Well, it had to happen… Glaxo have updated the prescribing information for Seroxat.
We will have to wait to see if the PIL changes at all (and when) – but surely it must change to reflect this major revision to the prescribing information (but it’s still too little too late).
One question for Glaxo – why are tablets not available in 5mg and 2.5mg strengths – to take this simple step would help all the patients who suffer from withdrawal symptoms when trying to stop taking the drug.
Two sections of the revised document are of particular interest – Special warnings and precautions for use and Undesirable effects – read them carefully:
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 section 4.3 Contraindications and section 4.5 Interactions with other medicinal products and other forms of interaction).
Use in Children and adolescents under 18 years of age.
Paroxetine should not be used in the treatment of children and adolescents under the age of 18 years. Suicide related behaviours (suicide attempts 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 needs, 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 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 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.
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.
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.
Caution is recommended in patients with severe renal impairment or in those with hepatic impairment. (see section 4.2 Posology and method of administration)
In patients with diabetes, treatment with an SSRI may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted.
As with other antidepressants, paroxetine should be used with caution in patients with epilepsy.
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.
There is little clinical experience of the concurrent administration of paroxetine with ECT.
As with other SSRI’s, paroxetine infrequently causes mydriasis and should be used with caution in patients with narrow angle glaucoma or history of glaucoma.
The usual precautions should be observed in patients with cardiac conditions.
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.
There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura with SSRIs. Other haemorrhagic manifestations e.g. gastrointestinal haemorrhage have been reported. Elderly patients may be at an increased risk.
Caution is advised in patients taking SSRI’s 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 TCA’s, acetylsalicylic acid, NSAID’s, COX-2 inhibitors) as well as in patients with a history of bleeding disorders or conditions which may predispose to bleeding.
Drugs affecting gastric pH
In 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 treatment
Withdrawal 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 2 weeks, though in some individuals they may be prolonged (2-3 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).
4.8 Undesirable effects
Some of the adverse drug reactions listed below may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.Adverse drug reactions are listed below by system organ class and frequency. Frequencies are 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 reports.
Blood and lymphatic system disorders
Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes (mostly ecchymosis).
Very rare: thrombocytopenia.
Immune system disorders
Very rare: allergic reactions (including urticaria and angioedema).
Very rare: syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Metabolism & nutrition disorders
Common: increases in cholesterol levels, decreased appetite
Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to syndrome of inappropriate anti-diuretic hormone secretion (SIADH).
Common: somnolence, insomnia, agitation.
Uncommon: confusion, hallucinations
Rare: manic reactions, anxiety, depersonalisation, panic attacks, akathisia (see section 4.4 Special Warnings and Special Precautions for use).
These symptoms may also be due to the underlying disease.
Nervous system disorders
Common: dizziness, tremor.
Uncommon: extrapyramidal disorders.
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.
Common: blurred vision.
Very rare: acute glaucoma.
Ear and labyrinth disorders
Frequency not known: tinnitus.
Uncommon: sinus tachycardia.
Uncommon: transient increases or decreases in blood pressure.
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 disorders
Very common: nausea.
Common: constipation, diarrhoea, dry mouth.
Very rare: gastrointestinal bleeding.
Rare: 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 & subcutaneous tissue disorders
Uncommon: skin rashes, pruritus.
Very rare: photosensitivity reactions.
Renal & urinary disorders
Uncommon: urinary retention, urinary incontinence.
Reproductive system & breast disorders
Very common: sexual dysfunction
Very rare: priapism.
Rare: arthralgia, myalgia.
General disorders and administration site conditions
Common: asthenia, body weight gain.
Very rare: peripheral oedema.
WITHDRAWAL SYMPTOMS SEEN ON DISCONTINUATION OF PAROXETINE TREATMENT
Common: 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 sections 4.2 Posology and Method of Administration and, 4.4 Special warnings and Special precautions for use).
Adverse events from paediatric clinical trials
In 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 were: 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 special precautions for use)