Source: Health Products Regulatory Authority (ZA) Revision Year: 2021 Publisher: GlaxoSmithKline South Africa (Pty) Ltd, 39 Hawkins Avenue, Epping Industria 1, 7460
Known hypersensitivity to paroxetine or any excipients of AROPAX CR.
Concomitant use with serotonin precursors (see sections 4.4 and 4.5).
Children under the age of 18 years (see section 4.4).
AROPAX CR tablets should not be used in combination with monoamine oxidase (MAO) inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor and methylthioninium chloride (methylene blue)), or within 2 weeks of terminating treatment with MAO inhibitors. Likewise, MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with AROPAX CR tablets (see section 4.5).
AROPAX CR tablets should not be used in combination with thioridazine, as paroxetine can elevate plasma levels of thioridazine (see section 4.5), leading to the prolongation of the QTc interval on the ECG. Administration of thioridazine alone can lead to QTc interval prolongation with associated serious ventricular dysrhythmia such as torsades de pointes and sudden death.
AROPAX CR should not be used in combination with pimozide (see section 4.5).
AROPAX CR should not be used in pregnancy (see section 4.6).
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 AROPAX 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 AROPAX compared to those treated with placebo (see section 4.8). Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
Young adults, especially those with MDD, may be at increased risk for suicidal behaviour during treatment with AROPAX 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 18-24 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 25-64 years and ≥ 65 years), no such increase was observed. However the higher frequency observed in the younger adult population across psychiatric disorders may extend beyond the age of 24. Patients with major depressive disorder 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 improvement 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 AROPAX CR is prescribed can also 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, and should receive careful monitoring during treatment. 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 to therapy (see Akathisia and Mania and Bipolar Disorder below; section 4.8).
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing AROPAX CR, 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.
The use of AROPAX CR 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.
Development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with AROPAX CR treatment, particularly when given in combination with other serotonergic and/or neuroleptic medicines. As these syndromes may result in potentially life-threatening conditions, treatment with AROPAX CR 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. AROPAX CR 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).
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 AROPAX CR is not approved for use in treating bipolar depression.
AROPAX CR should be used with caution in patients with a history of mania.
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 AROPAX CR as a result of paroxetine’s irreversible inhibition of CYP2D6 (see section 4.5). This risk may increase with longer duration of co-administration. When tamoxifen is used for the treatment or prevention of breast cancer, practitioners should consider using an alternative antidepressant with little or no CYP2D6 inhibition.
Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs such as AROPAX CR, have reported an association with fractures.
Caution is recommended in patients with severe renal impairment or in those with hepatic impairment (see section 4.2).
In clinical trials in adults, 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 discontinuation symptoms is not the same as the medicine 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 selflimiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2- 3 months or more). It is therefore advised that AROPAX CR should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient’s needs (see ‘Discontinuation of AROPAX CR’, section 4.2).
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.
In clinical trials in children and adolescents, adverse events seen on treatment discontinuation occurred in 32% of patients treated with paroxetine compared to 24% of patients treated with placebo. Events reported upon discontinuation of paroxetine at a frequency of at least 2% of patients and which occurred at a rate at least twice that of placebo were: emotional liability (including suicidal ideation, suicide attempt, mood changes and tearfulness), nervousness, dizziness, nausea and abdominal pain (see section 4.8).
Skin and mucous membrane bleedings (including gastrointestinal and gynaecological bleeding) have been reported during treatment with paroxetine alone. AROPAX CR should therefore be used with caution in patients concomitantly treated with medicines that give an increased risk for bleeding and in patients with a known tendency for bleeding or those with predisposing conditions (see section 4.5).
Co-administration with risperidone may lead to increased toxicity thereof (see section 4.5).
The usual precautions should be observed in patients with cardiac conditions.
AROPAX CR should be used with caution in patients with epilepsy.
Overall the incidence of seizures is less than 0,1% in patients treated with paroxetine.
AROPAX CR should be discontinued in any patient who develops seizures.
There is little clinical experience of the concurrent administration of AROPAX CR with ECT.
AROPAX CR can cause mydriasis and should be used with caution in patients with narrow angle glaucoma.
Hyponatraemia has been reported, predominantly in the elderly. The hyponatraemia generally reverses on discontinuation of AROPAX CR.
The concomitant use of AROPAX CR and alcohol is not advised.
AROPAX CR contains lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine (see section 2).
AROPAX CR 12,5 mg contains Opadry Yellow (YS-1-2007): 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 late), an azo dye which may cause allergic-type reactions.
Clinical studies have shown the absorption and pharmacokinetics of paroxetine to be unaffected or only marginally affected (i.e. at a level which warrants no change in dosing regimen) by:
The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of medicine metabolising enzymes.
When AROPAX CR is to be co-administered with a known medicine metabolising enzyme inhibitor (e.g. sodium valproate), consideration should be given to using doses at the lower end of the range. No initial dosage adjustment is considered necessary when the AROPAX CR is to be coadministered with known medicine metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbitone, phenytoin). Any subsequent dosage adjustment should be guided by clinical effect (tolerability and efficacy).
Co-administration of fosamprenavir/ritonavir with AROPAX CR significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
Daily administration of AROPAX CR increases significantly the plasma levels of procyclidine. If anticholinergic effects are seen, the dose of procyclidine should be reduced.
Carbamazepine, phenytoin, sodium valproate. Concomitant administration showed no effect on pharmacokinetic/dynamic profile in epileptic patients.
SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium and suxamethonium.
Paroxetine inhibits the hepatic cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered medicines metabolised by this enzyme. These include certain tricyclic antidepressants (e.g. amitriptyline, nortriptyline, imipramine and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine), risperidone, atomoxetine, certain Type 1c antidysrhythmics (e.g. propafenone and flecainide) and metoprolol. Tamoxifen has an important active metabolite, endoxifen, which is produced by CYP2D6 and contributes significantly to the efficacy of tamoxifen. Irreversible inhibition of CYP2D6 by paroxetine leads to reduced plasma concentrations of endoxifen (see section 4.4).
An in vivo interaction study revealed no effect of paroxetine on alprazolam pharmacokinetics and vice-versa. Concurrent administration of AROPAX CR with alprazolam and other medicines that are CYP3A4 substrates would not be expected to cause a hazard.
Co-administration with serotonergic medicines may lead to an incidence of 5-HT associated effects (Serotonergic Syndrome; see sections 4.4 and 4.8).
Caution should be advised and a closer clinical monitoring is required when serotonergic medicines (such as L-tryptophan, triptans, tramadol, linezolid, SSRIs, lithium, fentanyl and St. John’s Wort – Hypericum perforatum preparations) are combined with AROPAX CR. Concomitant use of AROPAX CR and MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor and methylthioninium chloride (methylene blue)) is contra-indicated (see section 4.3).
Increased pimozide levels have been demonstrated in a study of a single low dose pimozide (2 mg) when co-administered with AROPAX CR. This is 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 AROPAX CR is contra-indicated (see section 4.3).
AROPAX CR should be administered with great caution to patients receiving oral anticoagulants. Preliminary data suggest that there may be a pharmacodynamic interaction between paroxetine and warfarin, which may result in increased bleeding in the presence of unaltered prothrombin times/INRs.
Some clinical studies have shown that SSRIs (including AROPAX CR) may affect sperm quality. This effect appears to be reversible following discontinuation of treatment. Changes in sperm quality may affect fertility in some men.
AROPAX CR should not be used during pregnancy (see section 4.3). Recent epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants, including AROPAX CR in pregnancy have reported an increase in risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects, associated with the use of paroxetine as contained in AROPAX CR.
There have been reports of premature birth in pregnant women exposed to paroxetine or other SSRIs. AROPAX CR should not be used during pregnancy.
Neonates should be observed if maternal use of AROPAX CR continues into the later stages of pregnancy, because there have been reports of complications in neonates exposed to paroxetine or other SSRIs late in the third trimester of pregnancy. Reported clinical findings have included: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying and somnolence. In some instances the reported symptoms were described as neonatal withdrawal symptoms. In a majority of instances the complications were reported to have arisen either immediately or soon (<24 hours) after delivery.
Epidemiological studies have shown that the use of SSRIs (including AROPAX CR) in pregnancy, particularly use in late pregnancy, was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The increased risk among infants born to women who used SSRIs late in pregnancy was reported to be 4 to 5 times higher than observed in the general population (rate of 1 to 2 per 1 000 pregnancies).
Small amounts of paroxetine are excreted into breast milk. AROPAX CR should not be used during lactation.
Clinical experience has shown that therapy with AROPAX CR is not associated with impairment of cognitive or psychomotor function. However, patients should be cautioned about their ability to drive a car and operate machinery.
Adverse 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. Common and uncommon events were generally determined from pooled safety data from a clinical trial population of >8000 paroxetine-treated patients and are quoted as excess incidence over placebo.
Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes
Common: increases in cholesterol levels, decreased appetite
Common: somnolence, insomnia, agitation, abnormal dreams (including nightmares)
Uncommon: confusion, hallucinations
Common: dizziness, tremor, headache
Uncommon: extrapyramidal disorders
Reports of extrapyramidal disorders including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication.
Common: blurred vision
Uncommon: mydriasis (see section 4.4)
Uncommon: postural hypotension
Common: yawning
Very common: nausea
Common: constipation, diarrhoea, vomiting, dry mouth
Common: sweating
Uncommon: skin rashes
Uncommon: urinary retention, urinary incontinence
Very common: sexual dysfunction
Common: asthenia, body weight gain.
The frequency of the following adverse events are unknown.
Blood & lymphatic system disorders: thrombocytopenia
Immune system disorders: severe allergic reactions (including anaphylactoid reactions and angioedema)
Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutritional disorders: hyponatraemia Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Psychiatric disorders: manic reactions
Nervous system disorders: convulsions, akathisia, restless legs syndrome (RLS),serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering tachycardia and tremor)
Eye disorders: acute glaucoma
Gastrointestinal disorders: gastrointestinal bleeding
Hepatobiliary disorders: elevation of hepatic enzymes, hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure)
Post-marketing reports of hepatic events (such as hepatitis, sometimes associated with jaundice, and/or liver failure), which may be fatal, have also been received. Discontinuation of AROPAX CR should be considered if there is prolonged elevation of liver function test results.
Skin & subcutaneous tissue disorders: severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis), urticaria, photosensitivity reactions
Reproductive system & breast disorders: hyperprolactinaemia/galactorrhoea, menstrual disorders (including menorrhagia, metrorrhagia and amenorrhoea)
General disorders & administration site conditions: peripheral oedema.
Common: dizziness, sensory disturbances, sleep disturbances, anxiety
Uncommon: agitation, nausea, sweating.
Discontinuation of AROPAX CR (particularly when abrupt) may lead to symptoms such as dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, headache, nervousness, vertigo, nausea, diarrhoea and sweating. In the majority of patients, these events are mild to moderate and are self-limiting. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when AROPAX CR treatment is no longer required, gradual discontinuation by dose tapering be carried out (see sections 4.2 and 4.4).
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
