PAROXETINE - GENERIC DRUG - PACKAGE LEAFLET - LEAFLETS

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Paroxetine - Generic Drug - Package Leaflet

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

Active ingredients: Paroxetine

PAROXETINA ACTAVIS 20 mg film-coated tablets

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

Paroxetine Actavis belongs to a group of medicines called SSRIs (selective serotonin reuptake inhibitors). The brains of all of us contain a substance called serotonin. In depressed or anxious people, serotonin levels are lower than in other people. It is not entirely clear how Paroxetine Actavis and the other SSRIs work but they may help increase serotonin levels in the brain. It is important to treat your depression or anxiety in the most suitable way to help you feel better.

Paroxetine Actavis is used to treat adults with depression (major depressive episodes) and / or anxiety disorders. The anxiety disorders that are treated with Paroxetine Actavis are:

obsessive-compulsive disorder (repetitive, obsessive thoughts with uncontrollable behavior),
panic disorder (panic attacks, including those caused by agoraphobia, i.e. fear of open spaces),
social anxiety disorder (fear or tendency to avoid social situations),
post traumatic stress disorder (anxiety caused by a traumatic event),
generalized anxiety disorder (generally feeling very anxious or nervous).

Contraindications When Paroxetine - Generic Drug should not be used

Do not use Paroxetine Actavis

If you are allergic to paroxetine, peanuts, soy, or any of the other ingredients of this medicine (listed in section 6).
If you are taking other medicines called monoamine oxidase inhibitors (MAO-Inhibitors, including moclobemide) or have taken them at any time in the previous two weeks. Your doctor will advise you on how to start taking Paroxetine Actavis once you have stopped taking the MAO inhibitor. Treatment with MAO inhibitors can only start 1 week after stopping treatment with Paroxetine Actavis.
If you are taking an antipsychotic called thioridazine or an antipsychotic called pimozide.
If you have been given Methylthioninium chloride (methylene blue) within the past 24 hours.

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

Talk to your doctor or pharmacist before taking Paroxetine Actavis if:

develop symptoms such as restlessness (akathisia). These symptoms can occur during the first few weeks of treatment. A dosage adjustment may be useful.
develop a disease called serotonin syndrome, causing some or all of the following symptoms to occur: confusion, restlessness, sweating, shaking, chills, hallucinations (strange visions or sounds), sudden twitching of muscles or a fast heartbeat . If you notice any of these symptoms, please contact your doctor immediately.
suffer or have suffered from mania (hyperactive behavior or thoughts).
your kidney or liver function is reduced.
suffer from diabetes.
suffer from epilepsy or have a previous history of seizures or convulsions.
you are undergoing electroconvulsive therapy (ECT).
suffer from glaucoma (increased pressure in the eye).
suffer from heart disease.
the sodium concentrations in your blood are too low.
have a history of bleeding disorders (eg bruising or bleeding from the gut).
are taking medicines that may increase the risk of bleeding (these include medicines that thin the blood, such as warfarin, antipsychotics such as perphenazine or clozapine, tricyclic antidepressants, medicines used to treat pain and inflammation called non-steroidal anti-inflammatory drugs or NSAIDs, such as acetylsalicylic acid, ibuprofen, colecoxib, etodolac, diclofenac, meloxicam).
you are taking a medicine called tamoxifen.

Children and adolescents

Paroxetine Actavis should not normally be used to treat children and adolescents under 18 years of age. You should be aware that, when taking this class of medicines, patients under 18 years of age have an increased risk of side effects such as suicide attempts, suicidal thoughts and hostility (essentially aggression, oppositional behavior and anger). ). Despite this, your doctor may prescribe Paroxetine Actavis for patients under the age of 18 if they consider it strictly necessary. If your doctor has prescribed Paroxetine Actavis for a patient under the age of 18 and you would like more information, please consult your doctor again. Your doctor should be told if any of the above symptoms appear or worsen while taking Paroxetine Actavis by a patient under the age of 18. In addition, the long-term safety effects of Paroxetine Actavis related to growth , maturation and cognitive and behavioral development in this patient group have not yet been demonstrated.

The following frequent common side effects (1 to 10 users in 100) have been found in paroxetine studies in patients under the age of 18: an increase in suicidal thoughts and suicide attempts, deliberate self-harm, hostility, aggression or enmity, lack of appetite, tremors, abnormal sweating, hyperactivity (too much energy), agitation, variable emotions (with crying and mood changes) and unusual bleeding or bruising (eg nosebleeds). These studies also showed that the same symptoms occurred in children and adolescents treated with sugar pills (placebo) instead of Paroxetine Actavis, although these were seen less often.

Some patients under the age of 18 involved in these studies experienced withdrawal effects when they stopped taking Paroxetine Actavis. These effects were mostly similar to those seen in adults after they had stopped Paroxetine Actavis (see Section 3, How to take Paroxetine Actavis, within the package insert). In addition, patients under the age of 18 have frequently (1-10 out of 100 patients) experienced stomach pain, nervousness and varying emotions (with crying, mood changes, self-harm attempts, suicidal thoughts and suicide attempts).

Thoughts of self-harm and worsening of the condition

Depressed and / or anxious people can sometimes have thoughts of harming or killing themselves. These effects can worsen when you first take antidepressants, because all drugs of this type take time to work.

Some patient groups may be more predisposed to experiencing these thoughts:

if you have already had a history of suicidal or self-harming thoughts.
If you are a young adult. Data from clinical trials have shown an increased risk of suicidal behavior in young adults (less than 25 years old) with psychiatric problems previously treated with an antidepressant.

If at any time you have thoughts of harming or killing yourself, contact your doctor immediately or go to a hospital.

It may be helpful to tell a friend or relative who is feeling depressed or have anxiety disorders and ask them to read this leaflet. some changes in his behavior.

Interactions Which drugs or foods can modify the effect of Paroxetine - Generic Drug

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Some medicines can affect the way Paroxetine Actavis works, or are more likely to cause side effects. Paroxetine Actavis can also affect the way some other medicines work. These include:

Drugs called monoamine oxidase inhibitors (MAO inhibitors, including moclobemide) used to treat e.g. depression or Parkinson's disease - see Do not use Paroxetine Actavis, in the package leaflet.
Thioridazine or pimozide, which are antipsychotics - see Do not use Paroxetine Actavis in this leaflet.
Acetylsalicylic acid, ibuprofen and other drugs called NSAIDs (non-steroidal anti-inflammatory drugs) such as celecoxib, etodolac, diclofenac and meloxicam, used for the treatment of pain and inflammation.
Tramadol, a pain reliever.
Medicines called triptans, such as sumatriptan, used to treat migraines.
Other antidepressants including other SSRIs and tricyclic antidepressants such as clomipramine, nortriptyline and desipramine.
St. John's wort, herbal preparation for depression.
Fentanyl, a pain reliever and anesthetic.
A dietary supplement called tryptophan.
Medicines such as lithium, risperidone, perphenazine, clozapine (also called antipsychotics) used to treat some psychiatric conditions. - A combination of fosamprenavir and ritonavir, used to treat human immunodeficiency virus (HIV) infection.
Phenobarbital, phenytoin, sodium valproate or carbamazepine, used to treat seizures or epilepsy.
Atomoxetine, used to treat attention deficit hyperactivity disorder (ADHD).
Procyclidine, used to relieve tremors, especially in the context of Parkinson's disease.
Warfarin or other medicines (called anticoagulants) used to thin the blood.
Propafenone, flecainide and drugs used to treat an irregular heartbeat.
Metoprolol, a beta blocker used to treat high blood pressure and heart problems.
Pravastatin, used to treat high cholesterol
Rifampicin, used to treat tuberculosis (TB) and leprosy.
Linezolid, an antibiotic.
Tamoxifen, a drug used for the treatment of breast cancer and female infertility.
Methylthioninium chloride (methylene blue), used in some operations.

Paroxetine Actavis with food, drink and alcohol

Paroxetine Actavis should be taken with food preferably in the morning. Do not drink alcohol while taking Paroxetine Actavis. Alcohol could worsen your symptoms or side effects.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

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

Pregnancy

In view of the small increase in the risk of birth defects (cardiovascular malformations) following taking Paroxetine Actavis during the first three months of pregnancy, it is important that you inform your doctor if you intend to become pregnant or if you have any. pregnancy Your doctor will need to decide whether treatment with Paroxetine Actavis is absolutely necessary or whether it is possible to switch to an alternative treatment.

Treatment with Paroxetine Actavis should not be stopped abruptly.

Make sure your midwife and / or doctor know you are taking Paroxetine Actavis. When taken during pregnancy, particularly in the last 3 months of pregnancy, drugs like Paroxetine Actavis may increase the risk of a serious condition in babies, called pulmonary hypertension. persistence of the infant (PPHN), which causes the baby to breathe faster and appear bluish. These symptoms typically begin during the first 24 hours after the baby is born. If this happens in your baby you should contact your midwife and / or doctor.

If you are taking Paroxetine Actavis during the last 3 months of pregnancy, please tell your doctor as your baby may have some symptoms at birth. These symptoms usually occur during the first 24 hours after the baby is born. They include difficulty sleeping or feeding properly, having breathing problems, blue skin or having a temperature that is too high or too low, feeling sick, crying a lot, having stiff or limp muscles, being lethargic, shaking, having too low a blood sugar being extremely agitated or having convulsions. If your baby has any of these symptoms at birth, contact someone who can advise you immediately.

Breastfeeding

It is possible that paroxetine passes into breast milk in small amounts. If you are using paroxetine, consult your doctor before you start breastfeeding your baby.

Fertility

Paroxetine has been shown to reduce sperm quality in animal studies. In theory, this could affect human fertility but, the impact on human fertility has not yet been observed.

Driving and using machines

This drug can cause side effects (dizziness, sleepiness or confusion) that affect your ability to concentrate and how fast you react. If these side effects concern you, do not drive cars, do not operate machinery and do not carry out any activity that requires alertness and concentration.

Paroxetine Actavis contains soy lecithin

If you are allergic to peanuts or soya do not use this medicine.

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

Always take this medicine strictly according to the prescriptions of your doctor. If you are unsure, ask your doctor or pharmacist.

It is recommended that Paroxetine Actavis be taken once daily in the morning with food. The tablets should not be chewed.

The tablet can be divided into equal halves.

Usual doses:

Adults

Depression:

The recommended dose is 20 mg per day.

Healing usually occurs within 1-2 weeks of starting treatment.

The dosage can only be increased by prescription. Your doctor may decide to gradually increase the dose, 10 mg at a time, until a maximum daily dose of 50 mg is reached.

Duration of treatment: At least 6 months to make sure you are symptom free.

Obsessive Compulsive Disorder:

The starting daily dose is 20 mg, which should be gradually increased, 10 mg at a time, until the recommended daily dose of 40 mg is reached. The maximum daily dose is 60 mg.

The dosage can only be increased by prescription.

Duration of treatment: Several months or longer.

Panic Disorders:

The starting daily dose is 10 mg, which depending on the effect and on prescription can be gradually increased, 10 mg at a time, until the recommended daily dose of 40 mg is reached. The maximum daily dose is 60 mg.

The dosage can only be increased by prescription.

Duration of treatment: Several months or longer.

Social anxiety disorder / social phobia, generalized anxiety disorder and post-traumatic stress disorder:

The recommended dose is 20 mg per day. The maximum daily dose is 50 mg.

The dosage can only be increased by prescription.

Duration of treatment: In case of long-term treatment, the doctor will assess the need for treatment at regular intervals.

Senior citizens:

The starting dose is the same as for adults. However, the dose should not exceed 40 mg per day.

Use in children and adolescents:

Paroxetine Actavis should not be used in children and adolescents under the age of 18 (see section: "be especially careful with").

Reduced kidney or liver function:

The dosage may need to be adjusted. Follow the instructions of your doctor.

Treatment with Paroxetine Actavis should not be stopped / stopped suddenly. This should only be done on the prescription of your doctor (see section "If you stop taking Paroxetine Actavis").

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

If you take more Paroxetine Actavis than you should

If you have taken more Paroxetine Actavis than indicated in this leaflet or prescribed by your doctor, contact your doctor, the emergency department or pharmacist.

The most common symptoms of an overdose are vomiting, dilated pupils, fever, changes in blood pressure, headache, involuntary muscle twitching, restlessness, anxiety and rapid heart rhythm.

If you forget to take Paroxetine Actavis

Do not take a double dose to make up for a forgotten one. Take your next dose at the usual time.

If you stop taking Paroxetine Actavis

Do not stop taking Paroxetine Actavis without checking with your doctor, even when you feel healthy.

Suddenly stopping Paroxetine Actavis after a certain period of treatment may result in the following symptoms:

Common side effects, affecting 1 to 10 users in 100:

Feeling of dizziness, unsteadiness and lack of balance
Sensations such as pins and needles, burning sensations and (less commonly) sensations of electric shock, including in the head, and buzzing, hissing, whistling, ringing or other persistent noises in the ears (tinnitus)
Sleep disturbances (vivid dreams, nightmares, inability to sleep)
Sense of anxiety
Headache.

Uncommon side effects, affecting 1 to 10 users in 1,000:

Malaise (nausea)
Sweating (including night sweats)
Feeling restless or agitated
Tremor (instability)
Sense of confusion or disorientation
Diarrhea (loose stools)
Emotional disturbances or irritation
Changes in vision
Fast or pounding heartbeat (palpitations)

When you stop taking Paroxetine Actavis your doctor will help you reduce your dose slowly over weeks or months - this reduces the chance of withdrawal effects. One method of gradually decreasing the dosage of Paroxetine Actavis is to reduce it by 10 mg per week. Most patients believe that symptoms on stopping Paroxetine Actavis are mild and disappear spontaneously within two weeks. For other people, these symptoms may be more severe or last longer.

If withdrawal effects occur during the dose reduction phase of the tablets, the doctor may decide for a more gradual reduction. If you experience severe withdrawal effects after stopping Paroxetine Actavis, please contact your doctor. He or she may ask you to resume taking the tablets and stop taking them more slowly.

If you have any further questions about the use of this product, ask your doctor or pharmacist.

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

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Talk to your doctor if any of the following side effects occur during treatment:

You may need to contact your doctor or go to the hospital immediately.

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

If you experience unusual bruising or bleeding, including blood in your vomit or stool, contact your doctor immediately or go to a hospital.
If you feel that you are unable to urinate, contact your doctor immediately or go to a hospital.

Rare side effects (may affect up to 1 in 1,000 people):

If you experience seizures (convulsions), contact your doctor immediately or go to a hospital.
If you feel restless and feel like you can't sit or stand still, you may have a disease called akathisia. These sensations may worsen by increasing the dosage of Paroxetine Actavis. If you feel like this, please contact your doctor.
If you feel tired, weak or dizzy and your muscles are sore, stiff or uncoordinated in your blood there may be sodium deficiency. If these symptoms apply to you, please contact your doctor.

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

Allergic reactions, which can be serious, to Paroxetine Actavis.

If you develop a skin rash characterized by red spots and bumps, swollen eyelids, face, lips, mouth or tongue, feel itchy or have difficulty breathing (shortness of breath) or swallowing and feeling faint or lightheaded resulting in collapse or loss of conscience, contact your doctor immediately or go to a hospital.

Severe skin rashes (including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis)

Severe rashes are potentially life-threatening and require immediate medical attention. These initially appear as circular patches, often with central blisters usually on the arms and hands or legs and feet, more severe rashes may include chest swelling and of the back. Additional symptoms may occur, such as infections of the eyes (conjunctivitis) or ulcers of the mouth, throat or nose. Serious forms of rash may progress to widespread peeling of the skin which can be life threatening. These rashes Severe skin rash is often preceded by headache, fever, muscle aches (flu-like symptoms) If you develop a skin rash or any of these symptoms, you should stop taking Paroxetine Actavis and contact your doctor immediately.

If you have some or all of the following symptoms, you may be suffering from a disease called serotonin syndrome. Symptoms consist of: confusion, restlessness, sweating, unsteadiness, chills, hallucinations (strange sounds or strange visions), sudden twitching of muscles or a rapid heartbeat. If you feel like this, please contact your doctor.
Acute glaucoma:

If you feel pain in your eyes and your vision is blurred, please contact your doctor.

Side effects with frequency not known (frequency cannot be estimated from the available data):

If at any time you have thoughts of harming or killing yourself, contact your doctor or go to a hospital immediately.

Other possible side effects during treatment

Very common side effects (may affect more than 1 in 10 people): malaise (nausea), changes in sexual interest or sexual performance (eg lack of orgasm and, in men, abnormal erection and ejaculation), reduced concentration .

Common side effects (may affect up to 1 in 10 people): decreased appetite, increased blood cholesterol levels, difficulty sleeping or insomnia, abnormal dreams (including nightmares), dizziness, tremors, agitation, blurred vision , yawning, dry mouth, constipation, diarrhea, sweating, fatigue, weight gain, vomiting, headache.

Uncommon side effects (may affect up to 1 in 100 people): confusion, hallucinations, slow or uncontrolled movements, also affecting the mouth and tongue, muscle stiffness, rapid pulse, temporary increase or decrease in blood pressure, rash, itching, involuntary urination (urinary incontinence), abnormal dilation of the pupil of the eye.

If you are a diabetic patient you may notice your blood sugar levels losing control while you are taking Paroxetine Actavis. Talk to your doctor about adjusting your insulin dosage or diabetes medicines.

Rare side effects (may affect up to 1 in 1,000 people): hyperactive behavior or thoughts (mania), restlessness, anxiety, a sense of detachment from oneself (depersonalization), panic attacks, (these symptoms could also be a consequence of the disease below), slow pulse, abnormal milk production in men and women, joint pain, muscle pain, effects on the liver (visible in liver function blood tests), restless legs syndrome (SGSR)

Very rare side effects (may affect up to 1 in 10,000 people): blood platelet concentrations that are too low, liver changes (hepatitis, jaundice and / or liver failure), hypersensitivity of the skin to sunlight, persistent and painful erection of the penis, accumulation of fluid in the arms and legs.

Side effects with frequency not known (frequency cannot be estimated from the available data):

ringing, hissing, whistling, ringing or other persistent noises in the ears (tinnitus), broken bones, aggression.

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 blister, tablet container or carton after "EXP". The expiry date refers to the last day of that month.

This medicinal product 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 Paroxetine Actavis contains

The active ingredient is paroxetine:

Each Paroxetine Actavis tablet contains 22.2 mg of paroxetine hydrochloride anhydrous, equivalent to 20 mg of paroxetine.

The other ingredients are:

Tablet core: magnesium stearate, methacrylate methyl methacrylate copolymer (Eudragit E100), sodium starch glycolate (type A), mannitol, microcrystalline cellulose.

Tablet coating: polyvinyl alcohol (partially hydrolyzed), titanium dioxide (E171), talc, soy lecithin (E322), xanthan gum (E415)

What Paroxetine Actavis looks like and contents of the pack

White to cream, round, biconvex, 10 mm diameter film-coated tablets with score line on beveled edges and on both sides and P20 embossed on one side.

The tablet can be divided into equal halves.

Pack sizes:

The blister contains 10, 12, 14, 28, 30 and 56 film-coated tablets.

White cylindrical tablet containers with white cap provided with desiccant powder (silica gel) containing: 20, 30, 60, 100 film-coated 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 Paroxetine - 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

PAROXETINA ACTAVIS 20 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

Paroxetine hydrochloride, anhydrous 22.2 mg equivalent to 20 mg of paroxetine.

Excipients with known effects: Soya lecithin 0.24 mg.

For the full list of excipients see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

White to cream, round, biconvex, 10 mm diameter film-coated tablet with score line on beveled edges and on both sides and P20 embossed on one side.

The tablet can be divided into equal doses.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of

- Major depressive episodes

- Obsessive / Compulsive Disorder (OCD)

- Panic syndrome with or without agoraphobia

- Social anxiety disorder / social phobia

- Generalized anxiety disorder

- Post-traumatic stress disorder

04.2 Posology and method of administration

Dosage

Major depressive episodes

The recommended dose is 20 mg per day. In general, improvement in patients begins after one week but may only become evident from the second week of therapy. As with all antidepressant drugs, the dosage should be reviewed and adjusted as necessary within the first 3 to 4 weeks after initiation of therapy and as deemed clinically appropriate thereafter. In some patients, who have an insufficient response to the 20 mg dose , the dose may be gradually increased up to a maximum of 50 mg per day, with gradual increases of 10 mg, based on the patient's response.

Patients with depression should be treated for a sufficient period of at least 6 months to ensure they are symptom-free.

Obsessive / Compulsive Disorder (OCD)

The recommended dose is 40 mg per day. Patients should be started on a dose of 20 mg per day and the dose may be gradually increased in 10 mg increments up to the recommended dose. If insufficient response to the recommended dose is observed after a few weeks, some patients may benefit from gradually increasing the dosage to a maximum of 60 mg per day. Patients with OCD should be treated for a sufficient period to ensure that are symptom-free. This period may be several months or even longer (see section 5.1)

Panic Disorder

The recommended dose is 40 mg per day. Patients should be started on a dose of 10 mg per day and the dose may be gradually increased in 10 mg increments up to the recommended dose based on the patient's response. A low starting dose is recommended to minimize the potential for worsening of panic symptoms, as has generally been observed in the initial treatment of this disorder. If insufficient response to the recommended dose is observed after a few weeks, some patients may benefit from gradually increasing the dosage to a maximum of 60 mg per day. Patients with panic disorder should be treated for a sufficient period of time. ensure they are symptom-free. This period may be several months or even longer (see section 5.1)

Social anxiety disorder / social phobia

The recommended dose is 20 mg per day. If insufficient response to the recommended dose is observed after a few weeks, some patients may benefit from gradually increasing the dose in 10 mg increments up to a maximum of 50 mg per day. Long-term use should be considered. periodically (see section 5.1.).

Generalized anxiety disorder

Post-traumatic stress disorder

Senior citizens

Increased plasma concentrations of paroxetine have been observed in elderly subjects, however the range of concentrations is similar to that seen in younger subjects. Treatment should begin at the same doses as in adults. In some patients, increasing the dose may be useful, but the maximum dose should not exceed 40 mg per day.

Pediatric population

Paroxetine should not be used for the treatment of children and adolescents as controlled clinical trials have shown that paroxetine is associated with an increased risk of suicidal behavior and hostility. Furthermore, efficacy was not adequately demonstrated in these clinical studies (see sections 4.4 and 4.8).

The use of paroxetine has not been studied in children under 7 years of age. Paroxetine should not be given, as safety and efficacy have not been demonstrated in this age group.

Impaired renal / hepatic function

Increased plasma concentrations of paroxetine have been reported in patients with severe renal impairment (creatinine clearance less than 30 ml / min) or in patients with hepatic impairment. Therefore, the dosage should be limited to the lowest doses of the dosage range.

General informations

Withdrawal symptoms observed following discontinuation of paroxetine treatment

Abrupt discontinuation of treatment should be avoided (see sections 4.4 and 4.8). The tapering regimen used in clinical trials utilized a tapering of the daily dose of 10 mg at weekly intervals. Intolerable symptoms should occur following If the dose is decreased or the treatment is stopped, consider resuming the previously prescribed dose, after which the treating physician will continue to decrease the dose but more slowly.

Method of administration

It is recommended that paroxetine be administered once daily in the morning with food. The tablets should be swallowed and not chewed.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to peanuts or soya.

Paroxetine is contraindicated in combination with monoamine oxidase inhibitors (MAO inhibitors). In exceptional cases, linezolid (an antibiotic which is a reversible non-selective MAO-Inhibitor) may be administered in combination with paroxetine unless the necessary equipment is available to monitor serotonin syndrome symptoms and blood pressure (see section 4.5). .

Paroxetine treatment can be initiated:

- two weeks after stopping treatment with a non-reversible MAO inhibitor or

- at least 24 hours after stopping treatment with a reversible MAO-inhibitor (eg moclobemide, linezolid, methylthioninium chloride (methylene blue; a pre-operative revealing agent which is a reversible non-selective MAO-inhibitor)).

At least one week must elapse after stopping a paroxetine treatment before starting therapy with a MAO inhibitor.

Paroxetine should not be used in combination with thioridazine since, as with other CYP450 2D6 hepatic enzyme inhibitors, paroxetine may elevate plasma thioridazine levels (see section 4.5). QTc interval associated with severe ventricular arrhythmias such as torsades de pointes and sudden death.

Paroxetine must not be administered in combination with pimozide (see section 4.5).

04.4 Special warnings and appropriate precautions for use

Treatment with paroxetine should be initiated with caution two weeks after cessation of treatment with irreversible MAO inhibitors or 24 hours after cessation of treatment with a reversible MAO inhibitor. Paroxetine dosage should be gradually increased until an optimal response is achieved (see sections 4.3 and 4.5).

Pediatric population

Paroxetine should not be used to treat children and adolescents less than 18 years of age. Suicidal behaviors (suicide attempts and suicidal thoughts) and hostility (mostly aggression, oppositional behavior and anger) were observed more frequently in clinical trials of children and adolescents treated with antidepressants than in those treated with placebo. If, for clinical reasons, it is nevertheless decided to initiate treatment, the patient should be carefully monitored for the appearance of suicidal symptoms. Furthermore, the effects on long-term safety in children and adolescents related to growth, maturation and cognitive and behavioral development have not yet been demonstrated.

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 occurs. As improvement may not occur during the first or immediate weeks of treatment, patients should be monitored closely until improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of improvement.

Other psychiatric conditions for which paroxetine is prescribed may also be associated with an increased risk of suicidal behavior. Furthermore, these conditions can be associated with major depressive disorder. The same precautions followed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events or those who have a significant degree of suicidal ideation prior to initiation of treatment have an increased risk of suicidal thoughts or suicide attempts, and should receive close monitoring during treatment. a meta-analysis of clinical trials with placebo-controlled antidepressants in adult patients with psychiatric disorders demonstrated an increased risk of suicidal behavior with antidepressants compared to placebo in patients less than 25 years of age (see also section 5.1).

Therapy must include "careful supervision of patients, particularly those at high risk, especially during the early stages of treatment and following dose modifications. Patients (and their carers) must be warned about the need to monitor for any clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior and to seek immediate medical attention if these symptoms occur.

Akathisia / psychomotor restlessness

The use of paroxetine has been associated with the development of akathisia, characterized by an internal feeling of restlessness and psychomotor agitation such as an inability to sit or stand still, usually associated with subjective malaise.This is most likely to happen within the first few weeks of treatment. In patients with these symptoms, increasing the dosage can be harmful.

Serotonin Syndrome / Neuroleptic Malignant Syndrome

On rare occasions, there have been reports of serotonin syndrome or neuroleptic malignant syndrome-like events in association with paroxetine treatment, particularly when administered concomitantly with other serotonergic and / or neuroleptic drugs. Since these syndromes can lead to potentially life-threatening conditions for the patient, treatment with paroxetine should be interrupted in the event of such events (characterized by a set of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuation in vital signs, changes in mental status including confusion, irritability, extreme agitation leading to delirium and coma), and symptomatic supportive treatment should be initiated. Paroxetine should not be used in combination with serotonin precursors (such as L-tryptophan, oxitriptan) due to the risk of serotonin syndrome (see sections 4.3 and 4.5).

Mania

As with other antidepressants, paroxetine should be introduced with caution in patients with a history of mania. Paroxetine treatment should be discontinued in patients entering a manic phase.

Impaired renal / hepatic function

Caution is recommended in patients with severe renal impairment or in patients with hepatic impairment (see section 4.2).

Diabetes

In diabetic patients, treatment with an SSRI can impair glycemic control. Adjustment of insulin and / or oral hypoglycemia may be necessary.

Epilepsy

As with other antidepressants, paroxetine should be introduced with caution in patients with epilepsy.

Convulsions

The overall incidence of seizures in patients treated with paroxetine is less than 0.1%. The drug should be discontinued if the patient develops seizures.

Electroconvulsive therapy (ECT)

Clinical experience with the concomitant use of paroxetine during electroconvulsive therapy is limited.

Glaucoma

As with other SSRIs, paroxetine infrequently causes mydriasis and should be used with caution in patients with narrow-angle glaucoma or a history of glaucoma.

Cardiac pathologies

In patients with heart disease the usual precautions should be observed.

Hyponatremia

Hyponatremia has been reported rarely, predominantly in the elderly. Caution should also be exercised in those patients at risk of hyponatremia, for example from concomitant medications and cirrhosis.

Hyponatremia is usually reversible after discontinuation of paroxetine.

Hemorrhage

After SSRI administration, cases of abnormal skin bleeding such as ecchymosis and purpura have been reported. Other haemorrhagic manifestations, for example gastrointestinal haemorrhages, have been reported. Elderly patients may be at increased risk.

Caution is advised in patients taking SSRIs concomitantly with oral anticoagulants, drugs known to affect platelet function, or other drugs that may increase the risk of bleeding [e.g. atypical antipsychotics such as clozapine, phenothiazine, most tricyclic antidepressants, acetylsalicylic acid , non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors] and in patients with a history of bleeding disorders or conditions that may predispose to bleeding.

Interactions with tamoxifen

Some studies have shown that the efficacy of Tamoxifen, measured as the risk of breast cancer recurrence / mortality, may be reduced when co-prescribed with paroxetine due to irreversible inhibition of CYP2D6 by paroxetine (see section 4.5). Paroxetine should always be avoided while using Tamoxifen for the treatment or prevention of breast cancer.

Withdrawal symptoms observed following discontinuation of paroxetine treatment

Discontinuation symptoms observed when treatment is stopped are common, particularly in the event of abrupt discontinuation (see section 4.8). In clinical trials, undesirable events observed with discontinuation of treatment occurred in 30% of patients taking paroxetine, compared with 20% of patients taking placebo. The onset of withdrawal symptoms is not the same in cases of which a drug is addictive or addictive. The risk of withdrawal symptoms may be dependent on several factors, including the duration of therapy, the dose and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia, electric shock sensation and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhea, palpitations, emotional instability, have been reported. irritability and visual disturbances. Generally, the intensity of these symptoms is mild to moderate, however in some patients they may be severe. They usually appear within the first few days of stopping treatment, but there have been very rare cases in which they have appeared in patients who inadvertently skipped. one dose.

Generally these symptoms are self-limiting, and usually resolve within two weeks, although in some individuals they may last longer (2-3 months or more). It is therefore advisable to gradually reduce the dose of paroxetine, when treatment is discontinued, over a period of several weeks or months, depending on the patient's needs (see "Withdrawal symptoms observed on withdrawal of Paroxetine", paragraph 4.2).

04.5 Interactions with other medicinal products and other forms of interaction

Serotonergic drugs

As with other SSRIs, concomitant administration of serotonergic drugs may lead to the onset of serotonin-associated effects (serotonin syndrome: see sections 4.3 and 4.4).

Caution should be advised and closer clinical monitoring is required in case of concomitant administration of serotonergic drugs (such as L-tryptophan, triptans, tramadol, linezolid, methylthioninium chloride (methylene blue), SSRIs, lithium, pethidine and preparations based on St. John's wort - Hypericum Perforatum) and paroxetine. Caution is also recommended with fentanyl used in general anesthesia or in the treatment of chronic pain.

The concomitant use of paroxetine and MAO inhibitors is contraindicated due to the risk of developing serotonin syndrome (see section 4.3).

Pimozide

In a study where a single reduced dose of pimozide (2 mg) was co-administered with 60 mg of paroxetine, an average of 2.5-fold increased levels of pimozide were shown. This can be explained by taking into account the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, the concomitant use of pimozide and paroxetine is contraindicated (see section 4.3).

Enzymes predisposed to drug metabolism

The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolizing enzymes. When paroxetine is administered concomitantly with a drug known to inhibit enzyme metabolism, the use of the lowest doses in the dosage range should be considered. When co-administered with drugs known to induce enzyme metabolism (e.g. carbamazepine, rifampicin, phenobarbital and phenytoin) or with fosamprenavir / ritonavir, no starting dose adjustment is required. Any subsequent modification of the paroxetine posology (either after initiation of therapy or after discontinuation of an enzyme inducer) should be based on clinical response (tolerability and efficacy).

Fosamprenavir / ritonavir

Concomitant administration of fosamprenavir / ritonavir 700/100 mg twice daily with paroxetine 20 mg daily to healthy volunteers for 10 days significantly decreased plasma paroxetine levels by approximately 55%. Plasma concentrations of fosamprenavir / ritonavir during co-administration with paroxetine were similar to the reference values observed in other studies, thus indicating that paroxetine has no significant effect on the metabolism of fosamprenavir / ritonavir. No data are available regarding the effects of long-term co-administration, exceeding 10 days, of paroxetine and fosamprenavir / ritonavir.

Procyclidine

Daily administration of paroxetine significantly increases the plasma levels of procyclidine. If anticholinergic effects are observed, the dose of procyclidine should be reduced.

Anticonvulsants

Carbamazepine, phenytoin, sodium valproate. Concomitant administration does not appear to show effects on the pharmacokinetic and pharmacodynamic profile in epileptic patients.

Inhibitory potency of paroxetine on CYP2D6

Like other antidepressants, including other SSRIs, paroxetine inhibits the hepatic cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered drugs metabolised by this enzyme. They include these drugs. some tricyclic antidepressants (e.g. clomipramine, nortriptyline and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see section 4.3), risperidone, atomoxetine, some Type 1c antiarrhythmics (e.g. propafenone and flecainide) and metoprolol is not recommended. "use of paroxetine in combination with metoprolol, administered in heart failure, due to the reduced therapeutic index of metoprolol in this indication.

Tamoxifen has an important active metabolite, endoxifen, which is produced by CYP2D6 and contributes significantly to the efficacy of Tamoxifen. Irreversible inhibition of CYP2D6 by paroxetine leads to reduced plasma concentrations of endoxifen (see section 4.4).

Alcohol

As with other psychotropic drugs, patients should be advised to avoid alcohol use while taking paroxetine.

Oral anticoagulants

There may be a pharmacodynamic interaction between paroxetine and oral anticoagulants. Concomitant use of paroxetine and oral anticoagulants may lead to increased anticoagulant activity and the risk of bleeding. Therefore paroxetine should be used with caution in patients receiving oral anticoagulants (see section 4.4).

NSAIDs, acetylsalicylic acid and other antiplatelet agents

A pharmacodynamic interaction between paroxetine and NSAID / acetylsalicylic acid may occur. Concomitant use of paroxetine and NSAIDs / acetylsalicylic acid may lead to an increased risk of bleeding (see section 4.4). Caution is advised in patients taking SSRIs concomitantly with oral anticoagulants, drugs known to affect platelet function, or others. drugs that may increase the risk of bleeding [eg atypical antipsychotics such as clozapine, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, NSAIDs, COX-2 inhibitors] and in patients with a history of bleeding disorders or conditions that may predispose to bleeding .

04.6 Pregnancy and lactation

Pregnancy

Some epidemiological studies have indicated an increased risk of congenital malformations, mostly cardiovascular (eg ventricular septal defects (the majority) and atrial septal defects) associated with taking paroxetine during the first trimester of pregnancy. The mechanism is unknown. The data indicate that the risk of giving birth to a newborn with a cardiovascular defect following maternal exposure to paroxetine is less than 2/100 (OR = 1.55 [1.182.04]) compared to an expected percentage for such defects. about 1/100.

Paroxetine should only be administered during pregnancy when strictly indicated. The physician, at the time of the prescription, will have to evaluate the option of alternative treatments in women who are pregnant or who are planning to become pregnant. Abrupt termination during pregnancy should be avoided (see "Withdrawal symptoms observed following discontinuation of paroxetine treatment", section 4.2).

Newborns should be monitored if maternal use of paroxetine continues into the later stages of pregnancy, particularly the third trimester.

The following symptoms may occur in newborns following maternal use of paroxetine in later stages of pregnancy: respiratory distress, cyanosis, apnea, convulsions, unstable temperature, difficulty in feeding, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, nervousness, irritability, lethargy, constant crying, drowsiness and difficulty falling asleep. These symptoms could be due to either serotonergic effects or withdrawal symptoms. In most cases, complications begin immediately upon delivery or soon after ( less than 24 hours).

Epidemiological data suggest that the use of SSRIs during pregnancy, particularly in the later stages, may increase the risk of persistent pulmonary hypertension in newborns (PPHN). The observed risk was approximately 5 in 1000 pregnancies. In the general population it is. there are 1-2 cases of PPHN per 1000 pregnancies.

Animal studies have shown reproductive toxicity but did not indicate direct or indirect harmful effects with respect to pregnancy, embryofoetal development, parturition or postnatal development (see section 5.3).

Feeding time

Small amounts of paroxetine are excreted in breast milk. In published studies, serum concentrations in breastfed infants were undetectable (

Fertility

Animal data have shown that paroxetine can affect sperm quality (see section 5.3). In-vitro data on human material show some effect on sperm quality however in humans patients treated with some SSRIs (including paroxetine) have shown that an effect on sperm quality appears to be reversible. No impact on human fertility has been observed so far. .

Clinical studies have shown that SSRIs (including paroxetine) can affect sperm quality. This effect appears to be reversible after stopping treatment. These studies did not examine the impact on fertility, but changes in sperm quality may affect fertility in some men.

04.7 Effects on ability to drive and use machines

Clinical experience has shown that paroxetine therapy is not associated with impaired cognitive or psychomotor functions.

However, as with all psychoactive drugs, patients should be advised to exercise caution when driving and operating machinery. Although paroxetine does not increase the psychic and motor damaging effects induced by alcohol intake, it is not recommended. "concomitant use of paroxetine and alcohol.

04.8 Undesirable effects

Some of the adverse drug reactions listed below may decrease in intensity and frequency with continued treatment and do not normally lead to discontinuation of therapy.

Side effects are listed below by organ, system / system and by frequency. Within each frequency group undesirable effects are presented in descending order of severity.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100,

Disorders of the blood and lymphatic system

Uncommon: abnormal bleeding, particularly affecting the skin and mucous membranes (mostly ecchymosis).

Very rare: thrombocytopenia.

Disorders of the immune system

Very rare: allergic reactions (including urticaria and angioedema).

Endocrine pathologies

Very rare: syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Metabolism and nutrition disorders

Common: decreased appetite, increased cholesterol levels.

Rare: hyponatremia. Hyponatremia has been reported mainly in elderly patients and is sometimes due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Psychiatric disorders

Common: somnolence, insomnia, agitation, abnormal dreams (including nightmares).

Occasional: confusion, hallucinations.

Rare: manic reactions, anxiety, depersonalization, panic attacks, akathisia (see section 4.4).

Frequency not known: suicidal ideation and behavior.

Cases of suicidal ideation and behavior have been reported during paroxetine therapy or early after treatment termination (see section 4.4).

These symptoms can also be due to the underlying disease.

Nervous system disorders

Very common: difficulty concentrating

Common: dizziness, tremors, headache

Uncommon: extrapyramidal disorders

Rare: convulsions, restless legs syndrome (SGSR).

Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, chills, tachycardia and tremor). There have been reports of extrapyramidal disorders, including orofacial dystonia, sometimes in patients already suffering from movement disorders or in patients receiving neuroleptics.

Eye disorders

Common: blurred vision.

Uncommon: mydriasis (see section 4.4).

Very rare: acute glaucoma.

Ear and labyrinth disorders

Frequency not known: tinnitus.

Cardiac pathologies

Uncommon: sinus tachycardia. Rare: bradycardia.

Vascular pathologies

Uncommon: transient increases or decreases in blood pressure, postural hypotension. Transient increases or decreases in blood pressure have been reported following treatment with paroxetine, usually in patients with pre-existing hypertension or anxiety.

Respiratory, thoracic and mediastinal disorders

Common: yawning.

Gastrointestinal disorders

Very common: nausea.

Common: constipation, diarrhea, vomiting, dry mouth.

Very rare: gastrointestinal bleeding.

Hepatobiliary disorders

Rare: increase in liver enzymes.

Very rare: hepatic events (such as hepatitis, sometimes associated with jaundice and / or liver failure).

Elevations of liver enzymes have been reported. In the post-marketing period, liver-related events (such as hepatitis, sometimes associated with jaundice and / or liver failure) have also been reported very rarely. prolonged increase in liver function test values.

Skin and subcutaneous tissue disorders

Common: sweating

Uncommon: skin rash, pruritus

Very rare: severe adverse skin reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), photosensitivity reactions.

Musculoskeletal and connective tissue disorders

Rare: arthralgia, myalgia.

Epidemiological studies, mainly conducted in patients aged 50 and older, show an increased risk of bone fractures in patients treated with SSRIs and tricyclic antidepressants. The mechanism leading to this risk is not known.

Renal and urinary disorders

Uncommon: urinary retention, urinary incontinence.

Diseases of the reproductive system and breast

Very common: sexual dysfunction.

Rare: hyperprolactinaemia / galactorea.

Very rare: priapism

General disorders and administration site conditions

Common: asthenia, body weight gain

Very rare: peripheral edema.

Withdrawal symptoms observed following discontinuation of paroxetine treatment

Common: dizziness, sensory disturbances, sleep disturbances, anxiety, headache.

Uncommon: agitation, nausea, tremor, confusion, sweating, emotional instability, visual disturbances, palpitations, diarrhea, irritability.

Discontinuation of paroxetine treatment (especially if abrupt) usually leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia, electric shock sensation and tinnitus), sleep disturbances (including vivid dreams), agitation have been reported or anxiety, nausea, tremor, confusion, sweating, headache, diarrhea, palpitations, emotional instability, irritability and visual disturbances Generally these events are mild to moderate and self-limiting, however in some patients they may be severe and / or prolonged. It is therefore recommended, if treatment with paroxetine is no longer necessary, to carry out a gradual interruption, conducted by a progressive decrease of the dose (see sections 4.2 and 4.4).

Pediatric population

The following adverse events occurred:

Increased suicide-related behaviors (including suicide attempts and suicidal thoughts), self-harming behavior and increased hostile attitude. Suicidal thoughts and suicide attempts were mainly observed in clinical trials with adolescents with Major Depressive Disorder. The increase hostile behavior has particularly occurred in children with OCD, especially in children under the age of 12. Additional events observed are: decreased appetite, tremor, sweating, hyperkinesis, agitation, emotional lability (including crying and mood fluctuations) and bleeding-related adverse events, predominantly of the skin and mucous membranes.

Events observed after paroxetine discontinuation / tapering are: emotional lability (including crying, mood fluctuations, self harm, suicidal thoughts and suicide attempts), nervousness, dizziness, nausea and abdominal pain (see section 4.4 "Special warnings and precautions for use').

See section 5.1 for more information on pediatric clinical studies.

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: www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Symptoms and signs:

Based on the available information regarding overdose with paroxetine, a large margin of safety appears evident. Experience in cases of paroxetine overdose indicated that, in addition to the symptoms described in section 4.8 "Undesirable effects", vomiting, fever and involuntary muscle contractions were also reported. Patients generally recovered without serious sequelae even in cases. in which paroxetine has been taken alone up to doses of 2000 mg. Events such as coma or ECG changes have occasionally been reported, very rarely with a fatal outcome, but generally when paroxetine has been taken in combination with others psychotropic drugs, with or without alcohol.

Treatment

A specific antidote is not known. Treatment should be based on the general measures used in the treatment of overdose with antidepressants. Where appropriate, gastric emptying by induction of emesis, gastric lavage, or both is recommended. After emptying, activated charcoal can be administered at a dose of 20 or 30 g every 4-6 hours during the first 24 hours after ingestion. Supportive therapy with careful observation and frequent monitoring of vital signs is indicated.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: antidepressants - selective serotonin reuptake inhibitors.

ATC code: N06A B05.

Mechanism of action

Paroxetine is a potent and selective inhibitor of the reuptake of 5-hydroxytryptamine (5-HT, serotonin); its antidepressant action and its efficacy in the treatment of obsessive compulsive disorder, social anxiety disorder / social phobia, generalized anxiety disorder, post-traumatic stress disorder and panic disorder are believed to be related to this specific inhibition of reuptake of 5-HT in brain neurons. Paroxetine is not chemically related to tricyclics, tetracyclics and other available antidepressants. Paroxetine has low affinity for muscarinic-type cholinergic receptors and animal studies have shown only weak anticholinergic properties. In agreement with this selectivity of action, some studies in vitro showed that, unlike tricyclic antidepressants, paroxetine has low affinity for alpha 1, alpha 2 and beta adrenoreceptors, for dopaminergic (D2) receptors, for 5-HT1-like and 5-HT2 receptors and for "histamine (H1). This lack of interaction with postsynaptic receptors in vitro has been confirmed by studies in vivo, which demonstrated the absence of depressive properties on the central nervous system and of hypotensive properties.

Pharmacodynamic effects

Paroxetine does not alter psychomotor functions and does not potentiate the depressant effects of ethanol. Like other selective serotonin reuptake inhibitors, paroxetine causes symptoms related to excessive stimulation of the serotonin receptor when administered to animals previously treated with inhibitors. monoamine oxidase (MAOI) or tryptophan. Behavioral and EEG studies indicate that paroxetine is weakly activating at doses generally greater than those required to inhibit serotonin reuptake. Activating properties are not inherently "amphetamine-like". Animal studies indicate that. paroxetine is well tolerated by the cardiovascular system. Paroxetine does not cause clinically significant changes in blood pressure, heart rate and ECG after administration to healthy subjects. Other studies indicate that paroxetine, unlike antidepressants that inhibit noradrenaline reuptake, has a more reduced propensity to inhibit antihypertensive effects of guanethidine.

Paroxetine, in the treatment of depressive disorders, demonstrates efficacy comparable to that of standard antidepressants. There is also some evidence that paroxetine may have therapeutic value in patients who are unresponsive to standard therapy. Administration of the dose in the morning has no adverse effect on the quality or duration of sleep. Additionally, patients may report improved sleep when they respond to paroxetine therapy.

Analysis of the tendency to suicide in adults

A "specific analysis of paroxetine in placebo-controlled studies in adults with psychiatric disorders showed a higher frequency of suicidal behavior in young adults (18-24 years) treated with paroxetine compared to those treated with placebo (2.19% vs 0, 92%). In the older age group, no such increase was observed. In adults with major depressive disorder (all ages), an increased frequency of suicidal behavior was observed in patients treated with paroxetine compared to those treated with placebo (0.32% vs 0.05%); all events observed were suicide attempts. However, the majority of these attempts (8 out of 11) occurred in young adults treated with paroxetine (see also paragarafo 4.4).

Dose response

In fixed dose studies, the dose response curve is flat, indicating no efficacy advantage in using higher than recommended doses. However, there are some clinical data that suggest that subsequent dose increases may be of benefit to some. patients.

Clinical efficacy and safety

The long-term efficacy of paroxetine in depression was demonstrated in a 52-week maintenance study designed to evaluate relapse prevention: relapses in patients treated with paroxetine (20-40 mg per day) occurred in the 12% of cases, compared to 28% of cases in patients taking placebo.

The long-term efficacy of paroxetine in the treatment of OCD was examined in three 24-week maintenance studies, designed to evaluate relapse prevention. In one of the three studies, a significant difference was achieved in the proportion of patients with relapses between paroxetine (38%) and placebo (59%).

The long-term efficacy of paroxetine in the treatment of panic disorder was demonstrated in a 24-week maintenance study designed to evaluate relapse prevention: relapses in patients treated with paroxetine (10-40 mg per day) occurred in 5% of cases, compared with 30% of cases in patients taking placebo.This was supported by a 36-week maintenance study.

The long-term efficacy of paroxetine in the treatment of social and generalized anxiety disorders and post-traumatic stress disorder has not been sufficiently demonstrated.

Pediatric population

In short-term clinical trials (up to 10-12 weeks) in children and adolescents, paroxetine-treated patients have been observed with a frequency of at least 2% of patients and have occurred with at least twice the rate of placebo the following adverse events: increased suicidal behaviors (including suicide attempts and suicidal ideation), self-harming behavior and increased hostile attitude. Suicidal thoughts and suicide attempts were mainly observed in clinical trials in adolescents with major depressive disorder . The increase in hostility occurred particularly in children with OCD, and especially in younger children under the age of 12. Additional events that were repeatedly observed in paroxetine compared to placebo were: decrease in "appetite, tremor, sweating, hyperkinesis, agitation, emotional lability (incl use crying and mood fluctuations).

In studies using a tapering regimen, symptoms reported during the tapering phase or for a withdrawal of paroxetine with a frequency of at least 2% of patients and occurred at least twice as fast as placebo were : emotional lability (including crying, mood fluctuations, self harm, suicidal thoughts and suicide attempts), nervousness, dizziness, nausea and abdominal pain (see section 4.4).

In five parallel group studies lasting eight weeks to eight months of treatment, bleeding-related adverse events, predominantly of the skin and mucous membranes, were observed in patients treated with paroxetine with a frequency of 1.74% compared with at 0.74% observed in the placebo group treated patients.

05.2 "Pharmacokinetic properties

Absorption

Paroxetine is well absorbed after oral administration and undergoes first pass metabolism. Due to first pass metabolism, the amount of paroxetine available in the systemic circulation is less than that absorbed from the gastrointestinal tract. In case of increased body burden following higher single doses or multiple doses, partial saturation of the first pass effect and a reduction in plasma clearance occur. This leads to a disproportionate increase in plasma concentrations of paroxetine and therefore Pharmacokinetic parameters are not constant, resulting in non-linear kinetics. However, non-linearity is generally modest and is limited to those subjects who achieve low plasma levels at low doses. Steady-state systemic levels are achieved within 7-14 days of onset. treatment with immediate or controlled release formulations and pharmacokinetics do not appear to change during long-term treatment.

Distribution

Paroxetine is widely distributed in tissues and pharmacokinetic calculations indicate that only 1% of the paroxetine present in the body is found in the plasma. About 95% of the paroxetine present in plasma is bound to proteins at therapeutic concentrations. No correlation has been demonstrated between paroxetine plasma concentrations and clinical effects (adverse events and efficacy). The passage into human breast milk, and into the fetuses of laboratory animals, occurs in small quantities.

Biotransformation

The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are readily eliminated. In view of their relative lack of pharmacological activity, they are extremely unlikely to contribute to the therapeutic effects of paroxetine.

Metabolism does not compromise the selectivity of action of paroxetine on neuronal reuptake of serotonin.

Elimination

Urinary excretion of unchanged paroxetine is generally less than 2%, while that of metabolites is about 64% of the dose. Approximately 36% of the dose is excreted in the faeces, probably via bile, of which unchanged paroxetine represents less than "1% of the dose. Therefore paroxetine is almost completely eliminated by metabolism. Excretion of metabolites is biphasic, being initially the result of first pass metabolism and subsequently controlled by the systemic elimination of paroxetine. The elimination half-life is variable but is generally about 1 day.

Special patient populations

Elderly and Renal / Hepatic Function Impairment

Increased plasma concentrations of paroxetine have been observed in elderly subjects and in subjects with severe renal impairment or hepatic impairment, but the range of plasma concentrations is similar to that of healthy adult subjects.

05.3 Preclinical safety data

Toxicological studies were conducted in the rhesus monkey and in the albino rat; in both species the metabolic profile is similar to that described in humans. As expected with lipophilic amines, including tricyclic antidepressants, phospholipidosis was detected in rats. Phospholipidosis was not observed in primate studies lasting up to a year, at doses 6 times higher than the recommended range in clinical dosages.

Carcinogenesis: In two-year studies conducted in mice and rats, paroxetine did not show carcinogenic effects.

Genotoxicity: Genotoxicity was not observed in a series of tests in vitro And in vivo.

Reproductive toxicity studies in rats showed that paroxetine affects male and female fertility by reducing the fertility index and the pregnancy rate. In rats, higher infant mortality and delayed ossification were observed. The latter effects are likely related to maternal toxicity and are not considered to be a direct effect on the fetus / neonate.

06.0 PHARMACEUTICAL INFORMATION

06.1 Excipients

Core of the tablet:

Magnesium stearate, sodium starch glycolate (Type A), mannitol, microcrystalline cellulose

Tablet coating:

Copolymer of methacrylic acid-methyl methacrylate (Eudragit E100), polyvinyl alcohol - partially hydrolyzed, titanium dioxide (E 171), talc, soy lecithin (E 322), xanthan gum (E 415)