Quetiapine - Generic Drug - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Quetiapine

Quetiapine Mylan 50 mg prolonged release tablets
Quetiapine Mylan 150 mg prolonged release tablets
Quetiapine Mylan 200 mg prolonged release tablets
Quetiapine Mylan 300 mg prolonged release tablets
Quetiapine Mylan 400 mg prolonged release tablets

Why is Quetiapine used - Generic Drug? What is it for?

Quetiapine Mylan contains a substance called quetiapine. This substance belongs to a group of medicines called antipsychotics. Quetiapine Mylan can be used to treat several diseases, such as the following:

  • Bipolar depression and major depressive episodes in the context of major depressive disorder: one may feel sad, depressed, guilty, 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 aggressive or destructive behavior.
  • 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 Quetiapine Mylan is taken to treat major depressive episodes in the context of major depressive disorder, it should be used in addition to another medicine indicated to treat this disease.

Your doctor may continue to prescribe Quetiapine Mylan even if you feel better.

Contraindications When Quetiapine - Generic Medication should not be used

Do not take Quetiapine Mylan:

  • if you are allergic to quetiapine or any of the other ingredients of this medicine (listed in section 6)
  • 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 Quetiapine Mylan if it falls into any of the categories described above. If you are not sure, talk to your doctor or pharmacist before taking Quetiapine Mylan.

Precautions for use What you need to know before taking Quetiapine - Generic Drug

Talk to your doctor or pharmacist before taking Quetiapine Mylan 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 Quetiapine Mylan.
  • You are aware 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, you should not take Quetiapine Mylan, because this class of medicines, to which Quetiapine Mylan belongs, may increase the risk of stroke, or in some cases the risk of death in elderly patients with dementia.
  • You or someone in your family have a history of blood clot related disorders, as medicines of this type have been associated with the formation of blood clots.

Contact your doctor immediately if you experience the following symptoms after taking Quetiapine Mylan:

  • A combination of fever, severe muscle stiffness, sweating or a low level of consciousness (a disease called 'neuroleptic malignant syndrome'). Immediate medical treatment may be needed.
  • 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). These conditions can be caused by this type of medicine.

See your doctor as soon as possible if you experience:

  • Fever, flu-like symptoms, sore throat or any other infection, as these could be a consequence of a very low white blood cell count, which may require Quetiapine Mylan 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 have thoughts of harming or killing 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 are a young adult. Information from clinical studies has shown an increased risk of suicidal thoughts and / or suicidal behavior in young adults under the age of 25 with depression.

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

Weight gain has been reported in patients receiving quetiapine. Your body weight needs to be checked regularly by both you and your doctor.

Children and adolescents

Quetiapine Mylan should not be used in children and adolescents under 18 years of age.

Interactions Which drugs or foods may change the effect of Quetiapine - Generic Drug

Tell your doctor if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription and herbal medicines.

Do not take Quetiapine Mylan 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 or lithium (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 (medicines 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.

Quetiapine Mylan with food, drink and alcohol

  • Quetiapine Mylan can be affected by food, and you should therefore take the tablets at least one hour before a meal or before bedtime.
  • Pay attention to the amount of alcohol you consume. This is important because the combined effect of Quetiapine Mylan and alcohol may promote sleepiness.
  • Do not drink grapefruit juice while you are being treated with Quetiapine Mylan, as it can affect the way the medicine works.

Warnings It is important to know that:

Pregnancy and breastfeeding

If you are pregnant, think you may be pregnant or are planning to have a baby or are breast-feeding, ask your doctor or pharmacist for advice before taking this medicine.

You should not take Quetiapine Mylan during pregnancy without first discussing it with your doctor. Quetiapine Mylan should not be taken while breastfeeding.

The following symptoms may occur in newborn babies of mothers who have taken quetiapine during the last trimester (the last three months of their pregnancy): shaking, muscle stiffness and / or weakness, sleepiness, agitation, breathing problems and difficulty in eating. If your baby shows any of these symptoms, contact your doctor.

Driving and using machines

The tablets can make you drowsy. Do not drive vehicles or use any tools or machines until you know what effect the tablets have on you.

Effect on urine screening tests

If you need to have a urine screening test, taking quetiapine may cause positive results for methadone or some medicines 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 can be performed.

Dose, Method and Time of Administration How to use Quetiapine - Generic Drug: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. Your doctor will decide on your starting dose. The maintenance dose (daily dose) will depend on the type of disease and 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.
  • Swallow the tablets whole with some 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 Quetiapine Mylan, 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 change your dose.

Senior citizens

If you are elderly, your doctor may change your dose.

Use in children and adolescents under 18 years of age

Quetiapine Mylan should not be used in children and adolescents under 18 years of age.

Overdose What to do if you have taken an overdose of Quetiapine - Generic Drug

If you take more Quetiapine Mylan than you should

If you take more Quetiapine Mylan than prescribed by your doctor, you may feel sleepy, feel dizzy and experience an abnormal heartbeat. Contact your doctor or the nearest hospital immediately. Take your Quetiapine Mylan tablets with you.

If you forget to take Quetiapine Mylan

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 Quetiapine Mylan

If you suddenly stop taking Quetiapine Mylan, you may have difficulty sleeping (insomnia), feel sick (nausea), or experience headache, diarrhea, being sick (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 this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Quetiapine - Generic Drug

Like all medicines, this medicine 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 ask your doctor or pharmacist.

Very common (may affect more than 1 in 10 people):

  • Dizziness (which can cause falls), headache, dry mouth
  • Feeling sleepy (which may go away over time as you continue treatment with Quetiapine Mylan) (which can lead to falls)
  • Withdrawal symptoms (symptoms that appear when you stop taking Quetiapine Mylan), which include inability to sleep (insomnia), feeling sick (nausea), headache, diarrhea, being sick (vomiting), dizziness and irritability. A gradual withdrawal of the medicine is recommended, over a period of at least 1 or 2 weeks.
  • Weight gain
  • Abnormal muscle movements, which include difficulty starting muscle movements, tremor, a feeling of restlessness or muscle stiffness without pain
  • Changes in the amount of certain fats in the blood (triglycerides and total cholesterol).

Common (may affect up to 1 in 10 people):

  • Rapid heartbeat
  • Feeling that the heart is racing, beating fast or a feeling of missing beats
  • Constipation, stomach upset (indigestion)
  • Feeling of weakness
  • Swelling of the arms or legs
  • Low blood pressure when standing up. This can cause dizziness or fainting (which can lead to 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
  • Wheezing
  • Vomiting (especially in elderly patients)
  • Fever
  • Changes in the amount of thyroid hormones in the blood
  • Decrease in the number of certain types of blood cells
  • Increases in the amount of liver enzymes measured in the blood
  • Increases in the amount of the hormone prolactin 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.

Uncommon (may affect up to 1 in 100 people):

  • Convulsions or seizures
  • Allergic reactions which may include 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
  • Diabetes
  • Changes in the electrical activity of the heart seen on the ECG (prolongation of the QT interval)
  • Slower than normal heart rate which may occur at the start of treatment and which may be associated with low blood pressure and fainting
  • Difficulty urinating
  • Fainting (can cause falls)
  • Stuffed nose
  • Decrease in the amount of red blood cells in the blood
  • Decrease in the amount of sodium in the blood.

Rare (may affect up to 1 in 1,000 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 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.
  • Walking, talking, eating or doing other activities while you sleep
  • Drop in body temperature (hypothermia)
  • Inflammation of the pancreas
  • A condition (called "Metabolic Syndrome") in which you may have a combination of 3 or more of the following symptoms: increase in fat around the "abdomen, decrease in" good cholesterol "(HDL-C), increase in one type of fat blood called triglycerides, increased blood pressure and increased blood sugar.
  • 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
  • Increase in blood creatine phosphokinase (a substance found in the muscles).

Very rare (may affect up to 1 in 10,000 people):

  • Severe rash, blisters or red patches on the skin
  • 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)
  • Serious condition with blistering of the skin, mouth, eyes and genitals (Stevens-Johnson syndrome)
  • Inappropriate secretion of antidiuretic hormone, which controls urine volume
  • Breakdown of muscle fibers and muscle pain (rhabdomyolysis)
  • Worsening of pre-existing diabetes.

Frequency not known (frequency cannot be estimated from the available data)

  • Rash with irregular red patches (erythema multiforme)
  • Sudden severe allergic reaction with symptoms such as fever, blistering and peeling of the skin (toxic epidermal necrolysis)
  • Withdrawal symptoms may occur in newborn babies of mothers who took Quetiapine Mylan during pregnancy.

The class of medicines to which Quetiapine Mylan belongs can cause heart rhythm problems, which can be serious and can be fatal in some serious cases.

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 , decreases in the amount of red blood cells, 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 the hormone prolactin 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.

Undesirable effects in children and adolescents

The same side effects seen in adults can also occur in children and adolescents.

The following side effects were seen more frequently in children and adolescents or were not seen in adults:

Very common (may affect 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
  • He retched
  • Abnormal muscle movements, including difficulty starting muscle movements, tremor, feeling restless or muscle stiffness without pain
  • Increased blood pressure.

Common (may affect up to 1 in 10 people):

  • Feeling weak, fainting (can cause falls)
  • Stuffed nose
  • Irritability.

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 the safety of this medicine.

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 package after "EXP". The expiry date refers to the last day of that month.

Quetiapine Mylan does not require any special storage conditions.

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.

What Quetiapine Mylan contains

  • The active ingredient is quetiapine. Quetiapine Mylan contains 50 mg, 150 mg, 200 mg, 300 mg or 400 mg of quetiapine (as quetiapine fumarate).
  • The other ingredients are:

Tablet core: hypromellose 2910, hypromellose 2208, microcrystalline cellulose, anhydrous sodium citrate, magnesium stearate.

Tablet coating: titanium dioxide (E171), hypromellose 2910, macrogol / PEG 400, polysorbate 80. The 50 mg, 200 mg and 300 mg tablets contain yellow iron oxide (E172) and red iron oxide (E172). The 50 mg and 300 mg tablets also contain black iron oxide (E172).

What Quetiapine Mylan looks like and contents of the pack

All formulations of Quetiapine Mylan prolonged-release tablets are capsule-shaped, film-coated tablets.

The 50 mg tablets are brown, debossed with "Q 50" on one side and plain on the other.

The 150 mg tablets are white, debossed with "Q 150" on one side and plain on the other.

The 200 mg tablets are yellow, debossed with "Q 200" on one side and plain on the other.

The 300 mg tablets are light yellow, debossed with "Q 300" on one side and plain on the other.

The 400 mg tablets are white, debossed with "Q 400" on one side and plain on the other.

- PVC / Aclar - Aluminum blisters in cardboard boxes.

50 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60 or 60x1 (unit dose with perforated blister) prolonged-release tablets.

150 mg: 30, 30x1 (unit dose with perforated blister), 60 or 60x1 (unit dose with perforated blister) prolonged-release tablets.

200 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60, 60x1 (unit dose with perforated blister), 100 or 100x1 (unit dose with perforated blister) prolonged-release tablets .

300 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60, 60x1 (unit dose with perforated blister), 100 or 100x1 (unit dose with perforated blister) prolonged-release tablets .

400 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60, 60x1 (unit dose with perforated blister), 100 or 100x1 (unit dose with perforated blister) prolonged-release tablets .

- HDPE containers of 60 tablets.

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.

More information about Quetiapine - Generic Drug can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 AUTHORIZATION NUMBER" PLACING ON MARKET09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORAN PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

QUETIAPINA MYLAN PROLONGED RELEASE TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 50 mg tablet contains 50 mg of quetiapine (as quetiapine fumarate)

Each 150 mg tablet contains 150 mg of quetiapine (as quetiapine fumarate)

Each 200 mg tablet contains 200 mg of quetiapine (as quetiapine fumarate)

Each 300 mg tablet contains 300 mg of quetiapine (as quetiapine fumarate)

Each 400 mg tablet contains 400 mg of quetiapine (as quetiapine fumarate)

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Prolonged-release tablet.

50 mg: Brown, film-coated, capsule-shaped tablets, debossed with "Q 50" on one side and plain on the other

150 mg: white, film-coated, capsule-shaped tablets, debossed "Q 150" on one side and plain on the other

200 mg: yellow, film-coated, capsule-shaped tablets, debossed with "Q 200" on one side and plain on the other.

300 mg: light yellow, film-coated, capsule-shaped tablets, debossed with "Q 300" on one side and plain on the other

400 mg: White, film-coated, capsule-shaped tablets, debossed with "Q 400" on one side and plain on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Quetiapine Mylan is indicated for:

• treatment of schizophrenia,

• treatment of bipolar disorder:

• for the treatment of moderate to severe manic episodes associated with bipolar disorder

• for the treatment of major depressive episodes associated with bipolar disorder

• for the prevention of relapse in patients with bipolar disorder, in patients whose manic or depressive episode has responded to treatment with quetiapine.

• adjunctive treatment of major depressive episodes in patients with Major Depressive Disorder (MDD) who have had a sub-optimal response to antidepressant drug monotherapy (see section 5.1). Before initiating treatment, physicians should consider the safety profile of quetiapine (see section 4.4).


04.2 Posology and method of administration

Dosage

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.

Adults

For the treatment of schizophrenia and moderate to severe manic episodes associated with bipolar disorder

Quetiapine Mylan should be administered at least one hour before a meal. 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 clinically justified, the dosage can be increased to 800 mg per day. The dose should be adjusted within an effective dose range ranging from 400 mg to 800 mg per day, depending on the patient's clinical response and tolerability. No dosage adjustment is necessary for maintenance therapy in schizophrenia.

For the treatment of depressive episodes associated with bipolar disorder

Quetiapine Mylan 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 group of patients treated with the 600 mg dose compared to patients treated with 300 mg (see section 5.1). Individual patients may benefit from treatment with the 600 mg dose. Doses above 300 mg should be administered by physicians experienced in the treatment of bipolar disorder. In individual patients, in the case of tolerance problems, clinical studies have shown that dose reduction to a minimum of 200 mg can be considered.

For the prevention of relapses in bipolar disorder

To prevent recurrence of manic, mixed, or depressive episodes in bipolar disorder, patients responding to Quetiapine Mylan for acute treatment of bipolar disorder should continue therapy with Quetiapine Mylan at the same dosage given at bedtime. The dose of Quetiapine Mylan can be adjusted based on the clinical response and tolerability of the individual patient over a range of 300 mg to 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 DDM:

Quetiapine Mylan should be administered in the evening, before bedtime. The daily dose at initiation of therapy 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 as therapy. add-on (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 monotherapy clinical studies. At higher doses there is an increased risk of adverse events. Physicians should therefore ensure that the lowest effective dose for treatment is used, starting with 50 mg / day. The need to increase the dose from 150 to 300 mg / day should be based on individual patient assessment.

Switching from quetiapine immediate-release tablets:

For more convenient dosing, patients currently treated with divided doses of immediate-release quetiapine tablets can be switched to treatment with Quetiapine Mylan at the equivalent total daily dose administered once daily. Individual dosage adjustments may be required.

Senior citizens

As with other antipsychotics and antidepressants, Quetiapine Mylan should be used with caution in elderly patients, especially during the initial stages of treatment. Progressive dose escalation of Quetiapine Mylan may need to be slower and the daily therapeutic dose may need to be reduced relative to younger patients. The mean plasma clearance of quetiapine was reduced by 30% - 50% in elderly patients compared to younger patients The starting dose for elderly patients is 50 mg / day The dose may be increased in 50 mg / day increments to an effective dose, depending on the clinical response and tolerability of the individual patient.

In elderly patients with major depressive episodes associated with DDM, 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 dose should be used. minimum effective, starting with 50 mg / day. If a dose increase to 300 mg / day is required, based on individual patient assessment, this 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

Quetiapine Mylan 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 reported in the sections 4.4, 4.8, 5.1 and 5.2.

Kidney damage

No dosage adjustment is necessary in patients with renal impairment.

Hepatic impairment

Quetiapine is extensively metabolised by the liver. Therefore, Quetiapine Mylan should be used with caution in patients with known hepatic impairment, particularly during the initial stages of treatment. The starting dose for patients with hepatic impairment should be 50 mg / day. Dose adjustment can be made in increments of 50 mg / day until the effective dose is reached, depending on the clinical response and tolerability of each individual patient.

Method of administration

Quetiapine Mylan should be administered once daily, between meals. The tablets should be swallowed whole and not divided, chewed or crushed.


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 antifungals, erythromycin, clarithromycin and nefazodone, is contraindicated (see section 4.5).


04.4 Special warnings and appropriate precautions for use

As Quetiapine Mylan has several indications, the safety profile of the drug should be taken into account with respect to the individual patient's diagnosis and the dose to be administered.

Long-term efficacy and safety in MDD patients have not been evaluated in add-on therapy, however long-term efficacy and safety have been evaluated in adult patients on monotherapy (see section 5.1).

Pediatric population

Quetiapine 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 with quetiapine have shown that in addition to the known safety profile observed in adults (see section 4.8), some adverse events occurred 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 has been identified that had never been previously reported in adult studies (increases in blood pressure) Changes in thyroid function tests have also been observed in children and adolescents.

Furthermore, the long-term implications of quetiapine treatment on growth and maturation 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 adolescent patients, 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 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, physicians should consider the potential risk of suicide-related events following abrupt discontinuation of quetiapine treatment due to known risk factors for the condition in question.

Other psychiatric disorders for which quetiapine is prescribed may also be associated with an increased risk of suicide-related events. In addition to this, these conditions 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 show a significant degree of suicidal ideation prior to initiation of treatment are known to be at an increased risk of suicidal ideation or suicide attempt, and should therefore undergo under close supervision 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, a higher risk of suicide-related events was observed in young adult patients (less than 25 years of age) treated with quetiapine than in patients. treated with placebo (3.0% vs 0%, respectively). In clinical trials of MDD patients, the incidence of suicide-related events observed in young adult patients (less than 25 years of age) was 2.1% (3/144) for quetiapine and 1.3% ( 1/75) for placebo.

Metabolic risk

Due to the observed risk of worsening of the metabolic profile, including possible changes in body weight, blood glucose (see hyperglycemia) and lipids observed in clinical studies, patients' metabolic parameters should be evaluated at the time of treatment initiation and changes in these parameters should be monitored regularly during the course of 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 restlessness and 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 predominantly mild to moderate in intensity. Patients experiencing severe sleepiness they may require more frequent checks for a minimum of 2 weeks from onset of drowsiness or until symptoms improve, and discontinuation of treatment should be considered.

Orthostatic hypotension

Quetiapine treatment has been associated with related orthostatic hypotension and 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 are familiar with the potential effects of the drug.

Quetiapine should be used with caution in patients with known cardiovascular disease, cerebrovascular disease or other conditions predisposing to hypotension. If orthostatic hypotension occurs, dose reduction or more gradual titration should be considered, especially in patients with cardiovascular disease. below.

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 instability and increased creatine phosphokinase. In such circumstances, quetiapine should be discontinued and appropriate medical therapy instituted.

Severe neutropenia and agranulocytosis

Severe neutropenia (white blood cell count and a history of drug induced neutropenia) has been reported uncommonly in clinical trials with quetiapine. However, some cases have occurred in patients with no pre-existing risk factors.

Quetiapine dosing should be discontinued in patients with a neutrophil count for signs and symptoms of infection, and the neutrophil count should be monitored regularly (until values ​​of 1.5 x 109 / L are exceeded) (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 signs / symptoms consistent with "agranulocytosis or" infection (eg fever, weakness, lethargy or sore throat) at any time during Quetiapine Mylan therapy. A white blood cell count and an absolute neutrophil count (ANC) should be performed promptly in such patients, 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 quetiapine therapy. In patients treated with hepatic enzyme inducers, quetiapine treatment should only be initiated if the physician considers that the benefits of quetiapine 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 has 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. Appropriate clinical monitoring is advisable in accordance with the guidelines of the antipsychotic used. Patients treated with any antipsychotic drug, including quetiapine, should be monitored for possible signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness), while patients with diabetes mellitus or risk factors for diabetes mellitus should be monitored regularly. for possible worsening of glucose control. Body weight must be checked regularly.

Lipids

In clinical studies with quetiapine, increases in triglycerides and LDL and total cholesterol, and decreases in HDL cholesterol have been observed (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 the absolute QT interval in clinical studies and during use according to the instructions in the SmPC. In post-marketing experience, prolongation of the QT interval 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. of quetiapine with drugs known to prolong QT interval or with concomitant neuroleptics, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalaemia or hypomagnesaemia (see section 4.5).

Cardiomyopathy and myocarditis

Cardiomyopathy and myocarditis have been reported in clinical trials and during post-marketing experience, however a causal relationship with quetiapine has not been established. Quetiapine treatment should be re-evaluated in patients with suspected cardiomyopathy or myocarditis.

Suspension

After abrupt cessation of quetiapine therapy, acute withdrawal symptoms such as insomnia, nausea, headache, diarrhea, vomiting, dizziness and irritability have been described. A "gradual discontinuation" over a period of at least 1-2 weeks is recommended (see section 4.8).

Elderly patients with dementia-related psychosis

Quetiapine is not licensed for the treatment of dementia-related psychosis.

In randomized placebo-controlled clinical trials conducted in a population of dementia patients treated with some atypical antipsychotics, an approximately 3-fold increased risk of cerebrovascular events was observed. 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.

In a meta-analysis performed on atypical antipsychotic drugs, an increased risk of death was reported compared to placebo in elderly patients with dementia-related psychosis. However, in two 10-week placebo-controlled clinical trials with quetiapine in the same patient population (n = 710); average 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 what expected for this population These data did not establish a causal relationship between quetiapine treatment 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 for aspiration pneumonia.

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 that may not report symptoms of constipation Patients with intestinal obstruction / ileus should be managed with careful monitoring and urgent medical assistance.

Venous thromboembolism (VTE)

Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic drugs. Since patients treated with antipsychotics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified 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 the post-marketing reports, while not all cases were confounded by 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 valproic acid / sodium valproate (divalproex) or lithium in acute moderate to severe manic episodes; however, the combination therapy was well tolerated (see sections 4.8 and 5.1). The data showed an additive effect at week 3.


04.5 Interactions with other medicinal products and other forms of interaction

Due to the primary central nervous system effects of quetiapine, Quetiapine Mylan should be used with caution in combination with other centrally active drugs and with alcohol.

Cytochrome P450 (CYP) 3A4 is the enzyme of the cytochrome P450 system primarily responsible for the metabolism of quetiapine. In an interaction study in healthy volunteers, co-administration of quetiapine (25 mg strength) with ketoconazole, an inhibitor of CYP3A4 , caused a 5- to 8-fold increase in quetiapine AUC. For this reason, concomitant use of quetiapine and CYP3A4 inhibitors is contraindicated. It is also recommended not to take grapefruit juice during quetiapine therapy.

In a study in patients treated with multiple doses to evaluate the pharmacokinetics of quetiapine, administered before and during treatment with carbamazepine (a known hepatic enzyme inducer), co-administration of carbamazepine significantly increased the clearance of quetiapine. This increase in clearance reduced the systemic exposure of quetiapine (as measured by AUC) to an average of 13% of the exposure during administration of quetiapine alone, although a more pronounced effect was observed in some patients. interaction may result in reduced plasma concentrations 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 (eg sodium valproate) (see section 4.4).

The pharmacokinetics of quetiapine were not significantly altered by concomitant administration of antidepressants based on imipramine (a known inhibitor of CYP 2D6) or fluoxetine (a known inhibitor of CYP 3A4 and CYP 2D6).

The pharmacokinetics of quetiapine were not significantly altered by concomitant administration of the antipsychotics risperidone or haloperidol. Concomitant use of quetiapine and thioridazine caused an increase in the clearance of quetiapine by approximately 70%.

The pharmacokinetics of quetiapine were not altered following co-administration with cimetidine.

The pharmacokinetics of lithium were not altered by co-administration with quetiapine.

In a 6-week, randomized, prolonged-release lithium and quetiapine study vs. placebo and prolonged-release quetiapine, in adult patients with acute mania, a higher incidence of extrapyramidal effects (particularly tremor), somnolence and weight gain was observed in the lithium add-on group compared to the placebo add-on group ( see section 5.1).

The pharmacokinetics of sodium valproate and quetiapine were not significantly altered when the two products were co-administered.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 conducted 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.

False positive results of enzyme immunoassays for methadone and tricyclic antidepressants have been reported in patients taking 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 modest amount of published data on exposure in pregnancy (that is, from 300 to 1000 pregnancy outcomes), including individual reports and some observational studies, does not suggest an increased risk of malformations due to treatment. However, on the basis of all available data, no definitive conclusions can be drawn. Studies in animals 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

Neonates exposed to antipsychotics (including quetiapine) during the third trimester of pregnancy are at risk for adverse reactions including extrapyramidal and / or withdrawal symptoms which may vary in severity and duration after birth. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, difficulty breathing, or feeding disturbances. Infants should therefore be closely monitored.

Feeding time

Based on very limited data from published reports on the excretion of quetiapine in human milk, the excretion of quetiapine at therapeutic doses appears to be inconsistent. Due to lack of solid data, a decision must be made whether to discontinue breastfeeding or to discontinue quetiapine therapy considering the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Fertility

The effects of quetiapine on human fertility were not monitored. Effects related to elevated prolactin levels were observed in rats, although these 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 sensitivity to the drug is known


04.8 Undesirable effects

The most commonly reported adverse drug reactions (ADRs) with quetiapine (≥10%) are somnolence, dizziness, headache, dry mouth, withdrawal symptoms, increased serum triglyceride levels, increased total cholesterol (mainly LDL cholesterol), decreased HDL cholesterol, weight gain, hemoglobin decrease and extrapyramidal symptoms.

The incidence of ADRs associated with quetiapine therapy is shown in the table below, 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 and

SOC Very common common Uncommon Rare Very rare Not known Pathologies of the haemolympho-poietic system Decrease in hemoglobin 23 Leukopenia 1, 29, decrease in neutrophil count, increase in eosinophils 28 Thrombocytopenia, anemia, decreased platelet count 14 Agranulocytosis 27 • Neutropenia 1 Disorders of the immune system • • Hypersensitivity (including allergic skin reactions) • Anaphylactic reaction 6 • Endocrine pathologies • Hyperprolactinaemia 16, decrease in total T425, decrease in free T425, decrease in total T325, increase in TSH25 Decreased free T325, hypothyroidism22 • Inappropriate secretion of antidiuretic hormone • Metabolism and nutrition disorders Increase in blood triglyceride levels 11.31, increase in total cholesterol (mainly LDL cholesterol) 12.31, decrease in HDL cholesterol 18.31, weight gain 9.31 Increased appetite, increased blood glucose to hyperglycemic levels 7, 31 Hyponatremia 20, diabetes mellitus1,5,6 Metabolic syndrome 30 Exacerbation of pre-existing diabetes • Psychiatric disorders • Abnormal dreams and nightmares Suicidal ideation and suicidal behavior 21 • Sleepwalking and other related events such as sleep talking and sleep-related eating disorder • • Nervous system disorders Dizziness 4, 17, somnolence 2.17, headache, extrapyramidal symptoms1, 22 Dysarthria Seizures 1, restless legs syndrome, tardive dyskinesia1, 6, syncope 4.17 • • • Cardiac pathologies • Tachycardia 4, palpitations 24 QT interval prolongation1,13,19 bradycardia33 • • • Eye disorders • Blurred vision • • • • Vascular pathologies • Orthostatic hypotension 4.17 • Venous thromboembolism 1 • • Respiratory, thoracic and mediastinal disorders • Dyspnea 24 Rhinitis • • • Gastrointestinal disorders Dry mouth Constipation, dyspepsia, vomiting 26 Dysphagia 8 Pancreatitis1, intestinal obstruction / ileus • • Hepatobiliary disorders • Elevations of serum alanine aminotransferase (ALT) 3 Elevations of gamma-GT levels 3 Increases in serum aspartate amino transferase (AST) 3 Jaundice6, hepatitis • • Skin and subcutaneous tissue disorders • • • • Angioedema6, Stevens-Johnson syndrome 6 Toxic epidermal necrolysis, erythema multiforme Musculoskeletal and connective tissue disorders • • • • Rhabdomyolysis • Renal and urinary disorders • • Urinary retention • • • Pregnancy, puerperium and perinatal conditions • • • • • Neonatal withdrawal syndrome 32 Diseases of the reproductive system and breast • • Sexual dysfunctions Priapism, galactorrhea, breast swelling, menstrual disorders • • General disorders and administration site conditions Withdrawal symptoms (discontinuation) 1.10 Mild asthenia, peripheral edema, irritability, pyrexia • Neuroleptic malignant syndrome1, hypothermia • • Diagnostic tests • • • Creatine phosphokinase increases 15 • •

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. An asymptomatic (shift from normal to> 3X ULN at any time) increase in serum transaminase (ALT, AST) or gamma-GT levels has been observed in some patients treated with quetiapine. These elevations were usually reversible with continued quetiapine therapy.

4. Like other antipsychotics with alpha1 adrenergic blocking activity, quetiapine commonly can induce orthostatic hypotension associated with dizziness, tachycardia and, in some patients, syncope, especially during the initial dose titration period (see section 4.4).

5. The frequency of these adverse reactions was calculated from post-marketing data only, based on the immediate-release quetiapine formulations.

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 vs. placebo was only observed in clinical trials in bipolar depression.

8. Based on> 7% weight gain from baseline weight. It occurs mainly 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.

10. Triglycerides ≥ 200mg / dL (≥ 2.258 mmol / L) (patients aged ≥ 18 years) or ≥ 150 mg / dL (≥ 1.694 mmol / L) (patients aged

11. Cholesterol ≥ 240mg / dL (≥ 6.2064 mmol / L) (patients aged ≥ 18 years) or ≥ 200mg / 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):> 20mcg / l (> 869.56 pmol / l) male,> 30 mg / l (> 1304.34 pmol / l) female at any time

16. Can lead to falls

17. HDL cholesterol

18. The incidence of patients having a change in QTc from

19. Change from> 132 mmol / L to ≤ 132 mmol / L on at least one occasion

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. Decreased hemoglobin ≤ 13 g / dL (8.07 mmol / L) male, ≤ 12 g / dL (7.45 mmol / L) female on at least one "occasion occurred in 11% of patients with quetiapine in all studies including open label extension For these patients, the mean maximum reduction in hemoglobin at any time was -1.50 g / dL.

23. These reports often occurred in the course of tachycardia, dizziness, orthostatic hypotension, and / or previous concomitant heart / respiratory disease.

24. Based on change from normal baseline to potentially clinically important value at any time post-baseline across all studies. Changes in total T4, FT4, total T3 and free T3 are defined as 5 mUI / L at any time.

25. Based on the rate of increased vomiting in elderly patients (≥ 65 years of age).

26. Based on change in neutrophils from> = 1.5 x 109 / L at baseline a

27. Based on change from normal baseline to potentially clinically important post-baseline value across all studies. Changes in eosinophils are defined as> 1 x 109 cells / l at any time.

28. Based on change from normal baseline to potentially clinically important value at any time post-baseline across all studies. Changes in white blood cells are defined as ≤ 3x109 cells / l at any time.

29. Based on adverse event reports of metabolic syndrome from all clinical trials with quetiapine.

30. In some patients, worsening of more than one of the metabolic factors of weight, blood glucose and lipids has been observed in clinical studies (see section 4.4).

31. See section 4.6

32. It may occur at or near the start of treatment and be associated with hypotension and / or syncope. Frequency based on adverse reaction reports of bradycardia and related events in all clinical studies 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 in children and adolescents associated with quetiapine therapy appearing more frequently than in adults, or not identified in the adult population.

The frequencies of adverse events are classified according to the following convention: Very common (≥1 / 10), Common (≥1 / 100,

SOC Very common common Endocrine pathologies Increased prolactin 1 • Metabolism and nutrition disorders Increased appetite • Nervous system disorders Extra-pyramidal symptoms 3, 4 Syncope Vascular pathologies Increased blood pressure 2 • Respiratory, thoracic and mediastinal disorders • Rhinitis Gastrointestinal disorders He retched • General disorders and administration site conditions • Irritability 3

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. Less than 1% of patients had an increase in prolactin levels> 100 mcg / L.

2. Based on exceeding clinically significant thresholds (adapted from National Institute of Health criteria) or increases of> 20 mmHg in systolic blood pressure or> 10 mmHg in diastolic blood pressure at any time in two acute clinical studies (3-6 weeks ) controlled with placebo 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: http://www.agenziafarmaco.gov.it/it/responsabili.


04.9 Overdose

Symptoms

In general, the reported signs and symptoms are attributable to an enhancement of the known pharmacological effects of the active ingredient, such as eg. somnolence and sedation, tachycardia and hypotension. Overdose may 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 develop overdose effects (see section 4.4, Cardiovascular Disorders).

Management of overdose

There is no specific antidote for quetiapine. In cases with severe manifestations, the possibility of multiple drug involvement should be considered, and intensive care procedures are recommended, including establishing and maintaining a patent airway to support adequate oxygenation and ventilation, and monitoring and support of the cardiovascular system.

Based on the published literature, patients with delirium and agitation and with an "obvious anticholinergic syndrome" can be treated with physostigmine, 1-2 mg (under continuous ECG monitoring). This is not recommended as standard treatment due to the potential adverse effect. of physostigmine on cardiac conductance Physostigmine can be used if there are no changes in the ECG. Do not use physostigmine in case of dysarrhythmias, any degree of heart block or prolongation of the QRS interval.

Although the prevention of absorption in cases of overdose has not been evaluated, gastric lavage may be considered in cases of severe intoxication, to be performed, if possible, within one hour of ingestion. Administration of gastric lavage should also be considered. Activated carbon.

In cases of quetiapine overdose, refractory hypotension should be treated with appropriate measures such as intravenous fluids and / or sympathetic mimetic agents. Epinephrine and dopamine should be avoided, as beta stimulation may worsen hypotension during the onset of "Quetiapine-induced alpha blockade.

Accurate medical supervision and appropriate monitoring must be ensured until the patient is recovered.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antipsychotics; Diazepine, oxazepine and thiazepine.

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 and antipsychotic properties. the reduced predisposition of quetiapine to induce extrapyramidal side effects (EPS) compared to typical antipsychotics.

Quetiapine and norquetiapine do not possess "appreciable affinity for benzodiazepine receptors but" high affinity for histaminergic and alpha-1 adrenergic receptors, with less affinity for alpha-2 adrenergics and several muscarinic receptors.

Inhibition of the norepinephrine transporter (NET) and partial agonist action at 5HT1A sites by norquetiapine could contribute to the therapeutic efficacy of Quetiapine Mylan as an antidepressant.

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 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 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. Following 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 exhibits a minimal propensity for dystonic manifestations in haloperidol sensitized or drug-free Cebus monkeys following acute or corneal administration (see section 4.8).

Clinical efficacy

Schizophrenia

The efficacy of prolonged-release quetiapine in the treatment of schizophrenia was demonstrated in a 6-week placebo-controlled clinical study conducted in patients meeting DSM-IV criteria for the diagnosis of schizophrenia, and in a clinical trial. active drug controlled on switching from immediate-release quetiapine to prolonged-release quetiapine in clinically stable outpatients with schizophrenia.

The primary outcome variable in the placebo-controlled study was the change from baseline control to final assessment of the PANSS total score. Administration of prolonged-release quetiapine 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 comparator-controlled clinical trial, which compared switching from one drug to another, the primary outcome variable was the proportion of patients who experienced lack of efficacy, i.e. who discontinued the study. due to lack of therapeutic efficacy or whose PANSS total score was increased by 20% or more in post-randomisation visits. In patients stabilized with immediate-release quetiapine at doses between 400 mg and 800 mg, efficacy was maintained unchanged when patients are switched to an equivalent daily dose of prolonged-release quetiapine in a single dose.

In a long-term study in stabilized schizophrenic patients treated with prolonged-release quetiapine for 16 weeks, prolonged-release quetiapine was more effective than placebo in preventing relapse. The estimated risk of relapse after 6 months of treatment was 14.3% for the quetiapine prolonged-release tablet group versus 68.2% for placebo-treated patients. The mean dose was 669 mg. There were no additional safety observations associated with prolonged-release quetiapine treatment for up to 9 months (mean 7 months). In particular, there was no increase in reports of EPS-related adverse events and weight gain with prolonged treatment with prolonged-release quetiapine.

Bipolar disorder

In the treatment of moderate to severe manic episodes in two monotherapy clinical trials, quetiapine demonstrated "superior efficacy to placebo in reducing manic symptoms at weeks 3 and 12." The efficacy of prolonged-release quetiapine was further demonstrated showing differences. significant compared to placebo in an additional 3-week study. Prolonged-release quetiapine was administered over a dose range of 400 to 800 mg / day, and the mean dose was approximately 600 mg / day. Data regarding the administration of quetiapine in combination with valproic acid / sodium valproate (divalproex) or lithium in acute moderate to severe manic episodes at weeks 3 and 6 are limited; however, the combination therapy was well tolerated. The data showed an additive effect at week 3. A second study did not demonstrate an additive effect at week 6.

In a clinical study in patients with depressive episodes associated with bipolar disorder type I or II, the administration of 300 mg / day of prolonged-release quetiapine showed greater efficacy than placebo in reducing the MADRS total score.

In 4 additional clinical trials with quetiapine, lasting 8 weeks in patients with moderate to severe depressive episodes associated with bipolar I or II disorder, immediate-release quetiapine 300 mg and 600 mg was significantly superior to placebo in Outcomes related to the efficacy parameters assessed: mean improvement in the MADRS score and clinical response of the patient with an improvement of at least 50% in the total MADRS score compared to baseline. There was no difference in the magnitude of effect between patients who received the 300 mg immediate-release dose of quetiapine 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 immediate-release quetiapine 300 or 600 mg was shown to be effective compared to placebo in terms of preventing 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 recurrence 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 long-term study (up to 2 years of treatment) evaluating 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 recurrence of any episode. mood alteration (manic, mixed or depressive) in patients with bipolar I disorder. The number of patients experiencing a mood-related event was 91 (22.5%) in the quetiapine group, respectively , 208 (51.5%) in the placebo group and 95 (26.1%) in the lithium group. In patients who responded to quetiapine treatment, when comparing continued treatment with quetiapine to switching to lithium, the results indicated that switching to lithium does not appear to be associated with an increase in the time to relapse of the "related event". humor.

Major depressive episodes associated with DDM

Two short-term (6-week) studies enrolled patients who had shown an inadequate response to at least one antidepressant drug. Quetiapine 150 mg and 300 mg / day administered as add-on therapy to ongoing antidepressant therapy (amitriptyline, bupropion, citalopram, duloxetine, escitalopram, fluoxetine, paroxetine, sertraline or venlafaxine) demonstrated "superior efficacy than antidepressant therapy alone in reducing the depressive symptoms, as demonstrated by the improvement in the MADRS total score (LS mean change vs placebo of 2-3.3 points).

Long-term efficacy and safety in patients with DDM have not been evaluated as add-on therapy, however these parameters have been evaluated in adult patients on monotherapy (see below).

The following studies were conducted with prolonged-release quetiapine alone, however prolonged-release quetiapine is indicated for complementary therapy only:

In three out of four short-term (up to 8 weeks) monotherapy studies in patients with major depressive disorder, prolonged-release quetiapine 50 mg, 150 mg and 300 mg / day demonstrated "superior efficacy than placebo in reducing the depressive symptoms, as evidenced by the improvement in the total score of the Montgomery-Ãàsberg Depression Rating Scale (MADRS) (mean change LS vs placebo of 2-4 points).

In a monotherapy relapse prevention study, patients with depressive episodes stabilized on open-label prolonged-release quetiapine treatment for at least 12 weeks were randomized to receive prolonged-release quetiapine once daily or placebo for up to 52 weeks. The mean prolonged-release quetiapine dose during the randomization phase was 177 mg / day. The incidence of relapse was 14.2% for prolonged-release quetiapine-treated patients and 34.4% for placebo-treated patients.

In a short-term (9-week) study in elderly non-dementia patients (aged 66 to 89 years) with major depressive disorder, prolonged-release quetiapine administered in flexible doses between 50 mg and 300 mg / day demonstrated superior efficacy to placebo in reducing depressive symptoms, as evidenced by the improvement in the MADRS total score (LS mean change vs placebo -7.54).

In this study, patients randomized to prolonged-release quetiapine were treated with 50 mg / day on Days 1-3, and the dose could then be increased to 100 mg / day on Day 4, to 150 mg / day on Day 8. and up to 300 mg / day, depending on clinical response and tolerability. The mean prolonged-release quetiapine dose was 160 mg / day. With the exception of the "incidence of extrapyramidal symptoms (see section 4.8 and" Clinical safety "below), the tolerability of prolonged-release quetiapine once daily in elderly patients was comparable to that in adults (aged 18 to 65 years). The proportion of randomized patients over 75 years of age was 19%.

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) Higher rates of extrapyramidal symptoms were observed in patients treated with quetiapine compared to patients treated with placebo in short-term placebo-controlled clinical trials in MDD and bipolar depression. placebo-controlled short-term clinical trials in bipolar depression, the pooled incidence of extrapyramidal symptoms was 8.9% for quetiapine versus 3.8% for placebo. In short-term placebo-controlled monotherapy clinical trials in the disorder major depressive, the pooled incidence of extrapyramidal symptoms was 5.4% for prolonged-release quetiapine and 3.2% for placebo. In a short-term placebo-controlled monotherapy clinical trial in elderly patients with major depressive disorder, the pooled incidence of extrapyramidal symptoms was 9.0% for quetiapine and 2.3% for placebo. Both in bipolar depression that in MDD, the incidence of single adverse events (eg. akathisia, extrapyramidal disorder, tremor, dyskinesia, dystonia, restlessness, involuntary muscle contractions, psychomotor hyperactivity and muscle rigidity) did not exceed 4% in all treatment groups .

In short-term (3 to 8 week duration) and fixed dose (50 mg / day to 800 mg / day) placebo-controlled studies, mean weight gain in patients treated with quetiapine ranged from 0.8 kg per day. the daily dose of 50 mg and 1.4 kg for the 600 mg daily dose (with a smaller increase for the 800 mg daily dose), versus 0.2 kg in patients treated with placebo. quetiapine which reported an increase in body weight of ≥7% 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 daily doses). mg), versus 3.7% of placebo-treated patients.

A 6-week, randomized, study with prolonged-release lithium and quetiapine vs. placebo and prolonged-release quetiapine, in adult patients with acute mania, indicated that the combination of prolonged-release quetiapine with lithium leads to a higher incidence of adverse events (63% vs 48% with prolonged-release quetiapine in combination The safety results show a higher incidence of extrapyramidal effects reported in 16.8% of patients in the lithium add-on group and 6.6% in the placebo add-on group, the majority of which consisted of tremors, reported in 15.6% of patients in the lithium add-on group and 4.9% in the placebo add-on group. The incidence of somnolence was higher in the prolonged-release quetiapine and add-on treatment group. lithium (12.7%) versus the prolonged-release quetiapine and placebo add-on group (5.5%). In addition, a greater percentage of patients treated in the lithium add-on group (8.0%) had weight gain (≥7%) at the end of treatment compared to patients in the placebo add-on group (4.7%).

Long-term relapse prevention studies involved 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 to receive quetiapine. or placebo. For patients randomized to quetiapine, mean weight gain during the open label period was 2.56 kg, and at week 48 of the randomisation period the mean weight gain was 3.22 kg, compared with the in open basal. For patients randomized to placebo, the mean weight gain during the open label period was 2.39 kg, and at week 48 of the randomisation period the mean weight gain was 0.89 kg, compared with the in open basal.

In placebo-controlled studies in elderly patients with dementia-related psychosis, the incidence of cerebrovascular adverse events per 100 patient-years was not higher in quetiapine-treated patients than in placebo-treated patients.

In all placebo-controlled short-term monotherapy clinical trials conducted in patients with starting neutrophil count ≥1.5 X 109 / L, the incidence of at least one neutrophil count 0.5 -

Quetiapine treatment has been associated with small dose-related decreases in thyroid hormone levels. The incidence of shifts in TSH level was 3.2% for quetiapine versus 2.7% for placebo. The incidence of mutually potentially clinically significant shifts in T3 or T4 and TSH levels in these clinical trials has been rare and changes in thyroid hormone levels are generally not associated with clinically symptomatic hypothyroidism. The reduction in total and free T4 was maximal in the first six weeks of quetiapine treatment, with no further reductions in long-term treatment. In approximately 2/3 of all cases, cessation of quetiapine therapy was associated with a "reversal of the effects on total and free T4, regardless of the duration of treatment.

Cataract / lens opacity

In a clinical study conducted to evaluate the cataractogenic power of quetiapine (200-800 mg / day) compared to risperidone (2-8 mg) in patients with schizophrenia or schizoaffective disorder, the percentage of patients with at least 21 months of exposure , which had an increase in the degree of lens opacification was no higher in the quetiapine group (4%) than in the risperidone group (10%).

Pediatric population

Clinical efficacy

The efficacy and safety of quetiapine 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 studies excluded patients with known unresponsiveness to quetiapine treatment. Quetiapine treatment 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 dosage (mania 400-600 mg / day; schizophrenia 400-800 mg / day), in 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 quetiapine 400 mg / day and -6.56 for quetiapine 600 mg / day. die. The rates of responders (YMRS improvement ≥ 50%) were 64% for quetiapine 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 quetiapine 400 mg / day and -9.29 for quetiapine 800 mg / day. die. Quetiapine was not superior to placebo in both the low-dose (400 mg / day) and 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 total score on the PANSS scale. Higher doses induced a numerically lower response rate in both mania and schizophrenia studies.

In a third short-term placebo-controlled monotherapy study with prolonged-release quetiapine in children and adolescents (10-17 years) 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 clinical trials with quetiapine described above, the incidence of extrapyramidal effects 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 and bipolar mania studies and 12.5% ​​vs. 6% in the bipolar depression study. The incidence of suicide-related events in the active arm vs. placebo 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 depresson study.

During the extension to the post-treatment follow-up phase of the bipolar depression study, there were two additional suicide-related events in two patients; one of these patients was on quetiapine at the time of the event.

Long-term security

An extension of the open-label acute clinical studies over a period of 26 weeks (n = 380 patients), with flexible doses of quetiapine ranging from 400 to 800 mg / day, provided additional safety data. Increases in blood pressure have been reported in children and adolescents and, with higher frequency in children and adolescents than in adults, increases in appetite, extrapyramidal symptoms and elevations in serum prolactin have been observed (see sections 4.4 and 4.8). .

For weight gain, when adjusted for long-term normal development, an increase of at least 0.5 standard deviations from baseline in Body Mass Index was used as a measure of clinically significant change; 18.3% of patients treated with quetiapine for up to 26 weeks met this criterion.


05.2 "Pharmacokinetic properties

Absorption

Quetiapine is well absorbed following oral administration. Prolonged-release quetiapine reaches peak plasma concentrations of quetiapine and norquetiapine approximately 6 hours after administration (Tmax). Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of those observed for quetiapine.

The pharmacokinetics of quetiapine and norquetiapine are linear and dose proportional for doses up to 800 mg administered once daily. When prolonged-release quetiapine administered once daily is compared to the same total daily dose of immediate-release quetiapine fumarate (immediate-release quetiapine) administered twice daily, the area under the plasma concentration-time curve (AUC ) is equivalent, but the maximum plasma concentration (Cmax) is 13% lower at steady state. When prolonged-release quetiapine is compared with immediate-release quetiapine, 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 resulted in statistically significant increases in prolonged-release quetiapine Cmax and AUC of 50% and 20%, respectively. It cannot be excluded that the effect of a high-fat meal on the formulation may be greater. In comparison, a light meal did not have a significant effect on quetiapine Cmax and AUC. It is recommended that controlled-release quetiapine be taken. once a day, without food.

Distribution

Quetiapine is approximately 83% bound to plasma proteins.

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. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. However in a specific study of cytochrome P450. interaction in psychotic patients no increase in cytochrome P450 activity was shown after administration of quetiapine.

Elimination

The elimination half-lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively.

Approximately 73% of the radiolabelled drug is excreted in the urine and 21% in the faeces, with less than 5% of the total radioactivity representing unchanged drug-related material. 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

Type

The pharmacokinetic profile of quetiapine does 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 to 65 years.

Kidney damage

The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml / min / 1.73m2) but the individual clearance values ​​are within the normal range for healthy subjects.

Hepatic impairment

The mean plasma clearance of quetiapine is reduced by approximately 25% in subjects with known hepatic impairment (stable alcoholic cirrhosis). As quetiapine is extensively metabolised by the liver, patients with hepatic impairment may have higher plasma drug levels and require dose adjustment (see section 4.2).

Pediatric population

Pharmacokinetic data were sampled in 9 children aged 10 to 12 years and 12 adolescents receiving steady-state 400 mg quetiapine twice daily. At steady state, dose-normalized plasma levels of the parent compound quetiapine in children and adolescents (aged 10 to 17 years) were generally similar to those in adults, although Cmax in children was positioned at the upper end of the range. of values ​​observed in adults. The AUC and Cmax, for the active metabolite norquetiapine were 62% and 49% higher in children (aged 10 to 12 years) and 28% and 14% respectively in adolescents, respectively. (aged 13-17) than adults.

No information is available on the use of prolonged-release quetiapine in children and adolescents.


05.3 Preclinical safety data

In a series of genotoxicity studies in vitro And in vivo no genotoxicity was shown. 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: in the rat, deposition of pigment in the thyroid gland was observed; in the monkey cynomolgus hypertrophy of thyroid follicular cells, lowered plasma T3 levels, decreased hemoglobin concentration and decreased red and white blood cell counts have been reported; Lens opacity and cataract have been reported in dogs (for cataract / lens opacity see section 5.1).

In an embryo-fetal toxicity study in rabbits, the fetal incidence of carpal / tarsal flexion was increased. This effect appeared in the presence of obvious maternal effects such as reduced weight gain. These effects were evident at similar maternal exposure levels or slightly higher than those in humans at the maximum therapeutic dose. The relevance of these findings to humans is unknown.

In a fertility study in rats the following were observed: marginal reduction in male fertility and pseudo-pregnancy, prolonged periods of estrus, increased precoital interval and reduced pregnancy frequency. These effects are related to elevated prolactin levels and are not directly relevant. for humans due to species differences in hormonal control of reproduction.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Nucleus

Hypromellose 2910

Hypromellose 2208

Microcrystalline cellulose

Sodium citrate anhydrous

Magnesium stearate.

Coating

Titanium dioxide (E171)

Hypromellose 2910

Macrogol / PEG 400

Polysorbate 80

Yellow iron oxide (E172) (50 mg, 200 mg and 300 mg tablets only)

Red iron oxide (E172) (50 mg, 200 mg and 300 mg tablets only)

Black iron oxide (E172) (50 mg and 300 mg tablets only).


06.2 Incompatibility

Not applicable.


06.3 Period of validity

2 years.


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

• PVC / Aclar - Aluminum blisters in cardboard boxes.

50 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60 or 60x1 (unit dose with perforated blister) prolonged-release tablets

150 mg: 30, 30x1 (unit dose with perforated blister), 60 or 60x1 (unit dose with perforated blister) prolonged-release tablets

200 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60, 60x1 (unit dose with perforated blister), 100 or 100x1 (unit dose with perforated blister) prolonged-release tablets

300 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60, 60x1 (unit dose with perforated blister), 100 or 100x1 (unit dose with perforated blister) prolonged-release tablets

400 mg: 10, 10x1 (unit dose with perforated blister), 30, 30x1 (unit dose with perforated blister), 60, 60x1 (unit dose with perforated blister), 100 or 100x1 (unit dose with perforated blister) prolonged-release tablets .

• HDPE containers of 60 tablets.

Not all pack sizes may be marketed.


06.6 Instructions for use and handling

No special instructions.

07.0 MARKETING AUTHORIZATION HOLDER

Mylan S.p.A., Via Vittor Pisani 20, 20124 Milan

08.0 MARKETING AUTHORIZATION NUMBER

043057013 - "50 MG EXTENDED RELEASE TABLETS" 10 TABLETS IN PVC / ACLAR-AL BLISTER

043057025 - "50 MG EXTENDED RELEASE TABLETS" 30 TABLETS IN PVC / ACLAR-AL BLISTER

043057037 - "50 MG EXTENDED RELEASE TABLETS" 60 TABLETS IN PVC / ACLAR-AL BLISTER

043057049 - "150 MG EXTENDED RELEASE TABLETS" 30 TABLETS IN PVC / ACLAR-AL BLISTER

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043057203 - "50 MG EXTENDED RELEASE TABLETS" 60 TABLETS IN HDPE CONTAINER

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043057241 - "200 MG EXTENDED RELEASE TABLETS" 10X1 TABLETS IN PVC / ACLAR-AL SINGLE-DOSE BLISTER

043057254 - "200 MG EXTENDED RELEASE TABLETS" 30X1 TABLETS IN PVC / ACLAR-AL SINGLE-DOSE BLISTER

043057266 - "200 MG EXTENDED RELEASE TABLETS" 60X1 TABLETS IN PVC / ACLAR-AL SINGLE-DOSE BLISTER

043057278 - "200 MG EXTENDED RELEASE TABLETS" 100X1 TABLETS IN PVC / ACLAR-AL SINGLE-DOSE BLISTER

043057280 - "200 MG EXTENDED RELEASE TABLETS" 60 TABLETS IN HDPE CONTAINER

043057292 - "300 MG EXTENDED RELEASE TABLETS" 10X1 TABLETS IN PVC / ACLAR-AL SINGLE-DOSE BLISTER

043057304 - "300 MG EXTENDED RELEASE TABLETS" 30X1 TABLETS IN PVC / ACLAR-AL SINGLE-DOSE BLISTER

043057316 - "300 MG EXTENDED RELEASE TABLETS" 60X1 TABLETS IN PVC / ACLAR-AL SINGLE-DOSE BLISTER

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043057330 - "300 MG EXTENDED RELEASE TABLETS" 60 TABLETS IN HDPE CONTAINER

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09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION

10.0 DATE OF REVISION OF THE TEXT

January 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL

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