Active ingredients: Quetiapine
Quentiax 25 mg film-coated tablets
Quentiax 100 mg film-coated tablets
Quentiax 150 mg film-coated tablets
Quentiax 200 mg film-coated tablets
Quentiax 300 mg film-coated tablets
Quentiax package inserts are available for pack sizes: - Quentiax 25 mg film-coated tablets, Quentiax 100 mg film-coated tablets, Quentiax 150 mg film-coated tablets, Quentiax 200 mg film-coated tablets, Quentiax 300 mg film-coated tablets
- Quentiax 150 mg prolonged-release tablets, Quentiax 200 mg prolonged-release tablets, Quentiax 300 mg prolonged-release tablets
- Quentiax 50 mg prolonged-release tablets
Why is Quentiax used? What is it for?
Quentiax contains a substance called quetiapine. This belongs to a group of medicines called antipsychotics. Quentiax can be used to treat serious diseases such as:
- Schizophrenia: Can see, hear or feel things that aren't there, believe things that aren't real, or feel unusually suspicious, anxious, confused, guilty, tense, or depressed.
- Mania: He may feel very excited, euphoric, agitated, enthusiastic or hyperactive or have poor judgment including being aggressive or disruptive.
- Bipolar depression: for which it can feel sad. He may feel depressed, guilty, lack energy, lose appetite and / or not be able to sleep.
Your doctor may continue to give you QUENTIAX when you feel better to prevent symptoms from returning.
Contraindications When Quentiax should not be used
DO NOT TAKE QUENTIAX:
- If you are allergic to quetiapine or any of the other ingredients of this medicine
- If you are taking any of the following medicines:
- some medicines to treat HIV.
- azole medicines (for fungal infections).
- erythromycin or clarithromycin (for infections).
- nefazodone (for depression).
Do not take Quentiax if what is indicated applies to you. If you are unsure, contact your doctor or pharmacist before taking Quentiax.
Precautions for use What you need to know before taking Quentiax
Talk to your doctor or pharmacist before taking Quentiax.
Before taking this medicine, tell your doctor if:
- If you or someone in your family have any heart problems, for example heart rhythm problems or if you are taking any medicines that may have an impact on the way your heart beats;
- If you have low blood pressure
- If you have had a stroke, especially if you are elderly;
- If you have liver problems;
- If you have ever had seizures;
- If you have diabetes or are at risk of having diabetes. If so, your doctor may check your blood sugar levels while you are taking Quentiax;
- If you know that you have had a low white blood cell count in the past (which may or may not have been caused by other medicines).
- If you are an elderly person with dementia (loss of brain function). If this is the case, you should not take Quentiax as the group of medicines to which Quentiax belongs may increase the risk of stroke, or in some cases the risk of death in older people with dementia.
- If you or someone in your family has a history of blood clots, as medicines like these have been associated with the formation of blood clots;
- If you have risk factors associated with inflammation of the pancreas (triglycerides, stones or alcohol consumption)
Tell your doctor immediately if you experience:
- A combination of high temperature (fever), severe muscle stiffness, sweating or a reduced level of consciousness (a disorder called 'neuroleptic malignant syndrome'). Immediate medical treatment may be required
- uncontrollable movements, mainly of the face or tongue,
- dizziness or a strong feeling of sleepiness. This could increase the risk of accidental injury (falls) in elderly patients
- Attacks (convulsions)
- A painful and long-lasting "erection (priapism)
These conditions can be caused by this type of medicine.
Thoughts of suicide or worsening of depression
If you are depressed, you can sometimes have thoughts of self-harm and suicide. These may increase at the start of treatment, as these medicines take time to work, usually around two weeks, but sometimes longer. These thoughts may also increase if you stop treatment abruptly. This is more likely to happen. have these thoughts if you are a young adult. Information from clinical trials has shown an increased risk of suicidal thoughts and / or suicidal behaviors in young adults aged less than 25 years with depression.
If you have thoughts of harming or killing yourself, contact your doctor at any time or go to hospital immediately. You may find it helpful to tell a friend or relative who has these symptoms, and ask them to read this leaflet. them to tell you if they think your symptoms are getting worse, or if they are worried about any other change in your behavior. Weight gain has been observed in patients taking Quentiax. You and your doctor need to check your weight regularly.
Interactions Which drugs or foods may change the effect of Quentiax
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Do not take Quentiax if you are taking any of the following medicines:
- Some HIV medicines,
- azole medicines (for fungal infections),
- 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);
- high blood pressure medicines;
- barbiturates (for difficulty sleeping);
- thioridazine (another antipsychotic medicine);
- medicines that can affect the way your heart beats, for example medicines that can cause an imbalance of electrolytes (low levels of potassium or magnesium) such as diuretics (medicines that cause increased urine production) or some antibiotics (medicines to treat infections).
Before you stop taking any medicine, tell your doctor.
Quentiax with food, drink and alcohol
- Quentiax can be taken with or without food.
- Pay attention to the amount of alcohol ingested. This is because the combined effect of Quentiax with alcohol can make you sleepy.
- Do not drink grapefruit juice while taking Quentiax. It can affect the way the medicine works.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. You should not take Quentiax during pregnancy unless you have discussed this with your doctor. You should not take Quentiax while breastfeeding.
In infants whose mothers used Quentiax in the last trimester (last three months of pregnancy) the following symptoms may occur: shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems and difficulty in eating. If your baby develops any of these symptoms you may need to contact your doctor.
Driving and using machines
Your tablets can make you feel sleepy. Therefore, do not drive or use machines until you know how the tablets work on you.
Quentiax contains lactose
If you have been told by your doctor that you have an "intolerance to some types of sugar, please inform your doctor before taking this medicine.
Effects on urine drug control
If you are being tested for drugs in your urine, taking certain tests, taking Quentiax may cause positive results for methadone or for certain depression drugs called tricyclic antidepressants, even if you are not taking these. If this happens, a more specific test may be done.
Dose, Method and Time of Administration How to use Quentiax: Posology
Always take this medicine exactly as your doctor or pharmacist has told you. If you are unsure, you should consult your doctor or pharmacist.
Your doctor will decide on the starting dose. The maintenance dose (daily dose) will depend on the type of disease you have and your needs, but will generally be between 150mg and 800mg,
- You will take the tablets once a day, at bedtime or twice a day, depending on your illness.
- Swallow the tablets whole with a glass of water.
- You can take the tablets regardless of meals.
- Do not drink grapefruit juice while taking Quentiax. It can affect the way the medicine works.
- Do not stop taking your tablets even if you feel better, unless your doctor tells you to.
Liver problems
If you have liver problems your doctor may change your dose.
Older people
If you are elderly your doctor may change your dose.
Use in children and adolescents
Quentiax is not recommended for people under the age of 18.
If you forget to take Quentiax
Do not take a double dose to make up for a forgotten tablet. If you forget a dose, take it as soon as you remember. If it is almost time for your next dose, wait until you take that.
If you stop taking Quentiax
If you stop taking Quentiax abruptly, you may not be able to sleep (insomnia), you may feel sick (nausea), or you may have headache, diarrhea, vomiting, dizziness or irritability. Your doctor may suggest that you reduce the dose gradually before stopping treatment.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Quentiax
If you take more than your normal dose, contact your doctor or the nearest hospital as soon as possible. Take your tablets with you. If you take more Quentiax than prescribed by your doctor, you may feel sleepy, dizzy, abnormal heart beat, low blood pressure , seizures, fainting, muscle damage, confusion, delirium, excitement, inability to empty the bladder or difficulty breathing.
Side Effects What are the side effects of Quentiax
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Very common (may affect more than 1 in 10 people):
- Dizziness (which can lead to falls), headache, dry mouth.
- Sleepiness (this may fade over time as you continue to take your Quentiax tablets), can lead to falls.
- Withdrawal symptoms (symptoms that occur when you stop taking Quentiax) include inability to fall asleep (insomnia), malaise (nausea), headache, diarrhea, vomiting, dizziness, and irritability. Gradual withdrawal for a period is recommended. at least 1-2 weeks.
- Weight gain.
- Reduced amount of hemoglobin or increased amount of certain fats in the blood (triglycerides and total cholesterol).
Common (may affect up to 1 in 10 people):
- Rapid heartbeat
- Abnormal heartbeat with the heart beating fast, with a rapid rhythm or with skipping beats
- Stuffed nose
- Constipation, stomach upset (indigestion)
- Feeling weak, fainting (can lead to falls).
- Swelling of the arms or legs.
- Low blood pressure when standing. This can lead to dizziness or fainting (can lead to falls).
- Increased blood sugar levels, increased liver enzyme levels, increases in the amount of a hormone called prolactin in the blood or changes in thyroid hormones
- Blurred vision.
- Abnormal muscle movements. These include difficulty starting muscle movements, tremors, feeling restless or painless muscle stiffness.
- Abnormal dreams and nightmares.
- Increased appetite.
- Feeling of irritation.
- Speech and language disorders.
- Thoughts of suicide and worsening of depression
- Shortness of breath
- Vomiting (mainly in the elderly)
- Fever
Uncommon (may affect up to 1 in 100 people):
- Decrease in blood sodium levels.
- Convulsions or fits.
- Allergic reactions which may include lumps (wheals), swelling of the skin and swelling around the mouth.
- Unpleasant sensation in the legs (also called restless legs syndrome).
- Difficulty swallowing.
- Sexual dysfunction.
- Uncontrollable movements, mainly of the face or tongue.
- Worsening of pre-existing diabetes.
- Changes in the electrical activity of the heart seen on ECG (prolongation of the QT interval), slow heartbeat
- Poor activity of the thyroid gland which can cause fatigue or weight gain (hypothyroidism).
- Reduced number of platelets (thrombocytopenia).
- Reduced number of red blood cells (anemia)
Rare (may affect up to 1 in 1,000 people):
- A combination of a high temperature (fever), sweating, stiff muscles, feeling sleepy or fainting (a disorder called 'neuroleptic malignant syndrome').
- Yellowing of the skin and eyes (jaundice). Inflammation of the liver (hepatitis)
- Painful and persistent erection (priapism).
- Swelling of the breasts and unexpected production of milk (galactorrhea)
- Menstrual disturbances.
- Blood clots in the veins, particularly 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 consult a doctor immediately
- Walking, talking or eating or doing other activities in your sleep
- Low body temperature.
- Inflammation of the pancreas
- Metabolic syndrome
- Severe reduction in the number of white blood cells which makes infections more likely (agranulocytosis).
- Increase in the levels of creatine phosphokinase in the blood (a substance found in the muscles).
Very rare (may affect up to 1 in 10,000 people):
- Severe disease with pustules on the skin, mouth, eyes and genitals (Stevens-Johnson Syndrome).
- Severe allergic reaction, (called anaphylaxis) which can cause difficulty in breathing or shock.
- Rapid swelling of the skin, usually around the eyes, lips and throat (angioedema).
- Inappropriate secretion of a hormone that controls urine volume.
- Breakdown of muscle fibers and pain in the muscles (rhabdomyolysis)
Not known (frequency cannot be estimated from the available data):
- Sudden severe allergic reaction with symptoms such as fever and blistering of the skin and peeling of the skin (toxic epidermal necrolysis), skin rash with irregular red spots (erythema multiforme).
- Severe reduction in the number of white blood cells (neutropenia).
The class of medicines that Quentiax belongs to can cause heart rhythm problems, which can be serious and in severe cases can be fatal.
Your doctor may ask you to have regular blood tests.
Additional side effects in children and adolescents
The same side effects that can occur in adults can also occur in children and adolescents. The following side effects have only been seen in children and adolescents:
Very common (may affect more than 1 in 10 people):
- Increased blood pressure.
The following side effects were seen more often in children and adolescents:
Very common (may affect more than 1 in 10 people):
- Increase in the amount of a hormone called prolactin in the blood. This increase can lead to:
- have swelling of the breasts and unexpected milk production in boys and girls.
- not having periods or having irregular periods in girls.
- Increased appetite.
- Abnormal muscle movements. These include difficulty starting muscle movements, tremors, feeling restless or painless muscle stiffness.
If you get any side effects not listed in this leaflet, talk to your doctor or pharmacist
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton, container and blister after EXP. The expiry date refers to the last day of the month.
This medicinal product does not require any special storage precautions.
HDPE tablet container:
The shelf life after first opening is 3 months.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What Quentiax contains
- The active ingredient is quetiapine. Each tablet contains 25 mg, 100 mg, 150 mg, 200 mg or 300 mg of quetiapine (as quetiapine hemifumarate).
- The other ingredients are: lactose monohydrate, calcium hydrogen phosphate dihydrate, microcrystalline cellulose, povidone, sodium starch glycolate (type A), magnesium stearate in the tablet core and hypromellose, titanium dioxide (E171), macrogol 4000, yellow iron oxide (E172) ( 25 mg and 100 mg tablets only) and red iron oxide (E172) (25 mg tablets only) in the film overlay.
What Quentiax looks like and contents of the pack
The 25 mg tablets are round, pale red film-coated tablets with a bevelled edge.
The 100 mg tablets are round, brown / yellow film-coated tablets.
The 150 mg tablets are round, white, film-coated with a beveled edge.
The 200 mg tablets are round, white film-coated tablets.
The 300 mg tablets are oblong, white film-coated tablets.
Quentiax film-coated tablets are available in packs of 6 (25 mg tablets only), 10, 20, 30, 30 x 1, 50, 60, 90, 98, 100, 100 x 1, 120 (only the 150 mg and 300 mg tablets), 180 (150 mg and 300 mg tablets only) or 240 (150 mg and 300 mg tablets only) tablets in blisters and 250 tablets (100 mg and 200 mg tablets only ) in a container (HDPE). 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
QUENTIAX TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 25 mg, 100 mg, 150 mg, 200 mg or 300 mg of quetiapine (as quetiapine hemifumarate).
Excipients with known effect:
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
The 25 mg tablets are round, pale red film-coated tablets with a bevelled edge.
The 100 mg tablets are round, brown / yellow film-coated tablets.
The 150 mg tablets are round, white, film-coated with a beveled edge.
The 200 mg tablets are round, white film-coated tablets.
The 300 mg tablets are oblong, white film-coated tablets.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Quentiax is 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 relapse in patients with bipolar disorder, in patients whose manic or depressive episodes have responded to treatment with quetiapine.
04.2 Posology and method of administration
Dosage
Adults:
For the treatment of schizophrenia
For the treatment of schizophrenia Quentiax should be administered twice daily. The total daily dose for the first four days of treatment is 50 mg (day 1), 100 mg (day 2), 200 mg (day 3) and 300 mg (day 4).
From day 4 onwards the dose should be titrated to the usual effective dose of 300 - 450 mg / day. Depending on the clinical response and individual patient tolerability to the drug, the dose can be adjusted within a range of 150 - 750 mg / day.
For the treatment of moderate to severe manic episodes associated with bipolar disorder
For the treatment of manic episodes associated with bipolar disorder Quentiax should be administered twice daily. The total daily dose for the first four days of therapy is 100 mg (day 1), 200 mg (day 2), 300 mg (day 3) and 400 mg (day 4).
Further dose adjustments, increased to a maximum of 800 mg / day, from day 6 should be at most increments of no more than 200 mg / day. Depending on the clinical response and individual patient tolerability to the drug, the dose can be adjusted within the range of 200 - 800 mg / day. The usual effective dose is in the range of 400 - 800 mg / day.
For the treatment of major depressive episodes in bipolar disorder
Quentiax should be administered once daily, 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 a 600 mg dose. Starting doses greater than 300 mg should be prescribed by a physician experienced in 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 relapse in bipolar disorder
To prevent relapse of manic, mixed, or depressive episodes in bipolar disorder, patients who have responded to quetiapine for acute treatment of bipolar disorder should continue therapy at the same dose.Based on the individual patient's clinical response and drug tolerability, the dose can be adjusted within a range of 300-800 mg / day administered twice daily.
It is important that the lowest effective dose is used for maintenance therapy.
Elderly patients:
Like other antipsychotics and antidepressants, Quentiax should be used with caution in the elderly, especially during the initial dosing period. Depending on the patient's clinical response and individual tolerability, the titration period may be longer and the daily dose may be lower than in younger patients. The mean plasma elimination of quetiapine is reduced by 30-50% in elderly subjects compared to younger patients.
Efficacy and safety have not been evaluated in patients over 65 years of age with depressive episodes in the context of bipolar disorder.
Pediatric population:
The use of Quentiax in children and adolescents under the age of 18 is not recommended due to a lack of data to support its use in this age group. Evidence available from placebo-controlled clinical trials is presented in sections 4.4, 4.8, 5.1, and 5.2.
Kidney failure:
No dose adjustment is necessary in patients with renal insufficiency.
Liver failure:
Quetiapine is extensively metabolised by the liver. Therefore Quentiax should be used with caution in patients with known hepatic insufficiency, especially at the beginning of the dosing period.
Patients with hepatic insufficiency should start on 25 mg / day. The dose may be increased in daily increments of 25 - 50 mg / day to an effective dose, subject to the clinical response and tolerability of the individual patient.
Method of administration
Quentiax can be given with or without meals
There are different dosing schedules for each indication. It should therefore be ensured that patients receive clear information on the appropriate dosage for their condition.
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 Quietapine has numerous indications, the safety profile of the product must be considered with respect to the patient's diagnosis and the dose to be administered.
Children and adolescents (10-17 years)
Quentiax is not recommended for use 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 have shown that in addition to the known safety profile identified in adults (see section 4.8), some adverse events occurred at a higher frequency in children and adolescents than in adults (increased appetite, increased serum prolactin and extrapyramidal symptoms) and an adverse event previously not observed in adult studies (increase in blood pressure) was identified. Changes in thyroid function have also been observed in children and adolescents.
Furthermore, the long-term safety implications of treatment on growth and maturity have not been studied beyond 26 weeks. The long-term implications for cognitive and behavioral development are unknown.
In placebo-controlled clinical trials in children and adolescents treated with quetiapine, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for schizophrenia and bipolar mania (see section 4.8). .
Suicide / suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self-harming behaviors and suicide (suicide-related events). The risk persists as long as significant remission occurs. Improvement may not occur during the first or subsequent weeks of treatment, patients should be closely monitored until such improvement occurs.
It is general clinical experience that the risk of suicide may increase during the early stages of remission.
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 being treated.
Other psychiatric conditions for which quetiapine is prescribed may also be associated with an increased risk of suicide-related events. Furthermore, these conditions may have concomitant morbidity with major depressive episodes. Therefore, the same precautions observed when treating patients with major depressive disorders should be observed 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 known to be at increased risk for suicidal thoughts or suicide attempts, and should be closely monitored. during treatment A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressants compared to placebo in patients less than 25 years old.
Drug therapy should be accompanied by close supervision of patients, particularly those at high risk, especially at the start of treatment and following dose changes. Patients (and their carers) should be advised of the need to monitor for any clinical worsening, suicidal behavior or thoughts and unusual changes in behavior and seek immediate medical attention if these symptoms occur.
In short-term placebo-controlled clinical trials in patients with major depressive episodes in bipolar disorder, an increased risk of suicide-related events was observed in young adult patients ( younger of 25 years of age) who were treated with quetiapine versus those treated with placebo (3.0% vs 0%, respectively).
Extrapyramidal symptoms
In placebo-controlled clinical trials in adult patients, quetiapine was associated with an increased incidence of extrapyramidal symptoms (EPS) compared to placebo in patients treated for major depressive episodes in bipolar disorder (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 distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is more likely to occur within the first few weeks of treatment. patients who develop these symptoms, increasing the dose may be harmful.
Tardive dyskinesia:
In the event of signs and symptoms of tardive dyskinesia, dose reduction or discontinuation of Quentiax should be considered. Symptoms of tardive dyskinesia may worsen or even occur 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, onset was usually within the first three days of treatment and was mainly mild or moderate in severity. Patients with bipolar depression who experience severe somnolence may require longer contact. frequent for a minimum of two weeks after the onset of somnolence, or until symptoms improve and discontinuation of treatment can be considered. Quetiapine treatment has been associated with orthostatic hypotension and related dizziness (see section 4.8) which, like somnolence, it usually occurs during the initial dose-titration period. This may increase the occurrence of accidental injury (falls), particularly in the elderly population. Therefore patients should be advised to exercise caution until they are familiar with the effects of the medicinal product.
Cardiovascular pathologies
Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or other conditions predisposing to hypotension.
Quetiapine can induce orthostatic hypotension, particularly during the initial titration period. If this happens, a dose reduction or gradual titration should be considered. In patients with latent cardiovascular disease, slower titration may be considered.
Convulsions
In controlled clinical trials, there was no difference in the incidence of seizures in patients treated with quetiapine or placebo. No data are available on the incidence of seizures in patients with a history of seizure disorder. Like 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 antipsychotics, including quetiapine (see section 4.8). Clinical manifestations include hyperthermia, altered mental status, muscle stiffness, autonomic instability and increased creatinine phosphokinase.
In this case, quietiapian should be discontinued and appropriate medical treatment administered.
Severe neutropenia
Severe neutropenia (neutrophil count leukopenia and / or neutropenia following discontinuation of quetiapine therapy has been uncommonly reported in clinical trials with quetiapine. Possible risk factors for neutropenia include pre-existing low levels of white blood cells (WBCs) and a history of Drug-induced neutropenia Quetiapine should be discontinued in patients with a neutrophil count for signs or symptoms of infection and neutrophil counts monitored (to exceed 1.5 x 109 / L) (see section 5.1).
Interactions
See also section 4.5.
Concomitant use of quetiapine with a potent hepatic enzyme inducer, such as carbamazepine or phenytoin, substantially reduces the plasma concentrations of quetiapine, which may affect the efficacy of quetiapine therapy.
Quetiapian therapy in patients using hepatic enzyme inducers should only be initiated if the physician considers that the benefits of quetiapine treatment outweigh the risks of discontinuing liver enzyme inducer therapy. It is important that any change in the use of inductors is gradual. If necessary, the inducer should be replaced by a non-inducing agent (eg sodium valproate).
Weight:
Weight gain has been reported in patients treated with quetiapine, and should be monitored and treated as clinically appropriate, according to antipsychotic guidelines (see sections 4.8 and 5.1).
Hyperglycemia
Hyperglycaemia and / or development or worsening of diabetes occasionally associated with keto-acidosis or coma has been reported rarely, including some fatal cases (see section 4.8). In some cases, previous weight gain has been reported which may be a predisposing factor. Appropriate clinical monitoring is advised according to antipsychotic use guidelines. Patients treated with any antipsychotic agent, including quetiapine, should be monitored for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight must be monitored regularly.
Lipids
An increase in triglycerides and total and LDL cholesterol and a decrease in HDL have been observed in clinical studies with quetiapine (see section 4.8). A change in lipids must be managed in a clinically appropriate manner.
Metabolic risk
As changes in weight, blood glucose (see hyperglycemia) and lipids have been observed in clinical trials, patients (including those with normal baseline values) may experience worsening of the metabolic profile in individual patients, which should be managed clinically appropriate (see also section 4.8).
QT prolongation
In clinical trials and from use in accordance with the summary of product characteristics, quetiapine was not associated with a persistent increase in absolute QT intervals. There have been reports of QT prolongation with quetiapine used in post-marketing experience. at therapeutic doses (see section 4.8) and overdose (see section 4.9). As with other antipsychotics, caution is required when prescribing Quentiax in patients with cardiovascular disease or a family history of QT prolongation. Caution should also be exercised when quetiapine is prescribed with drugs that prolong the QT interval or in concomitant therapy with other neuroleptics, especially in elderly subjects, in patients with congenital long QT syndrome in congestive heart failure, in cardiac hypertrophy, with l "hypokalaemia, or" hypomagnesaemia (see section 4.5).
Abstinence
Acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability have been described following abrupt cessation of quetiapine. A "gradual discontinuation of treatment," over at least one to two weeks is recommended (see section 4.8).
Elderly patients with dementia-related psychosis
Quetiapine is not approved for the treatment of dementia-related psychosis.
An approximately 3-fold increased risk of cerebrovascular adverse events with some atypical antipsychotics in the dementia population was seen in randomized placebo-controlled clinical trials. The mechanism of this increased risk is unknown. An increased risk for other antipsychotics or other patient groups cannot be excluded. Quetiapine should be used with caution in patients with stroke risk factors.
In a meta-analysis of atypical antipsychotic drugs, elderly patients with dementia-related psychosis were reported to be at an increased risk of death compared to placebo.
However, in two placebo-controlled, 10-week studies of quetiapine in the same patient group (n = 710; mean age: 83 years; range: 56-99 years) the incidence of mortality in patients treated with quetiapine was was 5.5% versus 3.2% in the placebo group. In these studies, patients died from a variety of causes that were in accordance with expectations for this population. These results do not establish a causal relationship between quetiapine treatment and death of elderly patients with dementia.
Dysphagia
Dysphagia (see section 4.8) has been reported with quetiapine. Quetiapine should be used with caution in patients at risk of aspiration pneumonia.
Venous thromboembolism (VTE)
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with quetiapine and preventive measures taken.
Pancreatitis
Cases of pancreatitis have been reported in clinical trials and post-marketing experience. Among the cases reported during the post-marketing phase, while not all cases were confounded by risk factors, many patients had known risk factors for the their association with pancreatitis, such as increased triglycerides (see section 4.4), gallstones and alcohol consumption.
Additional information
There are limited data on the administration of quetiapine in combination with valproate or lithium in the treatment of acute moderate / severe manic episodes; however the combination therapy was well tolerated (see sections 4.8 and 5.1). The data showed an additional effect at the third week.
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this drug.
04.5 Interactions with other medicinal products and other forms of interaction
Due to the primary central nervous system effects, quetiapine should be administered with caution in combination with other centrally active medicinal products and with alcohol.
Cytochrome P450 (CYP) 3A4 is the enzyme primarily responsible for the cytochrome P-450 mediated metabolism of quetiapine. In an interaction study in healthy volunteers, concomitant administration of quetiapine (at a dose of 25 mg) and ketoconazole (an inhibitor of CYP 3A4) caused a 5 to 8-fold increase in quetiapine AUC. For this reason, concomitant use of quetiapine with potent CYP 3A4 inhibitors is contraindicated. It is also recommended not to take quetiapine with grapefruit juice.
In a multiple-dose study to evaluate the pharmacokinetics of quetiapine before and during treatment with carbamazepine (a known hepatic enzyme inducer), concomitant administration of carbamazepine significantly increased the elimination of quetiapine.This increase in elimination reduced systemic exposure to quetiapine (as measured by AUC) by an average of 13% compared to those who received quetiapine alone, although a greater effect was observed in some patients. of this interaction, reduced plasma concentrations may be observed which may interfere with the efficacy of quetiapine therapy.
Concomitant administration of quetiapine and phenytoin (another inducer of the microsomal enzyme system) resulted in approximately 450% increases in quetiapine clearance.
In patients using hepatic enzyme inducers, quetiapine treatment should only be initiated if the physician considers that the benefits of quetiapine therapy outweigh the risks of discontinuing liver enzyme inducer therapy. It is important that any changes in the use of inductors be gradual. If necessary, the inducers should be replaced by a non-inducing agent (e.g. sodium valproate) (see section 4.4).
The pharmacokinetics of quetiapine were not significantly altered with concomitant administration of antidepressants, imipramine (known inhibitor of CYP 2D6) or fluoxetine (known inhibitor of CYP 3A4 and CYP 2D6).
The pharmacokinetics of quetiapine were not significantly altered with concomitant administration of antipsychotics, risperidone or haloperidol. Simultaneous use of quetiapine and thioridazine increased quetiapine elimination to an approximation of 70%.
The pharmacokinetics of quetiapine were not altered with co-administration with cimetidine.
The pharmacokinetics of lithium were not altered during concomitant administration of quetiapine.
The pharmacokinetics of sodium valproate and quetiapine were not altered to a clinically relevant extent when co-administered. A retrospective study of children and adolescents treated with valproate, quetiapine, or both, found a "higher incidence of leukopenia and neutropenia in the combination group" compared to the monotherapy groups.
Formal interaction studies of commonly used cardiovascular drugs have not been performed.
Caution should be exercised when quetiapine is administered concomitantly with medicinal products known to cause electrolyte imbalances or increases in the QT interval.
False positive results in the enzyme immunoassay for methadone and tricyclic antidepressants have been reported in patients taking quetiapine. Confirmation of equivocal immunoassay results by appropriate chromatographic technique is recommended.
04.6 Pregnancy and breastfeeding
Pregnancy
The safety and efficacy of quetiapine have not been evaluated during pregnancy. Animal studies to date have not shown harmful results. Possible effects on the eyes of embryos have not been examined. Therefore, quetiapine should only be used in pregnancy when the benefits justify the potential risks Withdrawal symptoms have been observed in neonates if quetiapine was used during pregnancy.
Newborns exposed to antipsychotic agents (including Quentiax) during the third trimester of pregnancy are at risk for side effects including extrapyramidal and / or withdrawal symptoms which may vary in severity and duration after delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and food intake disturbance. Infants should therefore be monitored closely.
Feeding time
Cases of quetiapine excretion into breast milk have been published however the degree of excretion was not constant. Breastfeeding women should be advised to avoid breastfeeding while taking quetiapine.
04.7 Effects on ability to drive and use machines
Quentiax has moderate influence on the ability to drive and use machines.
Given its effect primarily on the central nervous system, quetiapine may interfere with activities where alertness is required. Therefore, patients should be advised not to drive or operate machinery until individual susceptibility is known.
04.8 Undesirable effects
Summary of the safety profile
The most commonly reported undesirable effects with quetiapine are somnolence, dizziness, dry mouth, mild asthenia, constipation, tachycardia, orthostatic hypotension and dyspepsia.
Like other antipsychotics, use of quetiapine has been associated with weight gain, syncope, neuroleptic malignant syndrome, leukopenia, neutropenia and peripheral edema.
Tabulated list of adverse reactions
The incidences of ADRs associated with quetiapine therapy are presented in the table below according to the format recommended by the Council for International Organizations of Medical Sciences (CIOMS III Working Group 1995).
The frequency of undesirable effects is presented as follows: very common (> 1/10), common (≥ 1/100 e
Disorders of the blood and lymphatic system
- Very common: decreased hemoglobin 23
- Common: leukopenia1,29, neutrophil count decreased, eosinophils increased28
- Uncommon: thrombocytopenia, anemia, platelet count decreased14
- Rare: agranulocytosis 27
- Not known: neutropenia1
Disorders of the immune system
- Uncommon: hypersensitivity (including allergic skin reactions)
- Very rare: anaphylactic reaction 6
Endocrine pathologies
- Common: hyperprolactinaemia16, reductions in total T425, reductions in free T425, reductions in total T325, increases in TSH25
- Uncommon: reductions in free T325, hypothyroidism22
- Very rare: Inappropriate antidiuretic hormone secretion
Metabolism and nutrition disorders
- Very common: increases in triglyceride levels11.31, increases in total cholesterol (mainly LDL cholesterol) 12.31, reduction in HDL cholesterol18.31, weight gain9.31
- Common: increased appetite, increased blood glucose to hyperglycemic levels7,31
- Uncommon: Hyponatremia 20, diabetes mellitus1,5,6
- Rare: metabolic syndrome 30
Psychiatric disorders
- Common: abnormal dreams and nightmares, suicidal ideation and suicidal behavior 21
- Rare: sleepwalking and related reactions such as sleep talking and sleep-related eating disorder
Nervous system disorders
- Very common: dizziness4.17, headache, somnolence2.17
- Common: syncope4.17, extrapyramidal symptoms1.22, dysarthria
- Uncommon: convulsions1, restless legs syndrome, tardive dyskinesia1,6
Eye disorders
- Common: blurred vision
Cardiac pathologies
- Common: tachycardia4, palpitations24
- Uncommon: QT interval prolongation1,13,19, bradycardiaxx
Vascular pathologies
- Common: orthostatic hypotension4, 17
- Rare: venous thromboembolism 1
Respiratory, thoracic and mediastinal disorders
- Common: rhinitis, dyspnoea 24
Gastrointestinal disorders
- Very common: dry mouth
- Common: dyspepsia, constipation, vomiting 26
- Uncommon: dysphagia 8
- Rare: pancreatitis
Hepatobiliary disorders
- Common. increase in serum alanine aminotransferase (ALT, AST) 3 levels, increase in gamma-GT3 levels
- Rare: jaundice6, hepatitis
Skin and subcutaneous tissue disorders
- Very rare: angioedema6, Stevens-Johnson syndrome6
- Not known: toxic epidermal necrolysis, erythema multiforme
Musculoskeletal and connective tissue disorders
- Very rare: rhabdomyolysis
Pregnancy, puerperium and perinatal conditions
- Not known: neonatal withdrawal syndrome 32
Diseases of the reproductive system and breast
- Uncommon: sexual dysfunction
- Rare: priapism, galactorea, breast swelling, menstrual disorders
General disorders and administration site conditions
- Very common: withdrawal symptoms (discontinuation) 1.10
- Common: mild asthenia, peripheral edema, irritability, pyrexia
- Rare: neuroleptic malignant syndrome1, hypothermia
Diagnostic tests
- Rare: creatine phosphokinase increases 15
1. See section 4.4.
2. Somnolence usually occurs in the first two weeks of treatment and usually resolves with continued administration of quetiapine.
3. An asymptomatic increase (shift from normal to> 3X ULN at any time) in serum transaminase (ALT, AST) or gamma-GT levels has been observed in some patients treated with quetiapine. This increase usually resolved with continued quetiapine treatment.
4. Like other antipsychotics with alpha-1 adrenergic receptor blocking activity, quetiapine can commonly induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope especially during the initial titration period (see section 4.4).
5. Exacerbation of pre-existing diabetes has been reported in very rare cases
6. The frequency of these ADRs is calculated based on post-marketing experience with the immediate-release quetiapine formulation only.
7. 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.
8. An increase in the rate of dysphagia with quetiapine compared with placebo was only observed in clinical trials in bipolar depression.
9. Based on> 7% weight gain from baseline. It occurs mostly during the first few weeks of treatment.
10. 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 significantly decreased 1 week after discontinuation.
11. Triglycerides ≥200 mg / dL (≥2,258 mmol / L) (patients ≥18 years of age) or ≥150 mg / dL (≥1,694 mmol / L) (patients
12. Cholesterol ≥240 mg / dL (≥6,2064 mmol / L) (patients ≥18 years of age) or ≥200 mg / dL (≥5,172 mmol / L) (patients
13. See text below
14. Platelets ≤100 x 109 / L on at least one "occasion.
15. Based on clinical trial reports of undesirable effects related to creatine phosphokinase elevation not associated with neuroleptic malignant neuroleptic syndrome.
16. 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.
17. Can lead to falls
18. HDL cholesterol:
19. Incidence of patients who have had a change in QTc from
20. Go from> 132 mmol / L to ≤132 mmol / L on at least one "occasion.
21. Cases of suicidal ideation and suicidal behavior have been reported during quetiapine therapy or soon after treatment discontinuation (see sections 4.4 and 5.1).
22. See paragraph 5.1
23. There was a reduction in hemoglobin to ≤13 g / dL (8.07 mmol / L) in men, ≤12 g / dL (7.45 mmol / L) in women on at least one "occasion in" 11% of patients treated with quetiapine in all clinical trials including open label extensions. For these patients, the mean maximum reduction in hemoglobin at any time was -1.50 g / dL.
24. These cases often occurred in a scenario of tachycardia, dizziness, orthostatic hypotension and / or latent cardiac / respiratory disease.
25. Based on changes from normal baseline to potentially clinically important value at any time after baseline across all studies. Alterations of total T4, free T4, total T3 and free T3 are defined as 5 mIU / L at any time.
26. Based on the rate of increased vomiting in elderly patients (≥65 years of age).
27. Changes in neutrophils of ≥ 1.5 x 109 / L at baseline a
28. Based on changes from normal baseline to potentially clinically important value at any time after baseline across all studies. Changes in eosinophils are defined as> 1x 109 cells / L at any time.
29. Based on changes from normal baseline to potentially clinically important value at any time after baseline across all studies. Alterations in WBCs are defined as ≤ 3X109 cells / L at any time
30. Based on case reports of metabolic syndrome side effects in all clinical trials with quetiapine.
31. In some patients, worsening of more than one of the metabolic factors of weight, blood glucose and lipids was observed in clinical studies (see section 4.4).
32. See section 4.6.
XX. It can occur at or near the start of treatment and can be associated with hypotension and / or syncope. Case-based frequency of 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.
Children and adolescents (10 to 17 years of age)
The same adverse reactions described above for adults should be considered for children and adolescents. The table below summarizes adverse reactions that occur more frequently in treated children and adolescents (10-17 years of age) than in the adult population or adverse reactions that have not been identified in the adult population.
The incidence of adverse reactions is presented as follows: very common (> 1/10), common (≥ 1/100 e
Metabolism and nutrition disorders:
- Very common: increased appetite
Diagnostic tests
- Very common: increased prolactin1, increased blood pressure2.
Nervous system disorders:
- Very common. extrapyramidal symptoms 3
General disorders and administration site conditions
- Common: irritability 4
1. Prolactin levels (patients> 18 years of age):> 20 mcg / L (> 869.56 pmol / L) male; > 26 mcg / L (> 1130.428 pmol / L) females, at any time. Less than 1% of patients had an increase in prolatin levels> 100 mcg / L.
2. Based on changes above the clinically significant limit (adapted from National Institut of health criteria) or increases> 20 mmHg for systolic blood pressure or> 10 mmHg for diastolic blood pressure at any time in two acute clinical studies ( 3-6 weeks), placebo-controlled, in children and adolescents.
3. See paragraph 5.1
4. Note: The frequency is consistent with that seen in adults, but irritability may be associated with different clinical implications in children and adolescents than in adults.
04.9 Overdose
Symptoms
In general, the signs and symptoms reported were those of exaggeration of the known pharmacological effects of quetiapine, eg. somnolence, sedation, tachycardia and hypotension.
One fatal case has been reported in a clinical study following an overdose of 13.6 grams and in post-marketing experience with 6 gram doses of quetiapine alone. However, patient survival in overdose has been described. up to 30 grams of quetiapine. Cases of overdose of quetiapine alone leading to death or coma have been reported in post-marketing experience.
In addition, the following events have been reported in the quetiapine monotherapy overdose scenario: QT prolongation, seizures, status epilepticus, rhabdomyolysis, respiratory depression, urinary retention, confusion, delirium and / or agitation.
Patients with pre-existing severe cardiovascular disease may be at increased risk of the effects of overdose (see section 4.4: Cardiovascular Disorders).
Management of overdose
There is no specific antidote to quetiapine. In cases of severe signs, the possibility of multiple drug involvement should be considered and intensive care procedures including establishment and maintenance of the patient's airways, ensuring adequate oxygenation are recommended. and ventilation and monitoring and support of the cardiovascular system. Although inhibition of absorption in overdose has not been investigated, gastric lavage may be indicated in cases of severe poisoning, possibly within one hour of ingestion. Administration of activated charcoal should be considered.
In cases of quetiapine overdose, refractory hypotension should be treated with appropriate measures such as intravenous fluids and / or sympathetic mimetic agents. quetiapine.
Close medical supervision and monitoring should continue until the patient heals.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antipsychotics.
ATC code: N05AH04.
Mechanism of action:
Quetiapine is an atypical antipsychotic agent. Quetiapine and its active metabolite in human plasma, norquetiapine, interact with a broad spectrum of neurotransmitter receptors.
Quetiapine and norquetiapine have affinity for brain serotonin (5-HT 2) and dopamine D1 - and D2 receptors. The combination of a receptor antagonism with greater selectivity for 5HT2 receptors than for D2 receptors is believed to contribute to the clinical antipsychotic properties and reduced predisposition to induce extrapyramidal reactions (EPS) of quetiapine compared to typical antipsychotics. Furthermore, norquetiapine has a high affinity for the norepinephrine transporter (NET).
Quetiapine and norquetiapine also have high affinity for histaminergic and 1-adrenergic receptors, with a lower affinity for 2-adrenergic receptors and 5HT 1A serotonin receptors. Quetiapine has no appreciable affinity for muscarinic or benzodiazepine cholinergic receptors.
Pharmacodynamic effects
Quetiapine was found to be active in antipsychotic activity assessment tests, such as the active avoidance test. It also antagonizes the action of dopaminergic agonists, as assessed both from a behavioral and electrophysiological point of view, and increases the concentration of dopamine metabolites considered. neurochemical indicators of D2 receptor blocking activity.
In preclinical tests for the prediction of extrapyramidal reactions, quetiapine was different from typical antipsychotics by demonstrating an atypical profile. Chronic administration of quetiapine does not cause supersensitivity of dopaminergic D2 receptors. Quetiapine causes only weak catalepsy at doses effective for blocking dopamine D2 receptors. After chronic administration quetiapine demonstrates selectivity for the limbic system through a block of mesolimbic depolarization without nigrostriatal effect in which dopaminergic neurons are present. Quetiapine, after acute and chronic administration, has a minimal disposition to induce dystonic manifestations in haloperidol-sensitive or drug-free Cebus monkeys (see section 4.8).
Clinical efficacy:
Schizophrenia
In three placebo-controlled clinical trials in patients with schizophrenia, using variable doses of quetiapine, there was no difference in the incidence of extrapyramidal reactions or concomitant use of anticholinergics between the treatment groups and those treated with quetiapine.
A placebo-controlled clinical study evaluating fixed doses of quetiapine in the range of 75 - 750 mg / day showed no increase in extrapyramidal reactions or concomitant use of anticholinergics. The long-term efficacy of immediate-release quetiapine in prevention relapse of schizophrenia has not been verified in blinded clinical trials. In open-label studies, in patients with schizophrenia, quetiapine was effective in maintaining clinical improvement during follow-up therapy in patients who exhibited an initial response to treatment, suggesting long-term efficacy.
Bipolar disorder
In four placebo-controlled clinical trials, which evaluated quetiapine doses up to 800 mg / day for the treatment of moderate to severe manic episodes (two as monotherapy and two as adjunct to lithium or valproate), they were not Differences in treatment groups were observed between quetiapine and placebo in the incidence of EPS or concomitant use of anticholinergics.
In the treatment of moderate to severe manic episodes, quetiapine demonstrated superior efficacy to placebo in reducing manic symptoms at 3 and 12 weeks in two monotherapy studies. There are no data from long-term studies to demonstrate the efficacy of quetiapine in preventing subsequent episodes of mania or depression. Data for quetiapine in combination with valproate or lithium in moderate to severe manic episodes at 3 and 6 weeks are limited; however, combination therapy was well tolerated. Data demonstrated an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.
The mean quetiapine dose for responders was approximately 600 mg / day in the last week and approximately 85% of responders were taking a dose in the range of 400-880 mg / day.
In four 8-week clinical trials in patients with moderate to severe depressive episodes with bipolar I and II disorder, quetiapine 300 mg and 600 mg was significantly superior to placebo in treated patients in terms of relevant outcome measures such as: mean improvement in MADRS and clinical response defined as at least a 50% improvement in MADRS total score from baseline. There was no difference in effect magnitude between patients who received 300 mg immediate-release quetiapine and those who received 600 mg dose.
In the continuation phase of these two studies, it was shown that long-term treatment of patients who responded to immediate-release quetiapine 300 mg or 600 mg was effective in preventing relapse of depressive symptoms compared to treatment with placebo, but not the manic ones.
In patients with manic, depressive or mixed episodes, in two relapse prevention studies evaluating quetiapine in combination with mood stabilizers, the combination with quetiapine was superior to stabilizers alone in increasing the time to relapse. any episode of mood alteration (manic, mixed or depressive). Quetiapine was administered twice daily, for a total of 400 mg-800 mg / day as combination therapy with lithium or valproate.
In a long-term study (up to two years of treatment) evaluating relapse prevention in patients with manic, depressive or mixed episodes, quetiapine was superior to placebo in increasing the time to relapse in any event (of mania , mixed or depressive), in patients with bipolar I disorder. The number of patients with a mood disorder was 91 (22.5%) in the quetiapine group, 208 (51.5%) in the placebo group, respectively and 95 (26.1%) in the lithium treatment group. In patients responding to quetiapine, when comparing prolonged treatment with quetiapine to switching to lithium, the results indicated that switching to lithium treatment does not appear to be associated with an increase in the time to relapse of a mood disorder.
Clinical studies have shown that quetiapine is effective in schizophrenia and mania when given twice daily, although quetiapine has a "pharmacokinetic half-life of approximately 7 hours. This is further supported by data from a PET (emission tomography) study. of positron), which demonstrated that for quetiapine, the occupation of the D2 and 5HT 2 receptors was maintained for up to 12 hours. The safety and efficacy of doses above 800 mg / day have not been evaluated.
Clinical safety
In short-term, placebo-controlled clinical trials in schizophrenia and bipolar mania, the pooled incidence of extrapyramidal symptoms was similar to placebo (schizophrenia: 7.8% for quetiapine and 8.0% for placebo; bipolar mania: 11.2% for quetiapine and 11.4% for placebo) High rates of extrapyramidal symptoms were observed in patients treated with quetiapine compared to those treated with placebo in short-term, placebo-controlled clinical trials in manic depressive disorder and in bipolar depression. In short-term placebo-controlled clinical trials in bipolar depression the aggregate incidence of extrapyramidal symptoms was 8.9% for quetiapine compared to 3.8% for placebo. In short-term clinical trials The pooled incidence of extrapyramidal symptoms was 5.4% for prolonged-release quetiapine and 2.3% for placebo, placebo-controlled monotherapy in major depressive disorder. In both bipolar depression and manic depressive disorder, the incidence of individual adverse events (eg. Akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, involuntary muscle contractions, motor hyperactivity and muscle stiffness) did not exceed 4% in no treatment group.
In short-term, fixed-dose (50 mg / day to 800 mg / day) placebo-controlled studies (lasting 3 to 8 weeks), mean weight gain for quetiapine-treated patients ranged from 0.8 kg for the 50 mg daily dose to 1.4 kg for the 600 mg daily dose (with a smaller increase for the 800 mg daily dose), compared with 0.2 kg for patients treated with placebo. quetiapine-treated patients who had taken ≥7% body weight ranged from 5.3% for the 50 mg daily dose to 15.5% for the 400 mg daily dose (with a smaller increase for the 600 and 800 mg), compared with 3.7% for placebo-treated patients.
Longer period relapse prevention studies had an open-label period (4 to 36 weeks) during which patients were treated with quetiapine, followed by a randomized withdrawal period during which patients were randomized. quetiapine or placebo.
For patients randomized to quetiapine, mean weight gain during the open label period was 2.56 kg and by week 48 of the randomized period, mean weight gain was 3.22 from baseline open label. For patients randomized to placebo, mean weight gain during the open label period was 2.39 kg and by week 48 of the randomized period the mean weight gain was 0.89 kg from baseline open label.
In placebo-controlled studies of elderly patients with dementia-related psychosis, the incidence of cerebrovascular events per 100 patient years was no higher in quetiapine-treated patients than in placebo-treated patients.
In all short-term placebo-controlled monotherapy clinical trials in patients with baseline neutrophil count ≥1.5 x 109 / L, the incidence of at least one neutrophil episode 0.5-
Quetiapine treatment was associated with small dose-related reductions in thyroid hormone levels. The incidence of changes in TSH was 3.2% for quetiapine versus 2.7% for placebo. The incidence of potentially clinically relevant reciprocal changes in both T 3 or T 4 and TSH in these studies it was rare, and the observed changes in thyroid hormone levels were not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal within the first six weeks of quetiapine treatment, with no further reduction during long-term treatment. For approximately 2/3 of all cases, cessation of quetiapine treatment was associated with a "reversal of the effects on total and free T 4 regardless of treatment duration.
Cataracts / Lens opacification
In a clinical study to evaluate the cataractogenic potential of quetiapine (200-800 mg / day) versus risperidone (2-8 mg) in patients with schizophrenia or schizophrenic disorder, the percentage of patients with increased degree of lens opacity was no longer elevated with quetiapine (4%) compared to risperidone (10%) for patients with at least 21 months of exposure.
Pediatric population
Children and adolescents (10 to 17 years of age)
The efficacy and safety of quetiapine were evaluated in a 3-week placebo-controlled study for the treatment of mania (n = 284 patients from the US, aged 10-17 years). Approximately 45% of patients have a additional diagnosis of ADHD. In addition, a 6-week placebo-controlled study was conducted for the treatment of schizophrenia (n = 222 patients, aged 13-17 years). In both studies, patients who failed to respond to quetiapine were been excluded.
Quetiapine treatment started with 50mg / day and increased to 100mg / day on day 2; subsequently the dose was titrated to the optimal dose (mania 400-600 mg / day; schizophrenia 400-800 mg / day) using increases of 100 mg / day administered two or three times daily.
In the mania study, the mean difference in LS change from baseline on YMRS total scale (active minus placebo) was -5.21 for quetiapine 400 mg / day and -6.56 for quetiapine 600 mg / day. Response rates (YRMS increase ≥ 50%) were 64% for quetiapine 400 mg / day, 58% for 600 mg / day, and 37% in the placebo group.
In the schizophrenia study, the difference in LS mean change from baseline on the PANSS (active minus placebo) scale was -8.16 for quetiapine 400 mg / day and -9.29 for quetiapine 800 mg / day. Neither the lowest dose (400 mg / day) nor the highest dose regimen (800 mg / day) of quetiapine was superior to placebo compared to the proportion of patients who responded, defined as ≥ 30% reduction from baseline in total score PANSS. Both mania and schizophrenia at higher doses resulted in numerically lower response rates.
There are no data available on maintenance of effects or prevention of relapse in this age group.
An open-label 26-week phase of the acute trial (n = 380 patients), with flexible doses of quetiapine from 400 mg to 800 mg per day, provided additional safety data. Increased blood pressure was reported in children and adolescents and increased appetite, extrapyramidal symptoms and increased serum prolactin were reported with a higher frequency in children and adolescents than in adult patients (see sections 4.4. And 4.8).
Extrapyramidal symptoms
In a short-term placebo-controlled monotherapy study in adolescent patients (13 to 17 years of age) the overall incidence of extrapyramidal symptoms was 12.9% for quetiapine and 5.3% for placebo, although the incidence of individual adverse events (eg akathisia, tremor, extrapyramidal disorders, hypokinesia, restlessness, psychomotor hyperactivity, muscle rigidity, dyskinesia) did not exceed 4.1% in any treatment group.
In a short-term, placebo-controlled, monotherapy study in children and adolescents (10 to 17 years of age) with bipolar mania, the overall incidence of extrapyramidal symptoms was 3.6% for quetiapine and for quetiapine. 1.1% for placebo. In an open-label long-term study of schizophrenia and bipolar mania, the overall incidence of treatment-emergent extrapyramidal symptoms was 10%.
Weight gain
In short-term clinical trials in pediatric patients (10 to 17 years of age), 17% of quetiapine-treated patients and 2.5% of placebo-treated patients had ≥ 7% weight gain. To adjust for normal growth over a longer period, an increase of at least 0.5 standard deviation from baseline in BMI (Body Mass Index) was used as a measure of a clinically significant change: 18.3% of patients treated with quetiapine for at least 26 weeks met this criterion.
Suicide / suicidal thoughts or clinical worsening
In short-term placebo-controlled clinical trials in pediatric patients with schizophrenia, the incidence of suicide-related events was 1.4% (2/147) for quetiapine and 1.3% (1/175) for placebo in patients
05.2 Pharmacokinetic properties
Absorption
Following oral administration, quetiapine is well absorbed and extensively metabolised. The bioavailability of quetiapine is not significantly affected by administration with food. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of those observed for quetiapine.
Linearity / Non-linearity
The pharmacokinetic profiles of quetiapine and norquetiapine are linear over the approved dose range.
Distribution
Quetiapine is approximately 83% bound to plasma proteins.
Biotransformation
Following administration of radiolabelled quetiapine, quetiapine is extensively metabolised in the liver, with the parent compound constituting less than 5% of the parent compound in the urine and faeces. Education in vitro demonstrated that CYP3A4 is the major enzyme responsible for the cytochrome P450 mediated metabolism of quetiapine. Norquetiapine is mainly formed and eliminated via CYP3A4. 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
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. CYP inhibition is observed in vitro only at concentrations at least 5-50 times higher than those observed in humans at common effective doses between 300 and 800 mg / day in humans. Based on these results in vitro, Co-administration of quetiapine with other drugs is unlikely to result in "clinically significant inhibition of cytochrome P450 mediated metabolism of other drugs. Animal studies have established that quetiapine can induce cytochrome P450 enzymes. In a specific study of cytochrome P450. interaction in psychotic patients, however, no increase in cytochrome P450 activity was seen after administration of quetiapine.
Elimination
The elimination half-lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively.
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
Gender of belonging
The kinetics of quetiapine do not differ between men and women.
Senior citizens
In the elderly, the mean clearance of quetiapine is approximately 30-50% lower than that found in adults aged 18-65 years.
Renal impairment
The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance below 30 ml / min / 1.73 m2), but the individual clearance values are within the range of normal subjects.
Hepatic impairment
The mean plasma clearance of quetiapine is reduced by approximately 25% in people with known hepatic impairment (stable alcoholic cirrhosis). Since quetiapine is extensively metabolised by the liver, higher plasma concentrations can be expected in patients with hepatic impairment, and consequently dosage adjustments may be required (see section 4.2).
Pediatric population
Children and adolescents (10 to 17 years of age)
Pharmacokinetic data were examined in 9 children aged 10-12 years and 12 adolescents treated with quetiapine 400 mg twice daily, at steady state.
At steady state, plasma levels of the normalized dose of the precursor quetiapine in children and adolescents (10-17 years of age) were similar in adults, although Cmax in children is at the higher of the range observed in adults.
The AUC and Cmax of the active metabolite norquetiapine were higher, approximately 62% and 49% in children (10-12 years), respectively, and 28% and 14% in adolescents (13-17 years) compared to adults.
05.3 Preclinical safety data
There was no evidence of genotoxicity in a series of genotoxicity studies in vitro and in vivo.
The following deviations were evaluated in laboratory animals at clinically relevant exposure levels, which have not yet been confirmed by long-term clinical research.
Pigment deposition in the thyroid was observed in rats; follicular cellular hypertrophy, decreased plasma T3 levels, increased hemoglobin concentrations and decreased red and white blood cell counts were observed in cynomolgus monkeys; Lens opacities and cataracts were observed in dogs (for cataracts / lens opacities see section 5.1).
Taking these observations into account, the benefits of quetiapine treatment must be weighed against the risks to patient safety.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet :
Lactose monohydrate
Calcium hydrogen phosphate dihydrate
Microcrystalline cellulose
Povidone
Sodium starch glycolate (Type A)
Magnesium stearate
The film coating :
Hypromellose
Titanium dioxide (E171)
Macrogol 4000
Yellow iron oxide (E172) - only in 25 mg and 100 mg tablets
Red iron oxide (E172) - only in 25 mg tablets
06.2 Incompatibility
Not applicable.
06.3 Period of validity
5 years.
HDPE tablet containers :
The shelf life after first opening is 3 months.
06.4 Special precautions for storage
This medicine does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Blisters (PVC / Al): 6 (25 mg tablets only), 10, 20, 30, 30 x 1, 50, 60, 90, 98, 100, 100 x 1, 120 (150 mg tablets only and 300 mg), 180 (150 mg and 300 mg tablets only) or 240 tablets (150 mg and 300 mg tablets only) in a carton.
Polyethylene (HDPE) plastic container: 250 tablets (100mg and 200mg only) in one carton.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
Any unused product or waste material should be disposed of in accordance with local regulations
07.0 MARKETING AUTHORIZATION HOLDER
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
08.0 MARKETING AUTHORIZATION NUMBER
AIC n.
041195013 - "25 Mg Film Coated Tablets" 6 Tablets In Pvc / Al Blister
041195025 - "25 Mg Film Coated Tablets" 10 Tablets In Pvc / Al Blister
041195037 - "25 Mg Film Coated Tablets" 20 Tablets In Pvc / Al Blister
041195049 - "25 Mg Film Coated Tablets" 30 Tablets In Pvc / Al Blister
041195052 - "25 Mg Film Coated Tablets" 30x1 Tablets In Pvc / Al Blister
041195064 - "25 Mg Film Coated Tablets" 50 Tablets In Pvc / Al Blister
041195076 - "25 Mg Film Coated Tablets" 60 Tablets In Pvc / Al Blister
041195088 - "25 Mg Film Coated Tablets" 90 Tablets In Pvc / Al Blister
041195090 - "25 Mg Film Coated Tablets" 100 Tablets In Pvc / Al Blister
041195102 - "25 Mg Film Coated Tablets" 100x1 Tablets In Pvc / Al Blister
041195114 - "100 Mg Film Coated Tablets" 10 Tablets In Pvc / Al Blister
041195126 - "100 Mg Film Coated Tablets" 20 Tablets In Pvc / Al Blister
041195138 - "100 Mg Film Coated Tablets" 30 Tablets In Pvc / Al Blister
041195140 - "100 Mg Film Coated Tablets" 30x1 Tablets In Pvc / Al Blister
041195153 - "100 Mg Film Coated Tablets" 50 Tablets In Pvc / Al Blister
041195165 - "100 Mg Film Coated Tablets" 60 Tablets In Pvc / Al Blister
041195177 - "100 Mg Film Coated Tablets" 90 Tablets In Pvc / Al Blister
041195189 - "100 Mg Film Coated Tablets" 100 Tablets In Pvc / Al Blister
041195191 - "100 Mg Film Coated Tablets" 100x1 Tablets In Pvc / Al Blister
041195203 - "100 Mg Film Coated Tablets" 250 Tablets In Hdpe Container
041195215 - "150 Mg Film Coated Tablets" 10 Tablets In Pvc / Al Blister
041195227 - "150 Mg Film Coated Tablets" 20 Tablets In Pvc / Al Blister
041195239 - "150 Mg Film Coated Tablets" 30 Tablets In Pvc / Al Blister
041195241 - "150 Mg Film Coated Tablets" 30x1 Tablets In Pvc / Al Blister
041195254 - "150 Mg Film Coated Tablets" 50 Tablets In Pvc / Al Blister
041195266 - "150 Mg Film Coated Tablets" 60 Tablets In Pvc / Al Blister
041195278 - "150 Mg Film Coated Tablets" 90 Tablets In Pvc / Al Blister
041195280 - "150 Mg Film Coated Tablets" 100 Tablets In Pvc / Al Blister
041195292 - "150 Mg Film Coated Tablets" 100x1 Tablets In Pvc / Al Blister
041195304 - "150 Mg Film Coated Tablets" 120 Tablets In Pvc / Al Blister
041195316 - "150 Mg Film Coated Tablets" 180 Tablets In Pvc / Al Blister
041195328 - "150 Mg Film Coated Tablets" 240 Tablets In Pvc / Al Blister
041195330 - "200 Mg Film Coated Tablets" 10 Tablets In Pvc / Al Blister
041195342 - "200 Mg Film Coated Tablets" 20 Tablets In Pvc / Al Blister
041195355 - "200 Mg Film Coated Tablets" 30 Tablets In Pvc / Al Blister
041195367 - "200 Mg Film Coated Tablets" 30x1 Tablets In Pvc / Al Blister
041195379 - "200 Mg Film Coated Tablets" 50 Tablets In Pvc / Al Blister
041195381 - "200 Mg Film Coated Tablets" 60 Tablets In Pvc / Al Blister
041195393 - "200 Mg Film Coated Tablets" 90 Tablets In Pvc / Al Blister
041195405 - "200 Mg Film Coated Tablets" 100 Tablets In Pvc / Al Blister
041195417 - "200 Mg Film Coated Tablets" 100x1 Tablets In Pvc / Al Blister
041195429 - "200 Mg Film Coated Tablets" 250 Tablets In Hdpe Container
041195431 - "300 Mg Film Coated Tablets" 10 Tablets In Pvc / Al Blister
041195443 - "300 Mg Film Coated Tablets" 20 Tablets In Pvc / Al Blister
041195456 - "300 Mg Film Coated Tablets" 30 Tablets In Pvc / Al Blister
041195468 - "300 Mg Film Coated Tablets" 30x1 Tablets In Pvc / Al Blister
041195470 - "300 Mg Film Coated Tablets" 50 Tablets In Pvc / Al Blister
041195482 - "300 Mg Film Coated Tablets" 60 Tablets In Pvc / Al Blister
041195494 - "300 Mg Film Coated Tablets" 90 Tablets In Pvc / Al Blister
041195506 - "300 Mg Film Coated Tablets" 100 Tablets In Pvc / Al Blister
041195518 - "300 Mg Film Coated Tablets" 100x1 Tablets In Pvc / Al Blister
041195520 - "300 Mg Film Coated Tablets" 120 Tablets In Pvc / Al Blister
041195532 - "300 Mg Film Coated Tablets" 180 Tablets In Pvc / Al Blister
041195544 - "300 Mg Film Coated Tablets" 240 Tablets In Pvc / Al Blister
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 11/2011
10.0 DATE OF REVISION OF THE TEXT
October 2013
