Brands, Medical Use, Clinical Data
- Selective Serotonin Reuptake Inhibitors (SSRIs)
Brands / Synonyms
Aropax; Paroxetina [Inn-Spanish]; Paroxetine Hcl; Paroxetine [Usan:Ban:Inn]; Paroxetinum [Inn-Latin]; Paxil; Paxil CR; Pexeva; Seroxat
For the treatment of depression, depression accompanied by anxiety, obsessive compulsive disorder and panic attacks
Paroxetine, an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) type, has no active metabolites and has the highest specificity for serotonin receptors of all the SSRIs. It is used to treat depression resistant to other antidepressants, depression complicated by anxiety, panic disorder, social and general anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder, premature ejaculation, and hot flashes of menopause in women with breast cancer.
Mechanism of Action
Paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake. Paroxetine likely inhibits the reuptake of serotonin at the neuronal membrane, enhances serotonergic neurotransmission by reducing turnover of the neurotransmitter, therefore it prolongs its activity at synaptic receptor sites and potentiates 5-HT in the CNS; paroxetine is more potent than both sertraline and fluoxetine in its ability to inhibit 5-HT reuptake. Compared to the tricyclic antidepressants, SSRIs have dramatically decreased binding to histamine, acetylcholine, and norepinephrine receptors.
completely absorbed after oral dosing
LD50=500mg/kg (orally in mice); Coma, dizziness, drowsiness, facial flushing, nausea, sweating, tremor, vomiting
Biotrnasformation / Drug Metabolism
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs) or thioridazine is
PAXIL is contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in
As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when
they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness,
have been reported when tryptophan was administered to patients taking PAXIL. Consequently, concomitant use of
PAXIL with tryptophan is not recommended.
Monoamine Oxidase Inhibitors
Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis
in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience,
the concomitant administration of PAXIL and warfarin should be undertaken with caution
There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following
the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and
an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the
patient is advised.
Drugs Affecting Hepatic Metabolism
The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where PAXIL (30 mg once daily) was dosed orally for
4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with
oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently,
dosage adjustment of PAXIL after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on
cimetidine’s pharmacokinetics was not studied.
Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30-mg dose of PAXIL was administered at
phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%,
respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not
studied. Since PAXIL exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs
are both being chronically dosed. No initial dosage adjustment of PAXIL is considered necessary when coadministered with
phenobarbital; any subsequent adjustment should be guided by clinical effect.
When a single oral 30-mg dose of PAXIL was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine
AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to PAXIL administered alone. In a separate study,
when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin
AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear
pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial
dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by
Drugs Metabolized by Cytochrome P450IID6
Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many
tricyclics), are metabolized by the cytochrome P450 isozyme P450IID6. Like other agents that are metabolized by P450IID6,
paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this P450IID6 isozyme is saturated
early during dosing with PAXIL. In 1 study, daily dosing of PAXIL (20 mg once daily) under steady-state conditions increased
single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant
use of PAXIL with other drugs metabolized by cytochrome P450IID6 has not been formally studied but may require lower doses than
usually prescribed for either PAXIL or the other drug.
Therefore, coadministration of PAXIL with other drugs that are metabolized by this isozyme, including certain drugs effective in
the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine),
phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this
enzyme (e.g., quinidine), should be approached with caution.
However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels
of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS).
At steady state, when the P450IID6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes
that, unlike P450IID6, show no evidence of saturation (see PRECAUTIONS—Tricyclic Antidepressants).
Drugs Metabolized by Cytochrome P450IIIA4
An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a
substrate for cytochrome P450IIIA4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro
studies have shown ketoconazole, a potent inhibitor of P450IIIA4 activity, to be at least 100 times more potent than paroxetine as
an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and
cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine's
in vivo clearance predicts its effect on other IIIA4 substrates, paroxetine’s extent of inhibition of IIIA4 activity is not likely to
be of clinical significance.
Tricyclic Antidepressants (TCAs)
Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with PAXIL, because paroxetine may inhibit TCA
metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered
with PAXIL (see PRECAUTIONS—Drugs Metabolized by Cytochrome P450IID6).
Drugs Highly Bound to Plasma Protein
Because paroxetine is highly bound to plasma protein, administration of PAXIL to a patient taking another drug that is highly protein
bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects
could result from displacement of paroxetine by other highly bound drugs.
Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design
that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of
upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus,
patients should be cautioned about the use of such drugs concurrently with paroxetine.
Although PAXIL does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid
alcohol while taking PAXIL.
A multiple-dose study has shown that there is no pharmacokinetic interaction between PAXIL and lithium carbonate. However, since there
is little clinical experience, the concurrent administration of paroxetine and lithium should be undertaken with caution.
The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at
steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration
of paroxetine and digoxin should be undertaken with caution.
Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not
Daily oral dosing of PAXIL (30 mg once daily) increased steady-state AUC0- 24, Cmax, and Cmin values of procyclidine (5 mg oral once
daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the
dose of procyclidine should be reduced.
In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of
propranolol were unaltered during coadministration with PAXIL (30 mg once daily) for the final 10 days. The effects of propranolol on
paroxetine have not been evaluated
Reports of elevated theophylline levels associated with treatment with PAXIL have been reported. While this interaction has not been
formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.
Electroconvulsive Therapy (ECT)
There are no clinical studies of the combined use of ECT and PAXIL.