- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
MAJOR DEPRESSIVE EPISODEThe recommended dose is 20 mg daily. In general, improvement in patients starts after one week but may only become evident from the second week of therapy.As with all antidepressant medicinal products, dosage should be reviewed and adjusted if necessary within 3 to 4 weeks of initiation of therapy and thereafter as judged clinically appropriate. In some patients, with insufficient response to 20 mg, the dose may be increased gradually up to a maximum of 50 mg a day in 10 mg steps according to the patient's response.Patients with depression should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.
OBSESSIVE COMPULSIVE DISORDERThe recommended dose is 40 mg daily. Patients should start on 20 mg/day and the dose may be increased gradually in 10 mg increments to the recommended dose. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 60 mg/day.Patients with OCD should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer (see section 5.1 Pharmacodynamic properties).
PANIC DISORDERThe recommended dose is 40 mg daily. Patients should be started on 10 mg/day and the dose gradually increased in 10 mg steps according to the patient's response up to the recommended dose. A low initial starting dose is recommended to minimise the potential worsening of panic symptomatology, which is generally recognised to occur early in the treatment of this disorder. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually up to a maximum of 60 mg/day.Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer (see section 5.1 Pharmacodynamic properties).
SOCIAL ANXIETY DISORDER/SOCIAL PHOBIAThe recommended dose is 20 mg daily. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day. Long-term use should be regularly evaluated (see section 5.1 Pharmacodynamic properties).GENERALISED ANXIETY DISORDERThe recommended dose is 20 mg daily. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day. Long-term use should be regularly evaluated (see section 5.1 Pharmacodynamic properties).
POST-TRAUMATIC STRESS DISORDERThe recommended dose is 20 mg daily. If after some weeks on the recommended dose insufficient response is seen some patients may benefit from having their dose increased gradually in 10 mg steps up to a maximum of 50 mg/day. Long-term use should be regularly evaluated (see section 5.1 Pharmacodynamic properties). GENERAL INFORMATION
WITHDRAWAL SYMPTOMS SEEN ON DISCONTINUATION OF PAROXETINEAbrupt discontinuation should be avoided (see section 4.4 Special warnings and precautions for use and section 4.8 Undesirable effects). The taper phase regimen used in clinical trials involved decreasing the daily dose by 10 mg at weekly intervals. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate.
Special Populations:• Older peopleIncreased plasma concentrations of paroxetine occur in elderly subjects, but the range of concentrations overlaps with that observed in younger subjects. Dosing should commence at the adult starting dose. Increasing the dose might be useful in some patients, but the maximum dose should not exceed 40 mg daily. • Children and adolescents (7-17 years)Paroxetine should not be used for the treatment of children and adolescents as controlled clinical trials have found paroxetine to be associated with increased risk for suicidal behaviour and hostility. In addition, in these trials efficacy has not been adequately demonstrated (see section 4.4 Special warnings and precautions for use and section 4.8 Undesirable effects).• Children aged below 7 yearsThe use of paroxetine has not been studied in children less than 7 years. Paroxetine should not be used, as long as safety and efficacy in this age group have not been established.• Renal/hepatic impairmentIncreased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or in those with hepatic impairment. Therefore, dosage should be restricted to the lower end of the dosage range.
Method of administrationIt is recommended that paroxetine is administered once daily in the morning with food. The tablet should be swallowed rather than chewed. Shake bottle before use.
Paediatric populationParoxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
Suicide/suicidal thoughts or clinical worseningDepression 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 few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.Other psychiatric conditions for which paroxetine is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed 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 exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old (see also section 5.1).Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Akathisia/psychomotor restlessnessThe use of paroxetine has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Serotonin Syndrome/Neuroleptic Malignant SyndromeOn rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with treatment of paroxetine, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with paroxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Paroxetine should not be used in combination with serotonin-precursors (such as L-tryptophan, oxitriptan) due to the risk of serotonergic syndrome. (See Sections 4.3 Contraindications and 4.5 Interactions with other medicinal products and other forms of interaction).
ManiaAs with all antidepressants, paroxetine should be used with caution in patients with a history of mania. Paroxetine should be discontinued in any patient entering a manic phase.
Renal/hepatic impairmentCaution is recommended in patients with severe renal impairment or in those with hepatic impairment (see section 4.2 Posology and method of administration).
DiabetesIn patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted. Additionally, there have been studies suggesting that an increase in blood glucose levels may occur when paroxetine and pravastatin are co-administered (see section 4.5).
EpilepsyAs with other antidepressants, paroxetine should be used with caution in patients with epilepsy.
SeizuresOverall the incidence of seizures is less than 0.1% in patients treated with paroxetine. The drug should be discontinued in any patient who develops seizures.
Electroconvulsive therapy (ECT)There is little clinical experience of the concurrent administration of paroxetine with ECT.
GlaucomaAs with other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma or history of glaucoma.
Cardiac ConditionsThe usual precautions should be observed in patients with cardiac conditions.
HyponatraemiaHyponatraemia has been reported rarely, predominantly in the elderly. Caution should also be exercised in those patients at risk of hyponatraemia e.g. from concomitant medications and cirrhosis. The hyponatraemia generally reverses on discontinuation of paroxetine.
HaemorrhageThere have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Other haemorrhagic manifestations e.g. gastrointestinal and gynaecological haemorrhage have been reported. Elderly patients may be at an increased risk for non-menses related events of bleeding. Caution is advised in patients taking SSRIs concomitantly with oral anticoagulants, drugs known to affect platelet function or other drugs that may increase risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCAs, acetylsalicylic acid, NSAIDs, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions which may predispose to bleeding (see section 4.8). Interaction with tamoxifen Paroxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of endoxifen, one of the most important active metabolites of tamoxifen. Therefore, paroxetine should whenever possible be avoided during tamoxifen treatment (see section 4.5).
Drugs affecting gastric pHIn patients receiving oral suspension, the paroxetine plasma concentration may be influenced by gastric pH. In vitro data have shown that an acidic environment is required for release of the active drug from the suspension, hence absorption may be reduced in patients with a high gastric pH or achlorhydria, such as after the use of certain drugs (antacid drugs, histamine H2-receptor antagonists, proton pump inhibitors), in certain disease states (e.g. atrophic gastritis, pernicious anemia, chronic Helicobacter pylori infection), and after surgery (vagotomy, gastrectomy). The pH dependency should be taken into account when changing paroxetine formulation (e.g. the plasma paroxetine concentration may decrease after changing from tablet to oral suspension in patients with a high gastric pH). Caution is therefore recommended in patients when initiating or ending treatment with drugs increasing gastric pH. Dose adjustments may be necessary in such situations.
Withdrawal symptoms seen on discontinuation of paroxetine treatmentWithdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects). In clinical trials adverse events seen on treatment discontinuation occurred in 30% of patients treated with paroxetine compared to 20% of patients treated with placebo. The occurrence of withdrawal symptoms is not the same as the drug being addictive or dependence producing.The risk of withdrawal symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances have been reported. Generally these symptoms are mild to moderate; however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within two weeks, though in some individuals they may be prolonged (two-three months or more). It is therefore advised that paroxetine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see "Withdrawal Symptoms Seen on Discontinuation of Paroxetine", Section 4.2 Posology and method of administration).
Warnings for excipients
ParabensParoxetine oral suspension contains methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) (parabens), which are known to cause urticaria, generally delayed-type reactions, such as contact dermatitis, but rarely immediate reaction with bronchospasm.
Sunset Yellow Colouring AgentParoxetine oral suspension contains the colouring agent sunset yellow FCF (E110), which may cause allergic reactions.
Sorbitol E420Paroxetine oral suspension contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.
Serotonergic drugsAs with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of 5-HT associated effects (serotonin syndrome: see Section 4.4 Special warnings and precautions for use). Caution should be advised and a closer clinical monitoring is required when serotonergic drugs (such as L-tryptophan, triptans, tramadol, linezolid, methylthioninium chloride (methylene blue)), SSRIs, lithium, pethidine and St. John's Wort Hypericum perforatum preparations) are combined with paroxetine. Caution is also advised with fentanyl used in general anaesthesia or in the treatment of chronic pain. Concomitant use of paroxetine and MAOIs is contraindicated because of the risk of serotonin syndrome (see Section 4.3 Contraindications).
PimozideIncreased pimozide levels of on average 2.5 times have been demonstrated in a study of a single low dose pimozide (2 mg) when co-administered with 60 mg paroxetine. This may be explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use of pimozide and paroxetine is contraindicated (see Section 4.3 Contraindications).Drug metabolising enzymes The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolising enzymes. When paroxetine is to be co-administered with a known drug metabolising enzyme inhibitor, consideration should be given to using paroxetine doses at the lower end of the range.No initial dosage adjustment is considered necessary when the drug is to be co-administered with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbital, phenytoin) or with fosamprenavir/ritonavir. Any paroxetine dosage adjustment (either after initiation or following discontinuation of an enzyme inducer) should be guided by clinical effect (tolerability and efficacy).Neuromuscular BlockersSSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium and suxamethonium.Fosamprenavir/ritonavir: Co-administration of fosamprenavir/ritonavir 700/100 mg twice daily with paroxetine 20 mg daily in healthy volunteers for 10 days significantly decreased plasma levels of paroxetine by approximately 55%. The plasma levels of fosamprenavir/ritonavir during co-administration of paroxetine were similar to reference values of other studies, indicating that paroxetine had no significant effect on metabolism of fosamprenavir/ritonavir. There are no data available about the effects of long-term co-administration of paroxetine and fosamprenavir/ritonavir exceeding 10 days. Procyclidine: Daily administration of paroxetine increases significantly the plasma levels of procyclidine. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced.Anticonvulsants: carbamazepine, phenytoin, sodium valproate. Concomitant administration does not seem to show any effect on pharmacokinetic/dynamic profile in epileptic patients.
CYP2D6 inhibitory potency of paroxetineAs with 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. These include certain tricyclic antidepressants (e.g. clomipramine, nortriptyline, and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see section 4.3 Contraindications), risperidone, atomoxetine, certain Type 1c antiarrhythmics (e.g. propafenone and flecainide) and metoprolol. It is not recommended to use paroxetine in combination with metoprolol when given in cardiac insufficiency, because of the narrow therapeutic index of metoprolol in this indication.Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen, showing a 65-75% reduction in plasma levels of one of the more active forms of tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of tamoxifen has been reported with concomitant usage of some SSRI antidepressants in some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration with potent CYP2D6 inhibitors (including paroxetine) should whenever possible be avoided (see section 4.4).
AlcoholAs with other psychotropic drugs patients should be advised to avoid alcohol use while taking paroxetine.
Oral anticoagulantsA pharmacodynamic interaction between paroxetine and oral anticoagulants may occur. Concomitant use of paroxetine and oral anticoagulants can lead to an increased anticoagulant activity and haemorrhagic risk. Therefore, paroxetine should be used with caution in patients who are treated with oral anticoagulants (see section 4.4 Special warnings and precautions for use).
NSAIDs and acetylsalicylic acid, and other antiplatelet agentsA pharmacodynamic interaction between paroxetine and NSAIDs/acetylsalicylic acid may occur. Concomitant use of paroxetine and NSAIDs/acetylsalicylic acid can lead to an increased haemorrhagic risk (see section 4.4 Special warnings and precautions for use). Caution is advised in patients taking SSRIs, concomitantly with oral anticoagulants, drugs known to affect platelet function or increase risk of bleeding (e.g. atypical antipsychotics such as clozapine, phenothiazines, most TCAs, acetylsalicylic acid, NSAIDs, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions that may predispose to bleeding. Pravastatin An interaction between paroxetine and pravastatin has been observed in studies suggesting that co-administration of paroxetine and pravastatin may lead to an increase in blood glucose levels. Patients with diabetes mellitus receiving both paroxetine and pravastatin may require dosage adjustment of oral hypoglycaemic agents and/or insulin (see section 4.4).
Drugs affecting gastric pHIn vitro data have shown that dissociation of paroxetine from the oral suspension is pH-dependant. Therefore, drugs that alter gastric pH (such as antacid drugs, proton pump inhibitors or histamine H2-receptor antagonists) may affect plasma paroxetine concentrations in patients taking the oral suspension (see section 4.4).
PregnancySome epidemiological studies suggest an increased risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septum defects), associated with the use of paroxetine during the first trimester. The mechanism is unknown. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is less than 2/100 compared with an expected rate for such defects of approximately 1/100 in the general population. Paroxetine should only be used during pregnancy when strictly indicated. The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant. Abrupt discontinuation should be avoided during pregnancy (see "Withdrawal Symptoms Seen on Discontinuation of Paroxetine", section 4.2 Posology and method of administration).Neonates should be observed if maternal use of paroxetine continues into the later stages of pregnancy, particularly the third trimester. The following symptoms may occur in the neonate after maternal paroxetine use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty in sleeping. These symptoms could be due to either serotonergic effects or withdrawal symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.Epidemiological data have suggested that the use of SSRIs in pregnancy, particularly in late pregnancy, may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The observed risk was approximately five cases per 1000 pregnancies. In the general population one to two cases of PPHN per 1000 pregnancies occur.Animal studies showed reproductive toxicity, but did not indicate direct harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see Section 5.3 Preclinical Safety Data). Breast-feedingSmall amounts of paroxetine are excreted into breast milk. In published studies, serum concentrations in breast-fed infants were undetectable (<2 nanograms/ml) or very low (<4 nanograms/ml), and no signs of drug effects were observed in these infants. Since no effects are anticipated, breast-feeding can be considered.
FertilityAnimal data have shown that paroxetine may affect sperm quality (see section 5.3). In vitro data with human material may suggest some effect on sperm quality; however, human case reports with some SSRIs (including paroxetine) have shown that an effect on sperm quality appears to be reversible.Impact on human fertility has not been observed so far.
Blood and lymphatic system disordersUncommon: abnormal bleeding, predominantly of the skin and mucous membranes ( including ecchymosis and gynaecological bleeding). Very rare: thrombocytopenia.
Immune system disordersVery rare: severe and potentially fatal allergic reactions (including anaphylactoid reactions and angioedema).
Endocrine disordersVery rare: syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Metabolism and nutrition disordersCommon: increases in cholesterol levels, decreased appetite.Uncommon: altered glycaemic control has been reported in diabetic patients (see section 4.4). Rare: hyponatraemia.Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Psychiatric disordersCommon: somnolence, insomnia, agitation, abnormal dreams (including nightmares). Uncommon: confusion, hallucinations. Rare: manic reactions, anxiety, depersonalisation, panic attacks, akathisia (see section 4.4). Frequency not known: suicidal ideation, suicidal behaviour and aggression. Cases of suicidal ideation and suicidal behaviour have been reported during paroxetine therapy or early after treatment discontinuation (see section 4.4). Cases of aggression were observed in post marketing experience. These symptoms may also be due to the underlying disease
Nervous system disordersCommon: dizziness, tremor, headache, concentration impaired. Uncommon: extrapyramidal disorders. Rare: convulsions, restless legs syndrome (RLS). Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering, tachycardia and tremor).Reports of extrapyramidal disorder including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication.
Eye disordersCommon: blurred vision. Uncommon: mydriasis (see section 4.4 Special warnings and precautions for use). Very rare: acute glaucoma.
Ear and labyrinth disordersFrequency not known: tinnitus.
Cardiac disordersUncommon: sinus tachycardia. Rare: bradycardia.
Vascular disordersUncommon: transient increases or decreases in blood pressure, postural hypotension.Transient increases or decreases of blood pressure have been reported following treatment with paroxetine, usually in patients with pre-existing hypertension or anxiety.
Respiratory, thoracic and mediastinal disordersCommon: yawning.
Gastrointestinal disordersVery common: nausea. Common: constipation, diarrhoea, vomiting, dry mouth. Very rare: gastrointestinal bleeding.
Hepato-biliary disordersRare: elevation of hepatic enzymes. Very rare: hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure).Elevation of hepatic enzymes have been reported. Post-marketing reports of hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure) have also been received very rarely. Discontinuation of paroxetine should be considered if there is prolonged elevation of liver function test results.
Skin and subcutaneous tissue disordersCommon: sweating. Uncommon: skin rashes, pruritus Very rare: severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), urticaria, photosensitivity reactions.
Renal and urinary disordersUncommon: urinary retention, urinary incontinence.
Reproductive system and breast disordersVery common: sexual dysfunction. Rare: hyperprolactinaemia/galactorrhoea, menstrual disorders (including menorrhagia, metrorrhagia, amenorrhoea, menstruation delayed and menstruation irregular). Very rare: priapism.
Musculoskeletal and connective tissue disordersRare: arthralgia, myalgiaEpidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to this risk is unknown.
General disorder and administration site conditionsCommon: asthenia, body weight gain Very rare: peripheral oedema.
WITHDRAWAL SYMPTOMS SEEN ON DISCONTINUATION OF PAROXETINE TREATMENTCommon: dizziness, sensory disturbances, sleep disturbances, anxiety, headache. Uncommon: agitation, nausea, tremor, confusion, sweating, emotional instability, visual disturbances, palpitations, diarrhoea, irritability.Discontinuation of paroxetine (particularly when abrupt) commonly leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances have been reported. Generally these events are mild to moderate and are self-limiting; however, in some patients they may be severe and/or prolonged. It is therefore advised that when paroxetine treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 Posology and method of administration and section 4.4 Special warnings and precautions for use).ADVERSE EVENTS FROM PAEDIATRIC CLINICAL TRIALSThe following adverse events were observed:Increased suicidal related behaviours (including suicide attempts and suicidal thoughts), self-harm behaviours and increased hostility. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder. Increased hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age. Additional events that were seen are: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations), bleeding related adverse events, predominantly of the skin and mucous membranes.Events seen after discontinuation/tapering of paroxetine are: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain (see section 4.4 Special warnings and precautions for use).See section 5.1 for more information on paediatric clinical trials.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Symptoms and SignsA wide margin of safety is evident from available overdose information on paroxetine.Experience of paroxetine in overdose has indicated that, in addition to those symptoms mentioned under section 4.8 "Undesirable effects", fever and involuntary muscle contractions have been reported. Patients have generally recovered without serious sequelae even when doses of up to 2000 mg have been taken alone. Events such as coma or ECG changes have occasionally been reported and, very rarely with a fatal outcome, but generally when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol.
TreatmentNo specific antidote is known.The treatment should consist of those general measures employed in the management of overdose with any antidepressant. Administration of 20-30 g activated charcoal may be considered if possible within a few hours after overdose intake to decrease absorption of paroxetine. Supportive care with frequent monitoring of vital signs and careful observation is indicated. Patient management should be as clinically indicated.
Adult suicidality analysisA paroxetine-specific analysis of placebo controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behaviour in young adults (aged 18-24 years) treated with paroxetine compared with placebo (2.19% vs 0.92%). In the older age groups, no such increase was observed. In adults with major depressive disorder (all ages), there was an increase in the frequency of suicidal behaviour in patients treated with paroxetine compared with placebo (0.32% vs 0.05%); all of the events were suicide attempts. However, the majority of these attempts for paroxetine (8 of 11) were in younger adults (see also section 4.4).
Dose responseIn the fixed dose studies there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, there are some clinical data suggesting that up-titrating the dose might be beneficial for some patients.
Long-term efficacyThe long-term efficacy of paroxetine in depression has been demonstrated in a 52-week maintenance study with relapse prevention design: 12% of patients receiving paroxetine (20-40mg daily) relapsed, versus 28% of patients on placebo. The long-term efficacy of paroxetine in treating obsessive compulsive disorder has been examined in three 24-week maintenance studies with relapse prevention design. One of the three studies achieved a significant difference in the proportion of relapsers between paroxetine (38%) compared to placebo (59%). The long-term efficacy of paroxetine in treating panic disorder has been demonstrated in a 24-week maintenance study with relapse prevention design: 5% of patients receiving paroxetine (10-40mg daily) relapsed, versus 30% of patients on placebo. This was supported by a 36-week maintenance study. The long-term efficacy of paroxetine in treating social anxiety disorder and generalised anxiety disorder and Post-Traumatic Stress Disorder has not been sufficiently demonstrated. Adverse Events from Paediatric Clinical TrialsIn short-term (up to 10-12 weeks) clinical trials in children and adolescents, the following adverse events were observed in paroxetine-treated patients at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo: increased suicidal related behaviours (including suicide attempts and suicidal thoughts), self-harm behaviours and increased hostility. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder. Increased hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age. Additional events that were more often seen in the paroxetine compared to placebo group were: decreased appetite, tremor, sweating, hyperkinesia, agitation, emotional lability (including crying and mood fluctuations).In studies that used a tapering regimen, symptoms reported during the taper phase or upon discontinuation of paroxetine at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were: emotional lability (including crying, mood fluctuations, self-harm, suicidal thoughts and attempted suicide), nervousness, dizziness, nausea and abdominal pain (see section 4.4 Special warnings and precautions for use).In five-parallel group studies with a duration of eight weeks up to eight months of treatment, bleeding related adverse events, predominantly of the skin and mucous membranes, were observed in paroxetine-treated patients at a frequency of 1.74% compared to 0.74% observed in placebo-treated patients.
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