantiated by showing significant differences from placebo in another 3-week study. Seroquel prolonged-release tablets were administered over a dose range of 400 to 800 mg / day. and the mean dose was approximately 600 mg / day. Data regarding administration of Seroquel in combination with sodium or lithium valproate in the treatment of moderate to severe acute manic episodes at week 3 and week 6 are limited; however , the combination therapy was well tolerated Data showed an additive effect at week 3. A second study showed no additive effect at week 6.
In a clinical study conducted in patients with depressive episodes associated with bipolar I or II disorder, the administration of 300 mg / day of Seroquel prolonged-release tablets was "more effective than placebo in reducing the total score on the MADRS scale." .
In 4 additional 8-week clinical trials of quetiapine use in patients with moderate to severe depressive episodes associated with bipolar I or II disorder, Seroquel immediate release tablets 300 mg and 600 mg were shown to be significantly superior. placebo in treated patients, in outcomes related to the efficacy parameters assessed: mean improvement in the MADRS score and clinical response of the patient defined with an improvement of at least 50% in the total MADRS score from baseline. no difference in magnitude of effect between patients who received the 300 mg dose of Seroquel immediate release tablets and those who received the 600 mg dose.
In the continuation phase of two of these studies, long-term treatment of patients who responded to treatment with Seroquel immediate-release 300 mg or 600 mg tablets was shown to be effective compared to placebo in terms of prevention. depressive symptoms, but not manic symptoms.
In two relapse prevention studies evaluating the effect of quetiapine in combination with mood stabilizers in patients with manic, depressive or mixed episodes, the combination with quetiapine was superior to mood stabilizers alone in "increase the time to relapse of any mood episode (manic, mixed or depressive). Quetiapine was administered twice daily for a total of 400 mg-800 mg daily in combination therapy with lithium or valproate.
In a 6-week randomized clinical trial evaluating the use of lithium and SEROQUEL immediate-release tablets versus placebo and SEROQUEL immediate-release tablets in adult patients with acute mania, the difference in mean improvement was on the YMRS scale between the lithium add-on treatment group and the placebo add-on group was 2.8 points, while the difference in the% of responders (defined as an improvement in 50% measured on the YMRS scale from baseline visit) was 11% (79% in the lithium add-on group vs 68% in the placebo add-on group).
In a long-term study (up to two years of treatment), which evaluated the prevention of relapse in patients with manic, depressive or mixed episodes, quetiapine was shown to be superior to placebo in prolonging the time to relapse to reappearance of any mood episode (manic, mixed or depressive) in patients with bipolar I disorder. The number of patients who experienced a mood episode was 91 (22.5%) in the group, respectively treated with quetiapine, 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium group. Patients who responded to quetiapine treatment and then switched to lithium treatment experienced no additional benefit in relapse prevention compared to patients who continued quetiapine therapy.
Major depressive episodes associated with DCS
Two short-term (6-week) studies recruited patients who had experienced an inadequate response to at least one antidepressant drug. Seroquel prolonged-release tablets 150 mg and 300 mg / day, given as add-on treatment to ongoing antidepressant therapy (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine), demonstrated superior efficacy compared to antidepressant therapy alone in reducing depressive symptoms, as evidenced by the improvement in the total score on the MADRS scale (mean change LS vs placebo equal to 2-3, 3 points).
Long-term efficacy and safety in patients with MDD have not been evaluated as add-on therapy; however, these parameters have been evaluated in adult patients receiving monotherapy (see below).
The following studies were conducted with Seroquel prolonged-release tablets as monotherapy, however, Seroquel prolonged-release tablets are indicated for add-on therapy only:
In three out of four short-term (up to 8 weeks) monotherapy studies in patients with major depressive disorder, Seroquel prolonged-release tablets 50 mg, 150 mg and 300 mg / day demonstrated superior efficacy over placebo. in reducing depressive symptoms, as evidenced by the improvement of the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS) (mean change LS vs placebo of 2-4 points).
In a relapse prevention study conducted as monotherapy, patients with depressive episodes stabilized on open-label Seroquel prolonged-release treatment for at least 12 weeks were randomized to treatment with Seroquel prolonged-release once daily or placebo to a period of up to 52 weeks. The mean dose of Seroquel prolonged-release tablets during the randomized phase was 177 mg / day. The incidence of relapse was 14.2% for patients treated with Seroquel prolonged-release tablets and 34.4% for subjects who received placebo.
In a short-term (9-week) study in elderly non-dementia patients (aged 66 to 89 years) with major depressive disorder, Seroquel prolonged-release tablets administered in flexible doses ranging from 50 mg to 300 mg / day demonstrated superior efficacy to placebo in reducing depressive symptoms, as evidenced by the improvement in the total score on the MADRS scale (LS mean change vs placebo -7.54). In this study, patients randomized to treatment with Seroquel release tablets patients received 50 mg / day on Days 1-3 and the dose could then be increased to 100 mg / day on Day 4, 150 mg / day on Day 8 and up to 300 mg / day, depending on clinical response and tolerability. The mean dose of Seroquel prolonged-release tablets was 160 mg / day. Apart from the "incidence of extrapyramidal symptoms (see section 4.8 and" Clinical safety "below), the tolerability of Seroquel tablets Prolonged-release administered once daily in elderly patients was equivalent to that seen in adult subjects (aged 18 to 65 years). The percentage of randomized patients over 75 years of age was 19%.
Clinical safety
In short-term placebo-controlled clinical trials in patients with schizophrenia and bipolar mania, the pooled incidence of extrapyramidal symptoms was similar to that seen in combination with placebo (schizophrenia: 7.8% for quetiapine and 8.0 % for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo) There were higher rates of extrapyramidal symptoms in patients treated with quetiapine compared to those who received placebo in the "in the context of short-term placebo-controlled clinical trials conducted in subjects with DCS and bipolar depression. In short-term placebo-controlled clinical trials in bipolar depression, the pooled incidence of extrapyramidal symptoms was 8.9% for quetiapine, compared with 3.8% for placebo. In short-term, placebo-controlled clinical trials conducted as monotherapy in patients with major depressive disorder, the pooled incidence of extrapyramidal symptoms was 5.4% for Seroquel prolonged-release tablets and 3.2% for placebo. In a short-term placebo-controlled clinical trial conducted as monotherapy in elderly patients with major depressive disorder, the pooled incidence of extrapyramidal symptoms was 9.0% for Seroquel prolonged-release tablets and 2.3% for placebo. In bipolar depression and DCS, the incidence of single adverse events (eg. Akathisia, extrapyramidal syndrome, tremor, dyskinesia, dystonia, restlessness, involuntary muscle contractions, psychomotor hyperactivity and muscle stiffness) did not exceed 4% in any group of treatment.
In short-term, fixed-dose (50 mg / day to 800 mg / day), placebo-controlled clinical trials (lasting 3 to 8 weeks), mean weight gain for patients treated with quetiapine ranged from 0 , 8 kg for the daily dose of 50 mg to 1.4 kg for the daily dose of 600 mg (with a smaller increase recorded for the daily dose of 800 mg), compared to 0.2 kg for subjects who had received placebo. The percentage of quetiapine-treated patients who gained ≥7% body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (an increase lower recorded for daily doses of 600 and 800 mg), compared to 3.7% for subjects who received placebo.
A 6-week randomized clinical trial evaluating the use of lithium and SEROQUEL prolonged-release tablets versus placebo and SEROQUEL prolonged-release tablets in adult patients with acute mania found that the combination of SEROQUEL prolonged-release tablets prolonged-release lithium causes more adverse events (63% versus 48% for SEROQUEL prolonged-release tablets in combination with placebo). The safety results showed a "higher incidence of extrapyramidal symptoms reported in 16.8 % of patients in the lithium add-on group and 6.6% in the placebo add-on group, most of which consisted of tremors reported in 15.6% of patients in the lithium add-on group. lithium and 4.9% of the placebo add-on group. The incidence of somnolence was higher in the SEROQUEL prolonged-release tablets in combination with lithium add-on group (12.7%) compared to the SEROQUEL prolonged-release tablets and placebo add-on group. In addition, a higher percentage of patients treated in the lithium add-on group (8.0%) had weight gain (≥7%) at the end of treatment compared to subjects in the lithium group. treatment with the addition of placebo (4.7%).
Long-term relapse prevention studies involved an open-label period (ranging from 4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomized treatment interruption period during which subjects were randomized to treatment with quetiapine or placebo. For subjects randomized to quetiapine treatment, mean weight gain during the open label period was 2.56 kg and by week 48 of the randomized period it was 3.22 kg, compared to baseline values recorded in the open label. For patients randomized to placebo treatment, the mean weight gain during the open label period was 2.39 kg and by week 48 of the randomized period it was 0.89 kg, compared to the baseline values recorded in the open label. .
In placebo-controlled clinical trials conducted in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient-years was not higher in subjects treated with quetiapine than in subjects who had received the placebo.
In all placebo-controlled short-term monotherapy clinical trials conducted in patients with a baseline neutrophil count ≥1.5x109 / L, the incidence of at least one neutrophil count 0.5-
Quetiapine treatment has been associated with dose-related decreases in thyroid hormone levels. The incidence of TSH changes was 3.2% for quetiapine versus 2.7% for placebo. The incidence of potentially clinically significant reciprocal changes in T3 or T4 and TSH, found in these studies, was rare. and observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The decrease in total and free T4 was maximal within the first six weeks of quetiapine treatment, while no further reduction was seen during long-term treatment. In approximately 2/3 of all cases, discontinuation of quetiapine was associated with a reversal of the effects on total and free T4, regardless of the duration of therapy.
Cataract / lens opacity
In a clinical study to evaluate the cataractogenic potential of Seroquel (200-800 mg / day) versus risperidone (2-8 mg / day) in patients with schizophrenia or schizoaffective disorder, the percentage of subjects with an increased degree of opacification of the lens was not higher with Seroquel (4%), compared to risperidone (10%), for subjects subjected to at least 21 months of exposure.
Pediatric population
Clinical efficacy
The efficacy and safety of Seroquel were evaluated in a 3-week placebo-controlled clinical trial for the treatment of mania (n = 284 patients from the United States, aged 10-17 years). 45% of the patient population had an additional diagnosis of ADHD. In addition, a 6-week placebo-controlled study was performed for the treatment of schizophrenia (n = 222 patients aged 13-17 years). In both the studies excluded patients with known unresponsiveness to Seroquel treatment. Treatment with Seroquel consisted of a starting dose of 50 mg / day, increased to 100 mg / day on Day 2; thereafter the dose was progressively adjusted to achieve a targeted dosing (mania 400-600 mg / day; schizophrenia 400-800 mg / day) by increments of 100 mg / day divided into two or three daily administrations.
In the mania study, the difference in LS mean change from baseline in YMRS total score (active minus placebo) was -5.21 for Seroquel 400 mg / day and -6.56 for Seroquel 600 mg / day. die. The rates of responders (YMRS improvement ≥50%) were 64% for Seroquel 400 mg / day, 58% for 600 mg / day and 37% in the placebo arm.
In the schizophrenia study, the difference in LS mean change from baseline in PANSS total score (active minus placebo) was -8.16 for Seroquel 400 mg / day and -9.29 for Seroquel 800 mg / day. die. Quetiapine was not superior to placebo in either the low dose (400 mg / day) or high dose (800 mg / day) regimens in terms of the percentage of patients who responded to treatment, defined as a reduction ≥30% of the initial PANNS total score. Higher doses induced a numerically lower response rate in both mania and schizophrenia studies.
In a third short-term placebo-controlled monotherapy study of Seroquel prolonged-release tablets in children and adolescents (10-17 years of age) with bipolar depression, efficacy was not demonstrated.
There are no data on maintenance of effect or prevention of recurrence in this age group.
Clinical safety
In the short-term pediatric studies with quetiapine described above, the incidence of extrapyramidal symptoms (EPS) in the active arm vs placebo was 12.9% vs 5.3% in the schizophrenia study, 3.6% vs 1.1% in the bipolar mania study and 1.1% vs 0% in the bipolar depression study. The incidence of weight gain ≥7% from baseline body weight in the active arm vs placebo was 17% vs 2.5% in the schizophrenia studies and bipolar mania, and 12.5% vs 6% in the bipolar depression study. The incidence of suicide-related events in the active vs placebo arm was 1.4% vs 1.3% in the schizophrenia study, 1.0% vs 0% in the bipolar mania study, and 1.1% vs 0% in the bipolar mania study. Bipolar Depression Study. During an extended post-treatment follow-up phase of a bipolar depression study, there were two other suicide-related events in two patients, one of these patients having used quetiapine at the time of the event.
Long-term security
A 26-week extension to acute open-label studies (n = 380 patients) with variable dose Seroquel 400-800 mg / day provided additional safety data.Increases in blood pressure have been reported in children and adolescents and increased appetite, extrapyramidal symptoms and increases in serum prolactin levels have been reported with a higher frequency in children and adolescents than in adult patients (see sections 4.4 and 4.8).
Regarding weight gain, after adjusting for normal long-term growth, an increase of at least 0.5 standard deviation from baseline in the Body Mass Index (BMI) was used as a measure of a clinically significant change. ; 18.3% of patients who were treated with quetiapine for at least 26 weeks met this criterion.
05.2 Pharmacokinetic properties
Absorption:
Quetiapine is well absorbed following oral administration. Seroquel prolonged-release tablets reach peak plasma concentrations of quetiapine and norquetiapine approximately 6 hours after administration (Tmax). The steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of those observed for quetiapine.
The pharmacokinetic profile of quetiapine and norquetiapine is linear and proportional for doses up to 800 mg administered once daily. The area under the plasma concentration-time curve (AUC) of Seroquel prolonged-release tablets administered once daily is comparable to that obtained with the same total daily dose of immediate-release quetiapine fumarate (immediate-release Seroquel) administered twice per day, while the maximum plasma concentration (Cmax) is 13% lower at steady-state. When comparing Seroquel prolonged-release tablets and Seroquel immediate-release, the AUC of the metabolite norquetiapine is 18% lower.
In a study examining the effects of food on the bioavailability of quetiapine, a high-fat meal was observed to produce statistically significant increases in Cmax and AUC of Seroquel prolonged-release tablets of 50% and 20%, respectively. %. It cannot be excluded that the effect of a high fat meal on the formulation may be greater. In contrast, a light meal did not have a significant effect on quetiapine Cmax or AUC. It is recommended that Seroquel prolonged-release tablets be taken once daily between meals.
Distribution:
Plasma protein binding of quetiapine is approximately 83%.
Biotransformation:
After administration of radiolabelled quetiapine, the product is extensively metabolised in the liver and is found unchanged in the urine and faeces in amounts less than 5% of the parent compound.
Studies conducted in vitro demonstrated that CYP3A4 is the primary enzyme responsible for the cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is primarily produced and eliminated by CYP3A4.
Quetiapine and several of its metabolites (including norquetiapine) have been shown to be weak inhibitors in vitro of human cytochrome P450 activities 1A2, 2C9, 2C19, 2D6 and 3A4. In vitro CYP inhibition was observed only at concentrations about 5-50 times higher than those found in humans at doses between 300 and 800 mg / day. Based on these results in vitro Co-administration of quetiapine and other drugs is unlikely to cause "clinically significant inhibition of cytochrome P450 mediated metabolism of other drugs. Based on animal studies, it appears that quetiapine can induce cytochrome P450 enzymes. However, in in a specific interaction study conducted in psychotic patients, no increase in cytochrome P450 activity was found following administration of quetiapine.
Elimination:
The elimination half-life of quetiapine and norquetiapine is approximately 7 and 12 hours, respectively. Approximately 73% of the radiolabelled drug is excreted in the urine and 21% in the faeces, while less than 5% of the total radioactivity is accounted for by the drug. The mean molar dose fraction of free quetiapine and the active metabolite norquetiapine present in human plasma is excreted in the urine to an extent
Special populations
Sex:
The pharmacokinetic profile of quetiapine does not differ between the two sexes.
Senior citizens:
The mean clearance of quetiapine in elderly subjects is approximately 30% -50% reduced compared to that seen in adults aged 18 to 65 years.
Impaired renal function:
The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml / min / 1.73 m2), but the individual clearance values are within the normal range for healthy subjects.
Impaired liver function:
The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolised by the liver, the patient population with hepatic impairment may have higher plasma levels of the drug and dose adjustments may be required in these patients (see section 4.2).
Pediatric population
Pharmacokinetic data were sampled in 9 children aged 10-12 years and 12 adolescents receiving steady-state 400 mg quetiapine (Seroquel) twice daily. At steady-state, dose-normalized plasma levels of the parent compound, quetiapine, in children and adolescents (aged 10-17 years) were generally similar to those in adults, although Cmax in children was at the borderline. higher than the range of values observed in adults. The AUC and Cmax, for the active metabolite norquetiapine were approximately 62% and 49% higher in children (aged 10 to 12 years), and 28% and 14% respectively in adolescents (aged 13-17 years) compared to adults.
There is no information available on the use of Seroquel prolonged-release tablets in children and adolescents.
05.3 Preclinical safety data
A series of genotoxicity studies in vitro And in vivo showed no evidence of genotoxicity. In laboratory animals exposed to clinically relevant levels, the following changes have been observed, which to date have not been confirmed in long-term clinical research:
pigment deposition in the thyroid gland was observed in the rat; hypertrophy of thyroid follicular cells, decreased plasma T3 levels, decreased hemoglobin concentration, and decreased red and white blood cell counts have been reported in the cynomolgus monkey; Lens opacity and cataract have been reported in dogs (for cataract / lens opacity see section 5.1).
In an embryo-fetal toxicity study conducted in rabbits, the fetal incidence of carpal / tarsal flexion was higher. This effect appeared in the presence of overt maternal effects, including reduced weight gain. These effects were evident at exposure levels of women. mothers similar or slightly higher than those in humans at the maximum therapeutic dose. The relevance of this finding to humans is unknown.
A fertility study in rats found minimal reduction in male fertility and pseudogravancy, prolonged periods of diestrus, increased precoital interval and a reduced rate of pregnancies. These effects are related to elevated prolactin levels and are not directly relevant for man given the differences in hormonal control of reproduction between species.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Nucleus
Microcrystalline cellulose
Sodium citrate
Lactose monohydrate
Magnesium stearate
Hypromellose 2208
Coating
Hypromellose 2910
Macrogol 400
Titanium dioxide (E171)
Yellow iron oxide (E172) (50, 200 and 300 mg tablets)
Red iron oxide (E172) (25 mg tablets)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Blisters in polychlorotrifluoroethylene and polyvinyl chloride with aluminum
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
AstraZeneca S.p.A.
Volta Palace
Via F. Sforza
Basiglio (MI)
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. 032944124 - Seroquel 50 mg prolonged release tablets - 60 tablets
A.I.C. 032944163 - Seroquel 150 mg prolonged release tablets - 60 tablets
A.I.C. 032944136 - Seroquel 200 mg prolonged release tablets - 60 tablets
A.I.C. 032944148 - Seroquel 300 mg prolonged-release tablets - 60 tablets:
A.I.C. 032944151 - Seroquel 400 mg prolonged release tablets - 60 tablets:
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 5 November 2008
10.0 DATE OF REVISION OF THE TEXT
March 2015
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