Seroxat CR

Antidepressants , Central Nervous System , Drugs / November 14, 2016

Class: Central Nervous System
Dosage Form: Tablets
Description: Antidepressant serotonergic agent
Stock: Available
Manufacturer: GlaxoSmithKline (GSK)

Composition:

Active Ingredient:
Paroxetine hydrochloride…………12.5 and 25 mg
Excipients:
Hypromellose, Povidone, Lactose monohydrate, Magnesium Stearate, Colloidal Sillicon Dioxide, Glyercryl Behenate, Methacrylic Acid Copolymer Dispersion, Talc, Triethyl Citrate, Opadry Yellow (12.5 mg tablets), Opadry Pink (25 mg tablets), Yellow Ferric Oxide (12.5 mg tablets) and Red Ferric Oxide (25 mg tablets)

Properties:

Pharmacodynamics
Paroxetine is a potent and selective inhibitor of serotonin (5-hydroxytryptamine, 5-HT) reuptake and its antidepressant action and efficacy in the treatment of OCD and panic disorder is thought to be related to its specific inhibition of serotonin reuptake in brain neurons.
Paroxetine is chemically unrealated to the tricyclic, tetracyclic and other available antidepressants.
The principal metabolites of paroxetine are polar and conjugated products of oxidation and methylation, which are readily cleared. In view of their relative lack of pharmacological activity, it is most unlikely that they contribute to the therapeutic effects of paroxetine.
Metabolism does not compromise paroxetine’s selective action on neuronal 5-HT uptake.
Paroxetine has low affinity for muscarinic cholinergic receptors and animal studies have indicated only weak anticholinergic properties.
In accordance with this selective action, in vitro studies have indicated that, in contrast to tricyclic antidepressants, paroxetine has little affinity for alpha1, alpha2 and beta-adrenoceptors, dopamine (D2), 5-HT1 like, 5-HT2 and histamine (H1) receptors. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate lack of CNS depressant and hypotensive properties.
Paroxetine does not impair psychomotor function does not potentiate the depressant effects of ethanol.
As with other selective 5-HT uptake inhibitors, paroxetine causes symptoms of excessive 5-HT receptor stimulation when administered to animals previously given monoamine oxidase inhibitors (MAOIs) or tryptophan.
Behavioral and EEG studies indicated that paroxetine is weakly activating at doses generally above those required to inhibit 5-HT uptake. The activating properties are not “amphetamine-like” in nature.
Animal studies indicated that paroxetine is well tolerated by the cardiovascular system.
Paroxetine produces to clinically significant changes in blood pressure, heart rate and ECG after administration to healthy subjects.
Studies indicate that, in contrast to antidepressants which inhibit the uptake of noradrenaline, paroxetine has a much reduced propensity to inhibit the antihypertensive effects of guanethidine.

Pharmacokinetics
Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. Paroxetine CR tablets control the dissolution rate of paroxetine over a period of 4 to 5 hours. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until paroxetine CR tablets have left the stomach. Compared to immediate releases formulations of paroxetine, controlled release tablets have a reduced absorption rate.
Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of metabolites is about 64% of dose. About 30% of the dose is excreted in faeces, probably via the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism.
Metabolite excretion is biphasic, being initially a result of first-pass metabolism and subsequently controlled by systemic elimination of paroxetine.
The elimination half-life is variable but generally about 1 day.
Steady state systemic levels are attained by 7-14 days after starting treatment with immediate or controlled release formulations and pharmacokinetics do not appear to change during long-term therapy.
No correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy).
Due to first-pass metabolism, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract.
Paroxetine is extensively distributed into tissues and pharmacokinietic calculations indicate that only 1% of the paroxetine in the body resides in the plasma.
Approximately 95% of the paroxetine present in the plasma is protein bound at therapeutic concentrations.
Transfer to human breast milk, and to the fetuses of laboratory animals, occurs in small amounts.
Increased plasma concentrations of paroxetine occur in elderly subjects, in subjects with severe renal and in those with hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.

Pre-clinical Safety Data
Toxicology studies have been conducted in rhesus monkeys and albino rats; in both, the metabolic pathway is similar to that described for humans. As expected with lipophilic amines, including tricyclic antidepressants, phospholipidosis was detected in rats. Phospholipidosis was not observed in primate studies of up to one year duration at doses that were 6 times higher than the recommended range of clinical doses.
Carcinogenesis: In two year studies conducted in mice and rats, paroxetine had no tumorigenic effect.
Gentotoxicity: Gentotoxicity was not observed in a battery of in vitro and in vivo tests.

Indications:

1. Adults:
a) Major Depressive Disorder:
Seroxat CR  tablets are indicated for the treatment of major depressive disorder.
b) Panic Disorder:
Seroxat CR tablets have been shown to be effective in the treatment of panic disorder with or without agoraphobia.
c) Premenstrual Dysphoric Disorder:
Seroxat CR tablets are indicated for the treatment of premenstrual dysphoric disorder (PMDD).
d) Social Anxiety Disorder/Social Phobia:
Seroxat CR tablets have shown to be effective in the treatment of Social Anxiety Disorder/Social Phobia.
The effectiveness of Seroxat CR tablets in the long-term treatment of Social Anxiety Disorder/Social Phobia has not been evaluated. Therefore, if Seroxat CR tablets are to be administered for extended periods in the treatment of Social Anxiety Disorder/Social Phobia, the physician should periodically re-evaluate the long-term usefulness of Seroxat CR for the individual patient.

2. Children and Adolescents (less than 18 years):
All indications:
Seroxat CR is not indicated for use in children or adolescents aged less than 18 years (see Warnings and Precautions).
The efficacy of Seroxat CR tablets has not been studied in children or adolescents aged less than 18 years; however, controlled clinical studies with Seroxat IR tablets in children and adolescents with major depressive disorder failed to demonstrate efficacy, and do not support the use of Seroxat in the treatment of depression in this population (see Warnings and Precautions).
The safety and efficacy of Seroxat in children aged less than 7 years has not been studied.

Contraindicatons:

Known hypersensitivity to paroxetine and excipients.
Seroxat CR tablets should not be used in combination with monoamine oxidase inhibitors (MAOIs) (including linezolid, an antibiotic which is a reversible non-selective MAOI) or within 2 weeks of terminating treatment with MAOIs. Likewise, MAOIs should not be introduced within 2 weeks of cessation of therapy with Seroxat CR tablets (see Interactions).
Seroxat CR tablets should not be used in combination with thioridazone, because, as with other drugs which inhibit the hepatic enzyme CP450 2D6, paroxetine can elevate plasma levels of thioridazone (see Interactions). Administration of thioridazone alone can lead to QTc interval prolongation with associated serious ventricualr arrhythmia such as torsades de pointes, and sudden death.
Seroxat CR tablets should not be used in combination with pimozide (see Interactions).

Drug Interactions:

1. Serotonergic Drugs:
As with other SSRIs, co-administration with serotonerigc drugs may lead to an incidence of 5-HT assocaited effects (serotonin syndrome: see Warnings and Precautions). Caution should be adivsed and a closer clinical monitoring is required when serotongergic drugs (such as L-tryptophan, triptans, tramadol, SSRIs, lithium and St. John’s Wort – Hypericum perforatum-preparations) are combined with Seroxat CR. Concomitant use of Seroxat CR and MAOIs (including linezolid, an antibiotic which is a reversible non-selective MAOI) is contraindicated (see Contraindications).

2. Pimozide:
Increased pimozide levels have been demonstrated in a study of a single low dose pimozide (2 mg) when co-administered with paroxetine. 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 Seroxat CR tablets is contraindicated (see Contraindications).

3. Drug Metabolizing 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 metabolizing enzyme inhibitor, consideration should be given to using 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 metabolizing enzyme enducers (e.g. carbamazepine, rifampicine, phenobarbital, phenytoin). Any subsequent dosage adjustment should be guided by clinical effect (tolerability and efficacy).

4. Forsamprenavir/Ritonavir:
Co-administration of forsamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).
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.

5. Anticonvulsants:
Carbamazepine, phenytoin, sodium valproate. Concomitant administration does not seem to show any effect on pharmacokinetic/dynamic profile in epileptic patients.

6. CYP2D6 Inhibitory Potency of Paroxetine:
As 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 metabolized by this enzyme. These include certain tricylcic antidepressants (e.g. amitrptyline, nortriptyline, imipramine and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see Contraindications), risperidone, atomoxetine, certain Type 1c antiarrhythmics (e.g. propafenone and flecainide) and metoprolol.

7. CYP3A4:
An in vivo interaction study involvin the co-administration under steady state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokineitcs. A similar in vivo interaction study revealed no effect of paroxetine with terfenadine, alprazolam and other drugs that are CYP3A4 substrates would not be expected to cause a hazard.
Clinical studies ahve 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: food, antacids, digoxin, propanolol, alchohol – paroxetine does not increase the impairment of mental and motor skills caused by alcohol, however, the concomitant use of Seroxat and alcohol is not advised.

Side Effects:

Some of the adverse experiences listed below may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.
Adverse drugs 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. Rare and very rare events were generally determined from post-marketing data and refer to reporting rate rather than true frequency.

1. Blood and Lymphatic System Disorders:

  • Uncommon: Abnormal bleeding, predominantly of the skin and mucous membranes (mostly ecchymosis)
  • Very rare: thrombocytopenia

2. Immune System Disorders:

  • Very rare: Allergic reactions (including urticaria and angioedema)

3. Endocrine Disorders:

  • Very rare: Syndrome of inappropriate anti-diuretic hormone secretion (SIADH)

4. Metabolism and Nutrition Disorders:

  • Common: Increases in cholesterol levels, decreased appetite
  • Rare: Hyponatraemia
  • Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to syndrome of inappropriate anti-diuretic hormone secretion (SIADH)

5. Psychiatric Disorders:

  • Common: Somnolence, insomnia, agitation
  • Uncommon: Confusion, hallucinations
  • Rare: Manic reactions
  • These symptoms may be due to the underlying disease

6. Nervous System Disorders:

  • Common: Dizziness, tremor, headache
  • Uncommon: Extrapyramidal disorders
  • Rare: Convulsions, akathisia
  • Very rare: Serotonin syndrome (symptoms may include agitiation, confusion, diaphoresis, hallucinations, hyperreflexia, mycoclonus, shivering, tachycardia and tremors)
  • Reports of extrapyramidal disorders including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication

7. Eye Disorders:

  • Common: Blurred vision
  • Uncommon: Mydriasis (see Warnings and Precautions)
  • Very rare: Acute glaucoma

8. Cardiac Disorders:

  • Uncommon: Sinus tachycardia

9. Vascular Disorders:

  • Uncommon: Postural hypotension

10. Respiratory, Thoracic and Mediastinal Disorders:

  • Common: Yawning

11. Gastrointestinal Disorders:

  • Very common: Nausea
  • Common: Constipation, diarrhea, dry mouth
  • Very rare: Gastrointestinal bleeding

12. Hepato-biliary Disorders:

  • Rare: Elevation of hepatic enzymes
  • Very rare: Hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure)
  • Elevation of hepatic enzymes has 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.

13. Skin and Subcutaneous Tissue Disorders:

  • Common: Sweating
  • Uncommon: Skin rashes
  • Very rare: Photosensitivity reactions

14. Renal and Urinary Disorders:

  • Uncommon: Urinary retention, urinary incontinence

15. Reproductive System and Breast Disorders:

  • Very common: Sexual dysfunction
  • Rare: Hyperprolactinaemia/galactorrhoea

16. General Disorders and Administration Site Conditions:

  • Common: Asthenia, body weight gain
  • Very rare: Peripheral oedema

17. Symptoms Seen on Discontinuation of Paroxetine Treatment:

  • Common: Dizziness, sensory disturbances, sleep disturbances, anxiety headache
  • Uncommon: Agitiation, nausea, tremor, confusion, sweating, diarrhea
  • As with any psychoactive medicines, discontinuation of Seroxat (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, nausea, headache, tremor, confusion, diarrhea 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 paroxetine treatment is no longer required, gradual discontinuation by dose tapering be carried out (see Dosage and Administration and Warnings and Precautions).

18. Adverse Events from Pediatric Clinical Trials:
In pediatric clinical trials the following adverse events were reported at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia and agitation. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder. Hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age.
In studies that used a tapering regimen (daily dose decreased by 10 mg/day at weekly intervals to a dose of 10 mg/day for one week), symptoms reported during the taper phase or upon discontinuation of Seroxat at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were; emotional lability, nervousness, dizziness, nausea and abdominal pain (see Warnings and Precautions).

Dosage and Administration:

1. Adults:
Seroxat CR tablets should be administered as a single daily dose, usually in the morning, with or without food. Patients should be informed that Seroxat CR tablets should not be chewed or crushed, and should be swallowed whole.
a) Major Depressive Disorder:
The recommended initial dose is 25 mg/day. Some patients not responding to a 25 mg dose may benefit from dose increases in 12.5 mg/day increments, up to a maximum of 62.5 mg/day according to patient response. Dose changes should occur at intervals of at least one week.
As with all antidepressant drugs, dosage should be reviewed and adjusted if necessary within 2 to 3 weeks of initiation of therapy and thereafter as judged clinically appropriate.
Patients with depression should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months.
b) Panic Disorder:
Patients should begin treatment on 12.5 mg/day and the dose increased weekly in 12.5 mg/day increments according to patient response. Some patients may benefit from having their dose increased up to a maximum of 75 mg/day.
A low initial starting dose is recommended to minimize the potentail worsening of panic symptomatology which is generally recognised to occur early in the treatment of this disorder.
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.
c) Premenstrual Dysphoric Disorder:
The recommended initial dose is 12.5 mg/day. Some patients not responding to 12.5 mg dose may benefit from having their dose increased to 25 mg/day. Dose changes should occur at intervals of at least one week.
Patients with PMDD should be periodically assessed to determine the need for continual treatment.
d) Social Anxiety Disorder:
The recommended intial dose is 12.5 mg daily. Some patients not responding to a 12.5 mg dose may benefit from having dose increases in 12.5 mg/day increments as required, up to a maximum of 37.5 mg/day according to patient’s response. Dose changes should occur at intervals of at least one week.
e) Elderly:
Increased plasma concentrations of paroxetine occur in elderly subjects, but the range of concentrations overlaps with that observed in younger subjects.
Dosing should commence at 12.5 mg/day and may be increased up to 50 mg/day.
f) Children and adolescents (less than 18 years):
Seroxat CR is not indicated for use in children or adolescents aged less than 18 years (see Indications and Warnings and Precautions).
g) Renal/hepatic impairment:
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatine clearance <30 ml/min) or in those with hepatic impairment. The dosage should be restricted to the lower end of the range.

2. Discontinuation of Seroxat:
As with other psychoactive medications, abrupt discontinuation should generally be avoided (see Warnings and Precautions and Adverse Reactions). This taper phase regiment used in recent clinical trials involved a decrease in the daily dose by 10 mg/day (equivalent to 12.5 mg/day CR tablets) at weekly intervals.
When a daily dose of 20 mg/day (equivalent to 25 mg/day CR tablets) was reached, patients where continued on this dose for one week before treatment was stopped. 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.

Overdosage:

A wide margin of safety is evident from available overdose information on Seroxat.
Experience of Seroxat in overdose has indicated that, in addition to those symptoms mentioned under Adverse Reactions, vomiting, fever, blood pressure changes, involuntary muscle contractions, anxiety and tachycardia have been reported.
Patients have generally recovered without serious adequate 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 a fatal outcome, but generally when Seroxat was taken in conjunction with other psychotropic drugs with or without alcohol.
No specific antidote is known.
The treatment should consist of those general measures employed in the management of overdose with any antidepressant. Where appropriate, the stomach should be emptied by lavage. Following evacuation, 20 to 30 g of activated charcoal may be administered every 4 to 6 hours during the first 24 hours after ingestion. Supportive care with frequent monitoring of vital signs and careful observation is indicated.

Pregnancy and Lactation:

Animal studies have not shown any teratogenic or selective embryotoxic effects.
Recent epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is approximately 1/50, compared with an expected rate for such defects of approximately 1/100 infants in the general population.
The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant, and should only prescribe Seroxat CR if the potential benefit outweighs the potential risk. If a decision is taken to discontinue Seroxat CR treatment in a pregnant woman, the prescriber should consult Dosage and Administration – Discontinuation of Seroxat and Warnings and Precautions – Symptoms seen on Discontinuation of Seroxat Treatment in Adults.
There have been reports of premature birth in pregnant women exposed to paroxetine or other SSRIs, although a casual relationship with drug therapy has not been established.
Neonates should be observed if maternal use of Seroxat continues into the later stages of pregnancy, because there have been reports of complications in neonates exposed to Seroxat or other SSRIs late in the third trimester of pregnancy. However, a casual associated with drug therapy has not been confirmed. Reported clinical findings have included: respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypertonia, hypotonia, hyperrefelexia, 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.
In one epidemiological study, the use of SSRIs (including paroxetine) after the first 20 weeks of pregnancy, was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The absolute risk among those who used SSRIs late in pregnancy was reported to be about 6 to 12 per 1000 women, compared to 1 to 2 per 1000 women in the general population.
Small amounts of paroxetine are excreted into breast milk. In published studies, serum concentrations in breast-fed infants were undetectable (<2 ng/ml) or very low (<4 ng/ml). No signs of drug effects were observed in these infants. Nevertheless, Seroxat should not be used during lactation unless the expected benefits to the mother justify the potential risk for the infant.

Warnings:

1. Children and Adolescents (less than 18 years):
Treatment with antidepressants is associated with an increased risk of suicidal thinking and behavior 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 suicide (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior 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 behavioral development are lacking.

2. Clinical Worsening and Suicide Risk in Adults:
Young adults, especially those with MDD, may be at increased risk for suicidal behavior during treatment with Seroxat CR. An analysis of placebo controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behavior 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. In adults with MDD (all ages), there was a statistically significant increase in the frequency of suicidal behavior 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 18-30 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 behaviors (suicidale) 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 behavior, and these conditions may also be co-morbid with MDD. Additionally, patients with a history of suicidal behavior or thoughts, young adults, and those patient 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 suicide 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 caregivesrs 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/behavior or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. It should be recognized that the onset of some symptoms, such as agitation, akthisia or mania, could be related either to the underlying disease state of the drug therapy (see Akathisia and Mania and Bipolar Disorder below; Adverse Reactions).

3. Akathisia:
Rarely, the use of Seroxat or other SSRIs 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.

4. Serotonin Syndrome/Neuroleptic Malignant Syndrome:
On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in associated with Seroxat treatment, particularly when given in combination with other serotonergi and/or neuroleptic drugs. As these snydromes may result in potentially life-threatening conditions, treatment with Seroxat should be discontinued if such events (characterised by clusters of smyptomssuch as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitiation 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 syndromes (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 no 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 a risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. AS with all antidepressants, paroxetine should be used with caution in patients with a history of mania.

5. Monoamine Oxidase Inhibitors:
Treatment with Seroxat CR should be initiated cautiously at least 2 weeks after terminating treatment with MAOIs and dosage of Seroxat CR should be increased gradually optimal response is reached (see Contraindications, Interactions).

6. Renal/hepatic Impairment:
Caution is recommended in patients with severe renal impairment or in those with hepatic impairment (see Dosage and Administration).

7. Epilepsy:
As with other antidepressants, Seroxat CR should be used with caution in patients with epilepsy.

8. Seizures:
Overall, the incidence of seizures is less than 0.1% in patients treated with paroxetine . The drug should be discontinued in any patients who develops seizures.
9. ECT:
There is little clinical experience of the concurrent administration of paroxetine with ECT.
10. Glaucoma:
As with other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma.
11. Hyponatraemia:
Hyponatraemia has been reported rarely, predominantly in the elderly. The hyponatraemia generally reverses on discontinuation of paroxetine.
12. Haemorrhage:
Skin and mucous membrane bleedings (including gastrointestinal 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.
13. Cardiac Conditions:
The usual precautions should be observed in patients with cardiac conditions.14. 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 parasthesia, electric shock sensations and tinnitus), sleep distrubances (including intense dreams), agitiation 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 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that Seroxat should be gradually tapered when dicontinuing treatment over a period of several weeks or months, according to the patient’s needs (see Discontinuation of Seroxat, Dosage and Administration).
Symptoms seen on discontinuation of Seroxat treatment in children and adolescents:
In clinical trials in children and adolescents, adverse events see 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).

15. Effects on ability to drive and use machinery:
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.

Storage:

Store at room temperature, below 25°C.

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