Trivonor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRIVONOR (TRIVONOR)

Composition:

Active ingredient: paroxetine;

One tablet contains 25.83 mg of paroxetine mesylate, equivalent to 20 mg of paroxetine;

Excipients: calcium hydrogen phosphate, anhydrous; sodium starch glycolate; magnesium stearate;

Coating composition: lactose monohydrate, hydroxypropylmethylcellulose, titanium dioxide (E 171), polyethylene glycol 4000, yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: film-coated tablets ranging in color from yellow to orange, oval or round in shape. The tablets are embossed with "POT 20" on one side. Tablets have a notch on both sides.

Pharmacotherapeutic group. Antidepressants. ATC code N06A B05.

Pharmacological Properties

Pharmacodynamics

Paroxetine is a potent selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) reuptake. Its antidepressant effect and efficacy in the treatment of obsessive-compulsive and panic disorders are due to specific inhibition of 5-hydroxytryptamine uptake by brain neurons. Chemically, paroxetine differs from tricyclic, tetracyclic, and other known antidepressants.

The drug has low affinity for muscarinic cholinergic receptors. In contrast to tricyclic antidepressants, it has negligible affinity for alpha1-, alpha2-, and beta-adrenergic receptors, dopaminergic (D2) receptors, 5-HT1-like, 5-HT2, and histamine (H1) receptors; it does not affect psychomotor function and does not potentiate the depressant effect of ethanol.

Paroxetine does not affect cardiovascular system activity and does not cause clinically significant changes in blood pressure, heart rate, or ECG parameters. Unlike antidepressants that inhibit norepinephrine reuptake, paroxetine has a much smaller effect on the antihypertensive action of guanethidine.

Pharmacokinetics

After oral administration, paroxetine is rapidly absorbed and undergoes hepatic transformation. The main metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are rapidly eliminated from the body.

Approximately 64% of the administered dose of paroxetine is excreted in the urine, with less than 2% excreted unchanged. About 36% of the administered dose is excreted in feces as metabolites. Paroxetine metabolites are eliminated in two stages—first through first-pass hepatic metabolism and then through systemic elimination of paroxetine. The mean elimination half-life is approximately 1 day. Steady-state plasma concentrations are reached within 7–14 days after initiation of treatment, and the pharmacokinetics of the drug remain virtually unchanged during prolonged therapy.

No correlation has been found between plasma paroxetine concentrations and clinical effects (efficacy and adverse reactions).

Due to drug breakdown in the liver, the amount of paroxetine circulating in the blood is lower than the amount absorbed in the gastrointestinal tract. With increasing single doses or repeated dosing, partial saturation of the first-pass hepatic metabolic pathway occurs, resulting in reduced plasma clearance. This leads to a disproportionate increase in paroxetine plasma concentration and changes in pharmacokinetic parameters, resulting in nonlinear kinetics. However, this nonlinearity is generally minor and observed only in patients who achieve low plasma concentrations of the drug when low doses are administered.

Paroxetine is widely distributed in body tissues. The values of calculated pharmacokinetic parameters indicate that only 1% of the administered dose remains in the plasma.

At therapeutic concentrations, approximately 95% of paroxetine is protein-bound in plasma.

Increased plasma concentrations of paroxetine are observed in elderly patients and in patients with renal or hepatic impairment, but these levels remain within the range of fluctuations observed in healthy adult volunteers.

Clinical characteristics.

Indications.

Adults.

Major depressive disorder. Treatment of major depressive disorder.

Obsessive-compulsive disorder. Treatment of symptoms and prevention of relapses of obsessive-compulsive disorder.

Panic disorder. Treatment of symptoms and prevention of relapses of panic disorder with or without agoraphobia.

Social phobias/social anxiety disorders. Treatment of social phobias/social anxiety disorders.

Generalized anxiety disorder. Treatment of symptoms and prevention of relapses of generalized anxiety disorder.

Post-traumatic stress disorder. Treatment of post-traumatic stress disorder.

Contraindications.

Hypersensitivity to paroxetine or to any of the excipients of the medicinal product. Trivonor must not be used concomitantly with monoamine oxidase inhibitors (MAOIs), including linezolid—an antibiotic that is a reversible non-selective MAO inhibitor—and methylene blue (methylthioninium chloride), or within 2 weeks of discontinuing MAOI treatment.

Similarly, MAOIs must not be used within 2 weeks of discontinuing paroxetine treatment (see section "Interaction with other medicinal products and other forms of interaction").

Trivonor must not be used in combination with thioridazine, as paroxetine, like other drugs that inhibit the hepatic enzyme CYP450 2D6, may increase thioridazine levels (see section "Interaction with other medicinal products and other forms of interaction"). Use of thioridazine may lead to QT interval prolongation with associated severe ventricular arrhythmia (e.g., torsades de pointes) and sudden death.

Trivonor must not be prescribed in combination with pimozide (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Serotonergic medicinal products.

As with other selective serotonin reuptake inhibitors (SSRIs), concomitant use of serotonergic agents may lead to a 5-HT-related effect (serotonin syndrome).

Paroxetine should be used with caution together with serotonergic agents such as L-tryptophan, triptans, tramadol, other serotonin reuptake inhibitors, lithium, fentanyl, and St. John's wort (Hypericum perforatum), and patients must be closely monitored. Concomitant use of paroxetine with MAO inhibitors, including linezolid—an antibiotic that is a reversible non-selective MAO inhibitor—and methylene blue (methylthioninium chloride) is contraindicated (see section "Contraindications").

Pimozide.

Data from a study on the concomitant use of a single low dose of pimozide (2 mg) and paroxetine showed increased pimozide levels. This was explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see section "Contraindications").

Enzymes involved in drug metabolism.

The metabolism and pharmacokinetic parameters of paroxetine may be altered by induction or inhibition of enzymes involved in drug metabolism. When paroxetine is used concomitantly with drugs that inhibit enzymes, the lowest effective doses should be prescribed. When used concomitantly with enzyme-inducing drugs (carbamazepine, rifampicin, phenobarbital, phenytoin), no change in the initial dose of paroxetine is required. Dose adjustments during continued treatment should be made according to clinical response (tolerance and efficacy).

Neuromuscular blockers.

SSRIs may reduce plasma cholinesterase activity, leading to prolonged neuromuscular blocking effects of mivacurium and succinylcholine.

Fosamprenavir/ritonavir.

Concomitant use of fosamprenavir/ritonavir with paroxetine significantly reduces plasma levels of paroxetine. Dose adjustments during continued treatment should be based on clinical response (tolerance and efficacy).

Procyclidine.

Daily use of paroxetine significantly increases serum procyclidine levels. If anticholinergic effects occur, the procyclidine dose should be reduced.

Anticonvulsants.

Carbamazepine, phenytoin, sodium valproate. No effect on the pharmacokinetics/pharmacodynamics of the drug has been observed in epileptic patients when used concomitantly with these agents.

Ability of paroxetine to inhibit the CYP2D6 enzyme.

Paroxetine, like other antidepressants that are serotonin reuptake inhibitors, inhibits the activity of the CYP2D6 enzyme of the cytochrome P450 system. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered drugs metabolized by this enzyme. These include certain tricyclic antidepressants (e.g., amitriptyline, nortriptyline, imipramine, desipramine), phenothiazine antipsychotics (e.g., perphenazine and thioridazine), risperidone, atomoxetine, certain class 1c antiarrhythmics (e.g., propafenone and flecainide), and metoprolol.

Tamoxifen has an important active metabolite, endoxifen, produced by CYP2D6, which is a key component of tamoxifen's efficacy. Irreversible inhibition of CYP2D6 by paroxetine leads to reduced plasma concentrations of endoxifen (see section "Special precautions for use").

CYP3A4.

In vivo studies on the concomitant use of paroxetine and terfenadine—a substrate of the CYP3A4 enzyme—at steady-state plasma concentrations showed no influence of paroxetine on the pharmacokinetics of terfenadine. Similarly, in vivo interaction studies showed no effect of the drug on the pharmacokinetics of alprazolam, and vice versa. Concurrent administration of paroxetine with terfenadine, alprazolam, and other drugs that are substrates of CYP3A4 is not expected to be hazardous. Clinical studies have shown that absorption or pharmacokinetics of paroxetine are not affected or are minimally affected (i.e., do not require dose adjustment) by factors such as food, antacids, digoxin, propranolol, or alcohol. The medicinal product Trivonor does not potentiate the cognitive and motor impairments caused by alcohol; however, consumption of alcoholic beverages during paroxetine treatment is not recommended.

Oral anticoagulants.

Concomitant use of oral anticoagulants and paroxetine may result in pharmacodynamic interaction, potentially increasing anticoagulant activity and the risk of bleeding. Therefore, paroxetine should be prescribed with caution in patients receiving oral anticoagulants.

Non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and antiplatelet agents.

Concomitant use of non-steroidal anti-inflammatory drugs/acetylsalicylic acid and paroxetine may result in pharmacodynamic interaction, potentially increasing the risk of bleeding. Paroxetine should be prescribed with caution together with medicinal products that affect platelet function or increase the risk of bleeding.

Pravastatin.

The interaction between paroxetine and pravastatin observed in studies indicates that concomitant use of paroxetine and pravastatin may lead to increased blood glucose levels. Patients with diabetes receiving both paroxetine and pravastatin may require adjustment of the dosage of oral hypoglycemic agents and/or insulin (see section "Special precautions for use").

Special precautions for use.

Worsening of clinical condition and risk of suicide.

Young adult patients, especially those with severe depressive disorders, may have an increased risk of suicidal behaviour during treatment with paroxetine. In patients with depressive disorders, symptoms of depression and/or emergence of suicidal thoughts and behaviour may worsen regardless of whether they are taking antidepressants or not. This risk persists until significant remission occurs. The risk of suicide may increase in the early stages of recovery.

Other psychiatric disorders for which paroxetine is prescribed may also be associated with an increased risk of suicidal behaviour, and such disorders may coexist with major depressive episodes. Patients with a history of suicidal behaviour or ideation, younger patients, and patients with persistent suicidal ideation prior to initiation of treatment represent a high-risk group for suicide attempts and suicidal thoughts. All patients should be closely monitored for worsening of clinical condition (including development of new symptoms) and suicidal behaviour during treatment, particularly at the beginning of therapy or during dose changes (both increases and decreases). Patients (and caregivers) should be warned about the need for continuous monitoring for any worsening of condition (including emergence of new symptoms) and/or appearance of suicidal ideation/behaviour or thoughts of self-harm, and the necessity to seek immediate medical help if such symptoms occur.

It should be understood that the emergence of certain symptoms such as agitation or akathisia or mania may be related either to the underlying disease or to the course of treatment (see section "Adverse reactions").

In patients experiencing clinical worsening (including development of new symptoms) and/or emergence of suicidal thoughts/behaviour, especially if these symptoms are severe, sudden in onset, or previously unobserved, the treatment regimen should be modified, up to and including discontinuation of the drug.

Akathisia.

Use of paroxetine or other SSRIs may be associated with the development of akathisia — a condition characterized by inner restlessness and psychomotor agitation, such as inability to sit or stand still, combined with subjective feelings of discomfort. The likelihood of this occurring is greatest during the first weeks of treatment.

Serotonin syndrome/neuroleptic malignant syndrome.

In rare cases, treatment with paroxetine may be associated with the development of serotonin syndrome or neuroleptic malignant syndrome, particularly when used concomitantly with other serotonergic and/or neuroleptic agents. If symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations in vital signs, or changes in mental status (including confusion, irritability, extreme agitation progressing to delirium and coma) occur, paroxetine treatment should be discontinued immediately (as these symptoms are potentially life-threatening), and supportive symptomatic therapy should be initiated. Paroxetine should not be used in combination with serotonergic precursors (such as L-tryptophan, 5-hydroxytryptophan) due to the risk of serotonin syndrome (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Mania and bipolar disorders.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally accepted that treating such episodes with an antidepressant alone may increase the likelihood of triggering manic or mixed episodes in patients at risk for bipolar disorder. Before initiating antidepressant therapy, patients should be carefully evaluated for any risk of developing bipolar disorder. This evaluation should include a detailed patient history, including any history of suicide attempts, bipolar disorders, or depression in family members. It should be noted that paroxetine is not indicated for the treatment of depression in bipolar disorder. Paroxetine should be used with caution in patients with a history of manic episodes.

Tamoxifen.

Studies have shown that the efficacy of tamoxifen, measured by the risk of breast cancer recurrence or mortality, may be reduced when used concomitantly with paroxetine, as paroxetine is a potent irreversible inhibitor of CYP2D6 (see section "Interaction with other medicinal products and other forms of interaction"). This risk increases with longer duration of concomitant use. In patients receiving tamoxifen for breast cancer treatment, an alternative antidepressant with minimal or no CYP2D6 inhibition should be considered.

Bone fractures.

Studies investigating the risk of bone fractures with certain antidepressants, including SSRIs, have reported an association with fractures. The risk occurs during treatment and is highest in the early stages of therapy. The possibility of bone fractures should be considered when treating patients with paroxetine.

Monoamine oxidase inhibitors (MAOIs).

Paroxetine treatment should be initiated with caution, not earlier than 2 weeks after discontinuation of MAO inhibitors. The dose should be gradually increased until optimal response is achieved.

Renal/hepatic impairment.

Paroxetine should be used with caution in patients with severe renal or hepatic impairment.

Diabetes mellitus.

In patients with diabetes mellitus, treatment with serotonin reuptake inhibitors may alter glycaemic control, necessitating adjustment of insulin and/or oral hypoglycaemic agent doses. Additionally, clinical studies have indicated that elevated blood glucose levels may occur when paroxetine is used concomitantly with pravastatin.

Epilepsy.

Trivonor, like other antidepressants, should be used with caution in patients with epilepsy.

Seizures.

In patients treated with paroxetine, the overall incidence of seizures is less than 0.1%. If seizures occur, Trivonor should be discontinued.

Electroconvulsive therapy (ECT).

There is only limited clinical experience with the use of paroxetine in combination with electroconvulsive therapy.

Glaucoma.

Trivonor, like other serotonin reuptake inhibitors, may cause mydriasis and should therefore be used with caution in patients with closed-angle glaucoma.

Hyponatraemia.

Cases of hyponatraemia have occasionally been reported, mostly in elderly patients. In most cases, signs of hyponatraemia resolve after discontinuation of paroxetine.

Haemorrhage.

Skin and mucous membrane bleeding (including gastrointestinal and gynaecological bleeding) have been observed following paroxetine treatment. Therefore, paroxetine should be used with caution in patients receiving concomitant medications that increase the risk of bleeding, as well as in patients with a history of frequent bleeding or predisposition to bleeding. Elderly patients may be at increased risk of non-menstrual bleeding events.

Cardiac disorders.

Standard precautions should be observed when treating patients with concomitant cardiac diseases.

Sexual dysfunction.

SSRIs may cause symptoms of sexual dysfunction (see section "Adverse reactions"). In some cases, these symptoms may persist after discontinuation of treatment.

Symptoms observed upon discontinuation of paroxetine.

Symptoms upon discontinuation of the drug are not equivalent to drug dependence or addiction due to substance abuse.

Reported symptoms include dizziness, sensory disturbances (including paraesthesia, electric shock sensations, and tinnitus), sleep disturbances (including vivid dreams), agitation or anxiety, nausea, tremor, seizures, increased sweating, headache, diarrhoea. Generally, these symptoms are mild to moderate in severity, although in some patients they may be more intense. They typically occur within the first few days after discontinuation of the drug, although isolated cases have been reported in patients who accidentally missed a single dose. These symptoms usually resolve spontaneously within 2 weeks, although in some patients the process may be prolonged (2–3 months or longer). Therefore, it is recommended that paroxetine be tapered gradually over several weeks or months, depending on individual patient characteristics (see section "Dosage and administration").

Important information on excipients.

• This medicinal product contains 5.95 mg of sodium per tablet, i.e. practically sodium-free.
• If you have been diagnosed with an intolerance to certain sugars, consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Fertility.

It is known from clinical studies that SSRIs, including paroxetine, may affect sperm quality. These effects are considered reversible upon discontinuation of treatment. Changes in sperm parameters may affect fertility in some men.

Pregnancy.

Teratogenic or embryotoxic effects of paroxetine were not observed in animal studies.

Data from studies on pregnancy outcomes in women treated with antidepressants during the first trimester have reported an increased risk of congenital malformations, primarily cardiovascular (e.g., atrial or ventricular septal defects), associated with paroxetine use. Based on these data, it can be estimated that the risk of giving birth to an infant with a cardiac defect in women treated with paroxetine during pregnancy is approximately 1 in 50, compared to an expected risk of about 1 in 100 in the general population.

Physicians should consider the possibility of alternative treatments for pregnant women or women planning pregnancy, and paroxetine should be prescribed only when the expected benefit to the mother outweighs the potential risk to the fetus.

There are reports of preterm delivery in women treated with paroxetine or other SSRIs, although causal relationships with drug use have not been established. Newborns should be examined if the mother continued taking paroxetine during the third trimester, as complications in newborns have been reported following maternal treatment with paroxetine or other SSRIs during this period, although causal links have not been confirmed. Reported effects include respiratory distress, cyanosis, apnoea, seizures, temperature fluctuations, feeding difficulties, vomiting, hypoglycaemia, arterial hypertension, hypotension, hyperreflexia, tremor, irritability, lethargy, persistent crying, and somnolence. These symptoms are sometimes associated with drug discontinuation. In most cases, they occur immediately or shortly (<24 hours) after delivery.

Studies have shown that the use of SSRIs (including paroxetine) in pregnant women, particularly during late pregnancy, is associated with an increased risk of persistent pulmonary hypertension in the newborn. In women who used serotonin reuptake inhibitors during late pregnancy, this risk was increased 4–5 times compared to the general population.

Lactation.

A small amount of paroxetine is excreted in breast milk. No adverse effects of the drug on newborns have been observed; however, paroxetine should not be used during breastfeeding except when the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery.

Clinical experience with paroxetine suggests that the drug does not affect cognitive function or psychomotor performance.

However, as with other psychoactive drugs, patients should be warned about the possible impairment of ability to drive or operate machinery during treatment. Paroxetine does not potentiate the impairments in mental and motor performance caused by alcohol; however, concomitant use of paroxetine and alcohol is not recommended.

Dosage and Administration.

General recommendations.

The medicinal product Trivonor should be administered orally. It is recommended to take it once daily in the morning, with food. The tablet should be swallowed whole, without chewing.

As with all other antidepressants, the dose should be carefully individualized during the first 2–3 weeks of treatment and then adjusted according to clinical response.

The treatment course should be sufficiently long to ensure symptom remission. This period may last several months when treating depression, and even longer in obsessive-compulsive disorder and panic disorder. As with other agents used to treat psychiatric disorders, abrupt discontinuation of the medicinal product should be avoided.

Major depressive disorder. The recommended dose is 20 mg once daily. For some patients, dose escalation may be required. This should be done gradually, increasing the dose by 10* mg (up to a maximum of 50* mg daily), depending on the clinical effectiveness of treatment.

Obsessive-compulsive disorder. The recommended dose is 40 mg once daily. Treatment should be initiated at a dose of 20 mg and the dosage should be gradually increased by 10* mg weekly. If necessary, the dose may be increased up to the maximum dose of 60 mg daily.

Panic disorder. The recommended dose is 40 mg once daily. Treatment should be initiated at a dose of 10* mg daily, with weekly increments of 10* mg, depending on clinical response. In some patients, improvement may only be observed with the maximum daily dose of 60 mg.

To reduce the risk of potential worsening of panic disorder symptoms, which is commonly observed at the beginning of treatment, it is recommended to initiate therapy with a low dose of the medicinal product.

Social anxiety disorder/social phobia. The recommended dose is 20 mg once daily. For some patients, the dose may be gradually increased by 10* mg daily—depending on clinical response—up to 50* mg daily. The interval between dose increases should be at least 1 week.

Generalized anxiety disorder. The recommended dose is 20 mg once daily.

For some patients with insufficient response to 20 mg, the dose may be gradually increased by 10* mg daily, depending on clinical response, up to 50* mg daily.

Post-traumatic stress disorder. The recommended dose is 20 mg once daily.

For some patients with insufficient response to 20 mg, the dose may be gradually increased by 10* mg daily, depending on clinical response, up to 50* mg daily.

Discontinuation of Trivonor.

As with other medicinal products used in the treatment of psychiatric disorders, abrupt discontinuation should be avoided. A gradual dose reduction regimen may be used, involving a decrease of 10* mg daily every week. After reaching the dosage regimen of 20 mg daily, patients should continue taking the medication at this dose for another week before complete discontinuation. If severe symptoms occur during dose reduction or after discontinuation, consideration should be given to resuming treatment at the previous dose. Subsequently, dose reduction may continue, but at a slower rate.

Elderly patients. Initiate treatment with the standard initial adult dose, which may then be gradually increased up to 40 mg daily. Increased plasma concentrations of paroxetine have been observed in elderly patients; however, the concentration range in this patient group overlaps with that observed in younger patients.

Children. Trivonor is not indicated for the treatment of children.

Renal and hepatic impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min) or hepatic impairment, increased plasma concentrations of paroxetine are observed. Therefore, the dose should be reduced to the lower end of the dosing range in such patients.

* Use medicinal products containing paroxetine at the corresponding dosage strength.

Children.

Trivonor is not indicated for the treatment of children. According to results from controlled clinical trials, efficacy has not been demonstrated, and supporting data on the use of paroxetine in children with depression are lacking.

Overdose.

Symptoms. In cases of paroxetine overdose, in addition to the adverse reactions listed in the section "Adverse Reactions," symptoms such as elevated body temperature, changes in blood pressure, involuntary muscle contractions, agitation, and tachycardia have been observed. These effects generally resolve without serious consequences in most patients, even after ingestion of 2000 mg. Occasionally, coma or changes in ECG parameters have been reported; fatal outcomes are very rare and usually occur when paroxetine is taken concomitantly with other psychotropic agents or alcohol.

There is no specific antidote.

Treatment. Management of overdose should include general supportive and symptomatic measures, similar to those applied in overdose with other antidepressants. Supportive therapy with monitoring of vital functions and close observation of the patient’s condition in a hospital setting is indicated.

Adverse Reactions

The adverse effects listed below are classified by organ systems and frequency of occurrence. Frequency is defined as: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), including isolated cases; frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:
Uncommon – increased bleeding tendency, mainly of the skin and mucous membranes (including ecchymoses and gynecological bleeding); leukopenia; very rare – thrombocytopenia.

Immune system disorders:
Very rare – severe and potentially life-threatening allergic reactions (including anaphylactoid reactions and angioedema).

Endocrine system disorders:
Very rare – syndrome due to inadequate secretion of antidiuretic hormone.

Metabolism and nutrition disorders:
Common – increased cholesterol levels, decreased appetite; uncommon – there have been reports of altered glycaemic control in diabetic patients (see section "Special precautions"); rare – hyponatraemia. Hyponatraemia occurs mainly in elderly patients and is sometimes associated with syndrome due to inadequate secretion of antidiuretic hormone.

Psychiatric disorders:
Common – somnolence, insomnia, agitation, abnormal dreams (including nightmares); uncommon – confusion, hallucinations; rare – manic reactions, restlessness, depersonalization, panic attacks, akathisia; frequency not known – suicidal ideation, suicidal behaviour and aggression. These symptoms may also be related to the underlying disease.

Nervous system disorders:
Common – dizziness, tremor, headache; uncommon – extrapyramidal disorders; rare – seizures, akathisia, restless legs syndrome; very rare – serotonin syndrome (may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, tachycardia and tremor). Extrapyramidal disorders, including orofacial dystonia, are observed in patients with movement disorders or in patients treated with neuroleptics.

Eye disorders:
Common – blurred vision; uncommon – mydriasis (see section "Special precautions"); very rare – acute glaucoma.

Ear and labyrinth disorders:
Frequency not known – tinnitus.

Cardiac disorders:
Uncommon – sinus tachycardia, postural hypotension, transient increase or decrease in blood pressure; rare – bradycardia.

Respiratory, thoracic and mediastinal disorders:
Common – yawning.

Gastrointestinal disorders:
Very common – nausea; common – constipation, diarrhoea, vomiting, dry mouth; very rare – gastrointestinal haemorrhage; frequency not known – microscopic colitis.

Hepatobiliary disorders:
Rare – increased levels of liver enzymes; very rare – hepatic disorders (such as hepatitis, sometimes with jaundice and/or hepatic failure). There have been reports of increased liver enzyme levels. Very rare cases of hepatic adverse reactions (such as hepatitis, sometimes associated with jaundice and/or hepatic failure) have also been reported. Discontinuation of paroxetine should be considered if elevated liver function tests persist.

Skin and subcutaneous tissue disorders:
Common – increased sweating; uncommon – skin rash, pruritus; very rare – severe skin reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), urticaria, photosensitivity reactions.

Renal and urinary disorders:
Uncommon – urinary retention, urinary incontinence.

Reproductive system and breast disorders:
Very common – sexual dysfunction; rare – hyperprolactinaemia/galactorrhoea, menstrual disorders (including menorrhagia, metrorrhagia, amenorrhoea, delayed and irregular menstruation); very rare – priapism.

Musculoskeletal and connective tissue disorders:
Rare – arthralgia, myalgia. Epidemiological studies, conducted mainly in patients aged 50 years and older, suggest an increased risk of bone fractures in patients treated with SSRIs and tricyclic antidepressants. The mechanism leading to this risk is unknown.

General disorders:
Common – asthenia, weight gain; very rare – peripheral oedema.

Symptoms associated with drug discontinuation:
Common – dizziness, sensory disturbances, sleep disturbances, anxiety, headache; uncommon – agitation, nausea, tremor, confusion, increased sweating, diarrhoea, emotional lability, visual disturbances, palpitations, restlessness. As with other drugs used to treat psychiatric disorders, discontinuation of Trevonor (especially abrupt discontinuation) may lead to the emergence of symptoms such as dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, headache, tremor, confusion, diarrhoea, increased sweating, palpitations, restlessness, emotional lability, visual disturbances. In most patients, these symptoms are mild to moderate in severity and resolve without treatment. There is no specific risk group for the occurrence of these symptoms; therefore, if discontinuation of paroxetine treatment is required, the dose should be gradually reduced (see sections "Special precautions" and "Dosage and administration").

Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life.
3 years.

Storage conditions.
No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging.
14 film-coated tablets in a blister; 2 blisters in a cardboard pack.

Prescription status.
Prescription only.

Manufacturer.
Sintex España, S.L.

Manufacturer's address and place of business.
C/Castello, no 1, Sant Boi de Llobregat, Barcelona, 08830, Spain

Date of last review.