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Clinical worsening and suicide risk in adults: Young adults, especially those with MDD, may be at increased risk for suicidal behaviour during treatment with SEROXAT CR. An analysis of placebo-controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behaviour in young adults (prospectively defined as aged 18 to 24 years) treated with paroxetine compared with placebo (17/776 [2.19%] versus 5/542 [0.92%]), although this difference was not statistically significant. In the older age groups (aged 25 to 64 years and ≥65 years), no such increase was observed. In adults with MDD (all ages), there was a statistically significant increase in the frequency of suicidal behaviour in patients treated with paroxetine compared with placebo (11/3455 [0.32%] versus 1/1978 [0.05%]; all of the events were suicide attempts). However, the majority of these attempts for paroxetine (8 of 11) were in younger adults aged 18 to 30 years. These MDD data suggest that the higher frequency observed in the younger adult population across psychiatric disorders may extend beyond the age of 24.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. This risk persists until significant remission occurs. It is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which SEROXAT is prescribed can be associated with an increased risk of suicidal behaviour, and these conditions may also be co-morbid with MDD. Additionally, patients with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at a greater risk of suicidal thoughts or suicide attempts. All patients should be monitored for clinical worsening (including development of new symptoms) and suicidality throughout treatment, and especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. It should be recognised that the onset of some symptoms, such as agitation, akathisia or mania, could be related either to the underlying disease state or the drug therapy (see Akathisia and Mania and Bipolar Disorder as follows; Adverse Reactions).
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Akathisia: Rarely, the use of SEROXAT or other SSRIs has been associated with the development of akathisia, which is characterised 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.
Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with SEROXAT treatment, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with SEROXAT 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. SEROXAT should not be used in combination with serotonin-precursors (such as L-tryptophan, oxitriptan) due to the risk of serotonergic syndrome (see Contraindications and Interactions).
Mania and Bipolar disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that paroxetine is not approved for use in treating bipolar depression. As with all antidepressants, paroxetine should be used with caution in patients with a history of mania.
Tamoxifen: Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with SEROXAT CR as a result of paroxetine's irreversible inhibition of CYP2D6 (see Interactions). This risk may increase with longer duration of co-administration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
Bone fracture: Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association with fractures. The risk occurs during treatment and is greatest in the early stages of therapy. The possibility of fracture should be considered in the care of patients treated with SEROXAT CR.
Monoamine Oxidase Inhibitors: Treatment with SEROXAT CR should be initiated cautiously at least two weeks after terminating treatment with MAO inhibitors and dosage of SEROXAT CR should be increased gradually until optimal response is reached (see Contraindications, Interactions).
Epilepsy: As with other antidepressants, SEROXAT CR should be used with caution in patients with epilepsy.
Seizures: Overall 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.
Glaucoma: As with other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma.
Hyponatraemia: Hyponatraemia has been reported rarely, predominantly in the elderly. The hyponatraemia generally reverses on discontinuation of paroxetine.
Haemorrhage: Skin and mucous membrane bleedings (including gastrointestinal and gynaecological bleeding) have been reported following treatment with paroxetine. Paroxetine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding, and in patients with a known tendency for bleeding or those with predisposing conditions (see Adverse Reactions). SSRIs may increase the risk of postpartum haemorrhage (see Use in Pregnancy & Lactation).
Cardiac Conditions: The usual precautions should be observed in patients with cardiac conditions.
Symptoms seen on discontinuation of SEROXAT treatment in adults: In clinical trials in adults, adverse events seen on treatment discontinuation occurred in 30% of patients treated with SEROXAT compared to 20% of patients treated with placebo. The occurrence of discontinuation symptoms is not the same as the drug being addictive or dependence producing as with a substance of abuse.
Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea 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 to three months or more). It is therefore advised that SEROXAT should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see "Discontinuation of SEROXAT" under Dosage & Administration).
Sexual dysfunction: SSRIs may cause symptoms of sexual dysfunction. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.
Symptoms seen on discontinuation of SEROXAT treatment in children and adolescents: In clinical trials in children and adolescents, adverse events seen on treatment discontinuation occurred in 32% of patients treated with SEROXAT compared to 24% of patients treated with placebo. Events reported upon discontinuation of SEROXAT at a frequency of at least 2% of patients and which occurred at a rate at least twice that of placebo were: emotional lability (including suicidal ideation, suicide attempt, mood changes and tearfulness), nervousness, dizziness, nausea and abdominal pain (see Adverse Reactions).
SEROXAT CR 12.5 mg tablets only: The paroxetine 12.5 mg controlled release tablet coating (Opadry Yellow: YS-1-2007) contains the colouring agent Sunset Yellow Lake (FD&C Yellow No. 6 aluminium lake), an azo dye which may cause allergic-type reactions.
Effects on Ability to Drive and Use Machines: Clinical experience has shown that therapy with SEROXAT is not associated with impairment of cognitive or psychomotor function. However, as with all psychoactive drugs, patients should be cautioned about their ability to drive a car and operate machinery.
Although paroxetine does not increase the mental and motor skill impairments caused by alcohol, the concomitant use of SEROXAT CR and alcohol is not advised.
Renal/hepatic impairment: Caution is recommended in patients with severe renal impairment or in those with hepatic impairment (see Dosage & Administration).
Children and Adolescents (less than 18 years): Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. In clinical trials of SEROXAT in children and adolescents, adverse events related to suicidality (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in patients treated with SEROXAT compared to those treated with placebo (see Adverse Reactions). Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
