Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use
Treatment with paroxetine should be initiated cautiously two weeks after terminating treatment with an irreversible MAOI or 24 hours after terminating treatment with a reversible MAO inhibitor. Dosage of paroxetine should be increased gradually until an optimal response is reached (see sections 4.3 and 4.5).

3/15
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 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 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 restlessness
The 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 Syndrome
On 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 and 4.5).

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

Diabetes
In 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).


4/15
Epilepsy
As with other antidepressants, paroxetine 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 or history of glaucoma.

Cardiac Conditions
The usual precautions should be observed in patients with cardiac conditions.

QT Prolongation
Cases of QT interval prolongation have been reported during the post-marketing period.
Paroxetine should be used with caution in patients with a (family) history of QT interval prolongation, concomitant use of anti-arrhythmic medications or other medications that may potentially prolong QT interval, relevant pre-existing cardiac disease such as heart failure, ischaemic heart disease, heart block or ventricular arrhythmias, bradycardia, and hypokalaemia or hypomagnesemia (see section 4.3 and 4.5).


Hyponatraemia
Hyponatraemia 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.

Haemorrhage
There 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 
SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6 and 4.8).

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).

Withdrawal symptoms seen on discontinuation of paroxetine treatment

Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8). 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 
5/15
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 section 4.2).

Sexual dysfunction
Selective serotonin reuptake inhibitors (SSRIs) may cause symptoms of sexual dysfunction (see section 4.8). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs.

Sodium
Each paroxetine tablet contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’.

Effects on Driving

4.7 Effects on ability to drive and use machines

Clinical experience has shown that therapy with paroxetine 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 paroxetine and alcohol is not advised.