Professional Drug Information > Paroxetine Hydrochloride

Paroxetine (Systemic)

VA CLASSIFICATION
Primary: CN603
Secondary: CN900

Commonly used brand name(s): Paxil; Paxil CR.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antianxiety agent—

antidepressant—

antiobsessional agent—

antipanic agent—

Indications

Accepted

Depressive disorder, major (treatment)—Paroxetine is indicated for the treatment of major depressive disorder ^{{01} {87}}. Treatment of acute depressive episodes typically requires 6 to 12 months of antidepressant therapy ^{91}. Patients with recurrent or chronic depression may require long-term treatment ^{91}. Paroxetine has shown effective maintenance of antidepressant response for up to 52 weeks of treatment in a placebo-controlled trial ^{01}.

Generalized anxiety disorder (treatment)—Paroxetine is indicated for the treatment of generalized anxiety disorder (GAD).
^{102}
Obsessive-compulsive disorder (treatment)—Paroxetine is indicated for the treatment of obsessions and compulsions in patients with obsessive-compulsive disorder ^{{01} {87}}. Paroxetine has shown effective relapse prevention for up to 6 months of treatment in a placebo-controlled trial ^{01}.

Panic disorder (treatment)—Paroxetine is indicated for the treatment of panic disorder, with or without agoraphobia ^{{01} {87}}.

Social anxiety disorder (treatment)—Paroxetine is indicated for the treatment of social anxiety disorder or social phobia^{100}.


Pharmacology/Pharmacokinetics

Note: A wide range of intersubject variability has been observed in the pharmacokinetic parameters of paroxetine ^{{03} {24} {26} {38} {41} {42}}.


Physicochemical characteristics:

Chemical group—
    Phenylpiperidine ^{{01} {08} {41}}. Chemically unrelated to other selective serotonin reuptake inhibitors (SSRIs) ^{{01} {54}}, or to tricyclic ^{{54} {87}}, tetracyclic ^{{01} {87}}, or any other currently available antidepressants ^{01}.
Molecular weight—
    Paroxetine hydrochloride: 374.8 ^{{01} {87}}
    Paroxetine base: 329.37 ^{88}

Solubility
    5.4 mg of paroxetine hydrochloride per mL water ^{01}.

Mechanism of action/Effect:

Paroxetine potently and selectively inhibits neuronal serotonin reuptake ^{{03} {08} {18} {75}} through antagonism of the serotonin transporter ^{74}. Its antidepressant, antiobsessional, and antipanic activities are presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) ^{01}{101}. Paroxetine inhibits the active membrane ^{03} transport mechanism for reuptake of serotonin ^{{03} {41}}, which increases concentration of the neurotransmitter at the synaptic cleft ^{{03} {08}} and prolongs its activity at synaptic receptor sites ^{63}. Inhibition of serotonin reuptake also enhances serotonergic neurotransmission ^{{08} {41} {65}} by reducing turnover of the neurotransmitter via a negative feedback mechanism ^{03}. Paroxetine inhibits serotonin reuptake in vitro ^{63} more selectively ^{{02} {40} {64}} and more potently ^{{02} {40} {41} {54}} than do fluoxetine ^{{02} {40} {41} {54}}, sertraline ^{{02} {40} {41} {54}}, fluvoxamine ^{{40} {41} {54}}, zimeldine ^{58}, or clomipramine ^{{58} {64}}. Paroxetine very ^{01} weakly inhibits reuptake of norepinephrine ^{{01} {07} {18} {75}} and dopamine ^{{01} {03} {07}}.

Receptor binding studies have demonstrated that paroxetine does not interact directly ^{03} with central neurotransmitter receptor sites, including alpha ₁- ^{{41} {54} {87}}, alpha ₂- ^{{41} {54} {87}}, or beta- ^{{01} {87}{101}}adrenoreceptors, and dopamine D ₂ ^{{41} {54} {87}}, serotonin (5-hydroxytryptamine) 5HT ₁ ^{{01} {41}{101}} or 5HT ₂ ^{{01} {41} {54}}, or histamine H ₁ ^{{08} {41} {54}} receptors. Paroxetine has very weak affinity for the muscarinic-cholinergic receptor ^{{08} {41} {54}}, and does not inhibit monoamine oxidase ^{07}.


Other actions/effects:

Paroxetine potently ^{94} inhibits the P450 2D6 (CYP2D6) isoenzyme of the hepatic cytochrome P450 system ^{{70} {93} {94}}. In vitro studies indicate that paroxetine is a very weak inhibitor of CYP3A4 ^{01}{101}. This inhibition of isoenzyme CYP3A4 is not likely to be of clinical significance, and an in vivo study revealed no effect of paroxetine on the pharmacokinetics of terfenadine, a CYP3A4 substrate ^{01}{101}.

Paroxetine inhibits serotonin (5-HT) uptake by platelets as well as neurons ^{01}{101}.

At therapeutic doses, paroxetine does not significantly impair psychomotor function ^{{16} {17} {45} {59} {71} {77} {79}} and exerts no significant effects on heart rate ^{{16} {32} {45} {48} {58} {60}}, blood pressure ^{{16} {32} {44} {45} {48} {58} {60} {67} {80}}, or electrocardiogram (ECG) parameters ^{{16} {32} {44} {45} {48} {67}}. Also, paroxetine does not appear to induce epileptiform activity ^{{32} {53}} or to lower the seizure threshold ^{{40} {53}}.

Absorption:

Paroxetine is well absorbed ^{{20} {23} {42}} from both the suspension and tablet forms ^{01}{101}, with bioavailability for both dosage forms ranging from 50 to 100% ^{{07} {42}}. Bioavailability increases after multiple dosing ^{{20} {87}} due to partial saturation of first-pass metabolism ^{{01} {03} {87}{101}}. Absorption is not influenced by the presence of food, milk, or antacids ^{{28} {43}}.

Paroxetine extended-release tablets are designed to control the rate of medication release over 4 to 5 hours^{101}. These tablets have an enteric coating that delays the release of medication until the tablets have left the stomach^{101}.

Distribution:

Paroxetine is extensively distributed into tissues, with only 1% remaining in the systemic circulation ^{{03} {20}{100}{101}}. The volume of distribution (Vol _D) is large ^{{20} {42}} due to the lipophilic nature of paroxetine ^{{20} {42}}; values ranging from 3 to 28 L per kg of body weight (L/kg) have been reported ^{20}. Paroxetine is distributed into breast milk in concentrations similar to plasma concentrations ^{{03} {20} {87}}.

Protein binding:

Very high (95%) ^{{20} {29} {78}}. In vitro , protein binding of phenytoin and warfarin are not altered by paroxetine ^{01}.

Biotransformation:

Paroxetine undergoes extensive first-pass metabolism in the liver ^{{20} {23} {26} {29}{100}{101}}. At least 85% of a paroxetine dose ^{03} is oxidized ^{{20} {26} {29}} to a catechol intermediate ^{87} that undergoes subsequent methylation ^{20} and conjugation ^{20} to clinically inactive ^{{20} {29}} glucuronide ^{{13} {42}} and sulfate ^{{13} {42}} metabolites.

Metabolism is accomplished in part by cytochrome P450 2D6 (CYP2D6) ^{{01}{100}{101}}; saturation of this enzyme at clinical doses appears to account for the nonlinear kinetics observed with increasing dose and duration of paroxetine treatment ^{{01} {41} {87}{101}}. The elderly may be more susceptible to the saturation of hepatic metabolic capacity, leading to conversion to nonlinear kinetics, which results in increased plasma concentrations of paroxetine at lower-than-usual doses ^{{05} {23} {42}}.

Half-life:


Elimination:

About 24 hours ^{{43} {65} {71} {77} {79}} (range, 3 to 65 hours) ^{{07} {20} {42} {43}} in healthy adults. Due to partially saturable kinetics ^{21}, the elimination half-life may be increased in the elderly ^{{20} {21} {23} {78}}. However, there is wide intersubject variability ^{{20} {21} {24} {71} {77} {79}}. Half-life is prolonged in patients with severe hepatic ^{{08} {42} {78}} or renal ^{{20} {25} {42} {53}} function impairment.


Onset of action:

Antidepressant effects—Within 1 to 4 weeks ^{{01} {45}}, with improvement in sleep parameters usually occurring in 1 ^{55} to 2 weeks ^{56}.

Antiobsessional and antipanic effects—May require several weeks to occur ^{87}.

Time to peak concentration:

Immediate-release: Range, 2 to 8 hours ^{{24} {43} {48}}.

Extended-release: Range, 6 to 10 hours^{101}.

Time to steady-state serum concentration

Usually achieved in 7 to 14 days in most patients ^{{20} {23} {24} {58}}, although it may take considerably longer in some patients ^{01}.

Concentration

Peak plasma—Following dosing at 30 mg a day for 30 days in healthy volunteers ^{{03} {41}}, peak paroxetine plasma concentrations (C _max) ranged from 8.6 to 105 mcg/L ^{{03} {41}} (0.02 to 0.28 micromoles per L). Peak plasma concentrations are subject to wide interpatient variability ^{{06} {41}} because of first-pass metabolism ^{08}, and increase in a nonlinear fashion with increasing dose because of saturation of CYP2D6 ^{{01} {87}{101}}.

Steady-state serum—In nonelderly depressed patients receiving long-term dosing of 20 to 50 mg of paroxetine a day, mean steady-state serum concentrations ranged from 48.7 to 117 mcg/L ^{10} (0.13 to 0.31 micromoles per L). In 15 normal male subjects, steady-state area under the plasma concentration–time curve (AUC) was about eight times greater than was predicted from single-dose kinetics ^{01}. Nonlinearity is thought to be the result of increased systemic availability due to reduced first-pass metabolism ^{41}, rather than a decrease in systemic clearance ^{41}. There appears to be no correlation between paroxetine plasma concentrations and clinical efficacy ^{{38} {43} {67} {75}} or incidence of adverse effects ^{{38} {43} {62} {64} {67}}.

Mean plasma concentrations in patients with creatinine clearances below 30 mL per minute (mL/min) were fourfold greater than those in healthy volunteers ^{01}{101}. Mean plasma concentrations in patients with creatinine clearances of 30 to 60 mL/min and in patients with hepatic function impairment were twofold greater ^{01}{101}.

Elimination:


Renal—
        In the 10-day period following administration of 30 mg of a paroxetine solution, approximately 64% of the dose was excreted in the urine ^{{01} {20}{101}}, of which 2% or less was the parent compound ^{{01} {03} {20} {42}{101}}.



Fecal—
        In the 10-day period following administration of 30 mg of a paroxetine solution, about 36% of the dose was excreted in the feces ^{{01} {20}{101}}, of which unchanged paroxetine comprised less than 1% ^{01}{101}.



Precautions to Consider

Carcinogenicity

In 2-year carcinogenicity studies, a significantly greater number of male rats in the group receiving 3.9 times the maximum recommended human dose (MRHD) of 50 mg for depression and social anxiety disorder (3.2 times the MRHD of 60 mg for obsessive-compulsive disorder and panic disorder) on a mg per square meter of body surface area (mg/m ²) basis exhibited reticulum cell sarcomas than did rats receiving lower doses^{100}. Also, there was a significantly increased linear trend across dose groups for occurrence of lymphoreticular tumors in male rats. Female rats were unaffected^{100}. In mice receiving up to 2.4 times the MRHD for depression and social anxiety disorder (2 times the MRHD for obsessive-compulsive disorder and panic disorder) on a mg/m ² basis, there was a dose-related increase in the number of tumors in mice, but no drug-related increase in the number of mice with tumors^{100}. The relevance of these findings to humans is not known. ^{01}{100}

Mutagenicity

Paroxetine demonstrated no genotoxic effects ^{{01} {14}{101}} in a battery of five in vitro and two in vivo assays, including the bacterial mutation assay ^{01}{101}, mouse lymphoma mutation assay ^{{01} {14}{101}}, unscheduled DNA synthesis assay ^{{01} {14}{101}}, tests for cytogenetic aberrations in vivo in mouse bone marrow ^{01} and in vitro in human lymphocytes ^{01}, and a dominant lethal test in rats ^{{01} {14}{101}}.

Pregnancy/Reproduction
Fertility—
Rats administered paroxetine at doses 2.9 times the MRHD for depression and social anxiety disorder (2.4 times the MRHD for obsessive-compulsive disorder and panic disorder) on a mg/m ² basis had reduced pregnancy rates^{01}.

Irreversible reproductive tract lesions occurred in male rats in toxicity studies of 2 to 52 weeks duration ^{01}. These lesions comprised atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at doses 4.9 times the MRHD for depression and social anxiety disorder (4.1 times the MRHD for obsessive-compulsive disorder and panic disorder) on a mg/m ² basis ^{01}, and vacuolation of the epididymal tubular epithelium at doses 9.8 times the MRHD for depression and social anxiety disorder (8.2 times the MRHD for obsessive-compulsive disorder and panic disorder) on a mg/m ² basis ^{01}{100}.

Pregnancy—
A prospective study compared birth outcomes of 267 pregnancies that were exposed to the selective serotonin reuptake inhibitors (SSRIs) sertraline (50 mg/day, range 25 to 250 mg/day), paroxetine (30 mg/day, range 10 to 60 mg/day), or fluvoxamine (50 mg/day, range 25 to 200 mg/day) with those of 267 pregnancies that were exposed to medications or medical treatments known to be nonteratogenic ^{09}. Paroxetine was taken at some time during 97 of the SSRI-exposed pregnancies ^{09}. Based on interviews with the mothers 6 to 9 months after the births, no differences in the infants" gestational ages or mean birth weights, or in the rates of major malformations, spontaneous or elective abortions, or stillbirths were found between the two groups ^{09}. Also, no differences were found between infants exposed to SSRIs during the first trimester only and infants exposed to SSRIs throughout gestation ^{09}. The behavioral effects of in utero paroxetine exposure were not examined ^{09}.

No teratogenic effects ^{{01} {15}} or selective toxicity to the fetus ^{15} were demonstrated in studies in rats and rabbits receiving 9.7 and 2.2 times, respectively, the MRHD for depression and social anxiety disorder on a mg/m ² basis ^{01}. However, increased pup death during the first 4 days of lactation occurred in rats given doses 0.19 times the MRHD for depression and social anxiety disorder on a mg/m ² basis during the last trimester and continuing throughout lactation ^{01}{100}.

FDA Pregnancy Category C ^{01}{101}.


Labor and delivery—

The effect of paroxetine on labor and delivery is not known ^{01}{101}.

Breast-feeding

Paroxetine is distributed into breast milk ^{90} in concentrations similar to those found in plasma ^{20}.

Pediatrics

No information is available on the relationship of age to the effects of paroxetine in pediatric patients. Safety and efficacy have not been established ^{{01} {87}{101}}.


Geriatrics


No geriatrics-specific problems have been documented to date in studies that included geriatric patients ^{01}{101}. However, paroxetine clearance is reduced in the elderly ^{{01} {87}{101}}. Also, elderly patients are more likely to have age-related renal function impairment. Reduced paroxetine dosage is recommended for elderly patients ^{{01} {87}{101}}.


Pharmacogenetics

Approximately 2 to 10% of the adult population are slow metabolizers of CYP2D6 substrates ^{97}. These patients have a reduced ability to metabolize paroxetine and may be more likely to experience adverse effects ^{{97} {98}}. Paroxetine dosage reductions may be necessary in these patients ^{98}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Paroxetine is a potent ^{94} inhibitor of cytochrome P450 2D6 (CYP2D6) ^{{93} {94}}, but a very weak inhibitor of CYP3A4 ^{{01} {93}{101}}. Caution should be exercised when paroxetine is coadministered with medications that are metabolized by CYP2D6, such as tricyclic antidepressants ^{{64} {70} {87}}, phenothiazines (e.g., thioridazine) ^{01}{101}, or type IC antiarrhythmics (e.g., encainide, flecainide, or propafenone) ^{{01} {64}{101}}, or medications that inhibit CYP2D6, such as quinidine ^{01}{101}. Dosage reductions of paroxetine and/or the other medication may be necessary ^{01}{101}. Interactions with medications metabolized by the CYP3A4 isoenzyme are unlikely ^{{01}{100}{101}}.
At steady state with paroxetine, the CYP2D6 isoenzyme is saturated, and paroxetine metabolism is governed by other hepatic P450 enzymes, which appear to be nonsaturable ^{{01}{100}{101}}. Interactions with hepatic enzyme inducers ^{{20} {87}}, hepatic enzyme inhibitors ^{{20} {87}}, and other medications that are metabolized by the hepatic P450 enzyme system ^{{01} {20}}, other than those listed below, have not been studied and the possibility of a significant interaction should be considered ^{01}.
In vitro studies have shown little chance of paroxetine being displaced by other highly protein-bound agents; also, paroxetine is unlikely to displace other highly protein-bound medications ^{20}. In vivo , however, the potential exists for displacement of one highly protein-bound medication by another; increased free concentrations of the displaced agent could result, increasing the likelihood of adverse effects ^{{01}{100}{101}}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Alcohol    (although paroxetine has not been shown to alter alcohol metabolism and does not appear to potentiate cognitive and psychomotor ^{{17} {19} {61}} effects of alcohol in normal subjects, concomitant use is not recommended ^{{01} {83} {87}{101}})


» Antidepressants, tricyclic (TCAs)    (paroxetine may inhibit TCA metabolism ^{{93} {94} {96}}, leading to increased TCA plasma concentrations ^{{94} {95} {96}}, and possibly causing adverse effects ^{95}; maximum plasma concentration, area under the plasma concentration–time curve, and elimination half-life of a single 100-mg dose of desipramine were increased twofold, fivefold, and threefold, respectively, in subjects at steady-state receiving 20 mg per day of paroxetine ^{{01}{100}{101}}; plasma concentration of the TCA may need to be monitored ^{{01}{100}{101}}, and dosage reduction of either the TCA ^{{94} {95}} or paroxetine ^{87} may be required)


» Astemizole    (because paroxetine inhibits cytochrome P450 enzymes and may increase plasma concentrations of astemizole, thereby increasing the risk of cardiac arrhythmias, concurrent use is not recommended ^{99})


Cimetidine    (in one study, steady-state plasma concentrations of paroxetine were increased by approximately 50% during concurrent administration of cimetidine ^{87}; although the clinical significance of this interaction has not been definitively established ^{{42} {53}}, initial dosage reductions are not thought to be necessary, but subsequent dose titration should be based on clinical effects ^{29})


Digoxin    (mean digoxin area under the plasma concentration–time curve [AUC] decreased 15% in the presence of paroxetine; since there is little clinical experience with this combination, concurrent administration should be undertaken with caution ^{{01}{100}{101}})


» Moclobemide    (because of the potentially fatal effects of concomitant use of paroxetine and nonselective, irreversible monoamine oxidase [MAO] inhibitors, and the increased risk of development of the serotonin syndrome with concomitant use of paroxetine and the selective, reversible MAO-A inhibitor moclobemide, concurrent use is not recommended ^{86}; allowing 3 to 7 days to elapse between discontinuing moclobemide and initiating paroxetine therapy, and allowing 2 weeks to elapse between discontinuing paroxetine and initiating moclobemide therapy is advised ^{86})


» Monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline    (concurrent use of MAO inhibitors with paroxetine may result in potentially fatal ^{{01} {87}} reactions, which may include confusion, agitation, restlessness, and gastrointestinal symptoms, or possibly hyperpyretic episodes, severe convulsions, hypertensive crises, or the serotonin syndrome; concurrent use is contraindicated ^{{83} {87}}, and at least 14 days should elapse between discontinuation of one medication and initiation of the other ^{{01} {87}{100}{101}})


Phenobarbital or
Primidone    (primidone is partially metabolized to phenobarbital, which induces many cytochrome P450 enzymes; administration of either of these agents concomitantly with paroxetine may reduce the systemic availability of paroxetine ^{{01} {87}}; no initial dosage adjustments are recommended, but subsequent titration should be based on clinical effects ^{{01} {87}{100}{101}})


Phenytoin    (concomitant administration with paroxetine may decrease the systemic availability of either agent ^{{20} {53} {54}}; no initial dosage adjustments are recommended, but subsequent titration should be based on clinical effects ^{{01} {87}{100}{101}})


Procyclidine    (concurrent use may increase the systemic availability of procyclidine ^{{03} {20} {87}}; if anticholinergic effects occur, the dosage of procyclidine should be reduced ^{{01}{100}{101}})


» Serotonergics or other medications or substances with serotonergic activity (see Appendix II )    (increased risk of developing the serotonin syndrome, a rare but potentially fatal hyperserotonergic state; symptoms typically occur shortly [hours to days] after the addition of a serotonergic agent, such as paroxetine, to a regimen that includes serotonin-enhancing drugs or an increase in dosage of a serotonergic agent; symptoms include agitation, diaphoresis, diarrhea, fever, hyperreflexia, incoordination, mental status changes [confusion, hypomania], myoclonus, shivering, or tremor; if recognized early, the syndrome usually resolves quickly upon withdrawal of the offending agents ^{84})

    (concurrent use of tryptophan and paroxetine is not recommended ^{{54} {64} {87}})


Theophylline    (elevated theophylline concentrations have been reported during concurrent use ^{{01}{100}{101}}; monitoring of theophylline serum concentrations during concurrent use is recommended ^{{01}{100}{101}})


» Warfarin    (although paroxetine does not alter in vitro protein binding of warfarin ^{{01}{100}{101}}, a pharmacodynamic ^{87} interaction may exist that causes an increased bleeding diathesis ^{{29} {87}} despite unaltered prothrombin time ^{{03} {87}}; since there is little clinical experience, caution is advised when these agents are used concomitantly ^{{03} {87}})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Hematocrit or
Hemoglobin or
White blood cell counts    (may be decreased ^{{06} {53}})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Hepatic function impairment, severe    (paroxetine plasma concentrations and elimination half-life are increased ^{{01} {87}{100}{101}}; initial dosage should be reduced ^{{04} {62}}, starting at 10 mg once a day ^{{01} {08}{100}{101}}, and intervals between dosage increases should be lengthened ^{{01}{100}{101}})


Mania, history of    (activation of hypomania or mania has been reported in depressed patients treated with paroxetine ^{{07} {10} {53} {87}})


Neurological impairment, including developmental delay ^{91}    (risk of seizures may be increased ^{91})


» Renal function impairment, severe    (in patients with creatinine clearance < 30 mL per minute [mL/min] and in patients with creatinine clearance between 30 and 60 mL/min, mean plasma paroxetine concentrations were four and two times, respectively, the plasma concentrations seen in healthy volunteers ^{{01}{100}{101}}; initial dosage should be reduced ^{{03} {07} {20} {62}}, starting at 10 mg once a day ^{{01} {08}{100}{101}}, and intervals between dosage increases should be lengthened ^{{01}{100}{101}})


Sensitivity to paroxetine^{100}{101}
Seizures, history of    (as with other antidepressants, paroxetine should be introduced with caution ^{{01} {87}{100}{101}}; if seizures develop, paroxetine should be discontinued ^{{01} {87}{100}{101}})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Careful supervision of patients with suicidal tendencies    (recommended especially during early treatment phase before peak effectiveness of paroxetine is achieved ^{{01}{100}{101}}; prescribing the smallest number of tablets necessary for good patient management is recommended to decrease risk of overdose ^{{01} {87}{100}{101}})




Side/Adverse Effects

Note: Side effects are usually mild ^{{45} {51} {52} {55} {59} {65} {68}} and transient ^{{45} {59} {65} {68}}, with evidence of dose-dependency for some of the most common adverse effects ^{{01} {30}{100}{101}}. In addition, there is evidence of adaptation with continuing therapy ^{{37} {44} {52} {62} {76}} (over 4 to 6 weeks) ^{01} to some effects, such as nausea ^{{01} {06} {62}} and dizziness ^{01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent
    
Agitation ^{{34} {48} {68}}
    
myalgia, myasthenia, or myopathy ^{{01}{100}{101}} (muscle pain or weakness)
    
palpitation ^{79} (fast or irregular heartbeat)
    
skin rash ^{{62} {71} {77}}

Incidence rare
    
Abnormal bleeding ^{{01}{100}{101} {89}} (red or purple patches on skin)
    
extrapyramidal symptoms ^{{07} {81} {82}}
including akinesia ^{01} or hypokinesia ^{01} (absence of or decrease in body movements), dyskinesia ^{01} (unusual or incomplete body movements), dystonia ^{{01} {81}} ( unusual or sudden body or facial movements; inability to move eyes), and dysarthria ^{{01}{100}{101}} ( difficulty in speaking)
    
hyponatremia ^{{49} {72} {73}} (confusion; drowsiness; dryness of mouth; increased thirst; lack of energy; seizures)
    
mania or hypomania ^{{07} {08} {53}{100}{101}} (talking, feeling, and acting with excitement and activity you cannot control)
    
serotonin syndrome ^{{01} {07} {08} {62}{100}{101}} (diarrhea; fever; increased sweating; mood or behavior changes; overactive reflexes; racing heartbeat ; restlessness; shivering or shaking)

Note: Reports of abnormal bleeding have included a report of impaired platelet aggregation ^{{01} {89}}, which could be caused by paroxetine-induced platelet serotonin depletion ^{{01} {89}}. However, a causal relationship between paroxetine and abnormal bleeding has not been established ^{01}.
Hyponatremia has been reported mostly in elderly patients, some of whom were taking diuretics or were otherwise volume-depleted ^{{01}{100}{101}}.
Activation of mania/hypomania occurred in about 1% of unipolar ^{{01} {07} {53}} and in about 2% of a subset of bipolar patients ^{{01} {07} {08} {53}} during premarketing testing ^{{01}{100}{101}}.
The serotonin syndrome is most likely to occur shortly (within hours to days) after a paroxetine dosage increase or the addition of another serotonergic agent to the patient"s regimen. The syndrome may include cardiac arrhythmias, coma, disseminated intravascular coagulation, hypertension or hypotension, renal failure, respiratory failure, seizures, or severe hyperthermia. ^{22}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Asthenia ^{{44} {50} {51} {53}{100}{101}} ( unusual tiredness or weakness)
    
constipation ^{{31} {37} {46} {48}{100}{101}}
    
diarrhea ^{{45} {52} {66} {67}{100}}
    
dizziness ^{{56} {58} {67} {68}{100}{101}}
    
drowsiness ^{{33} {36} {47} {55} {57}}
    
dryness of mouth ^{{67} {71} {77} {79}}
    
headache ^{{31} {48} {67} {68}{101}}
    
increased sweating ^{{12} {34} {35} {55} {67}{100}{101}}
    
insomnia ^{{67} {68} {71} {77}{100}{101}} (trouble in sleeping )
    
nausea ^{{12} {47} {53} {68}{100}{101}}
    
sexual dysfunction, especially ejaculatory disturbances ^{{34} {71} {77} {79}{100}{101}} or anorgasmia ^{74} (decreased sexual ability)
    
tremor ^{{35} {71} {77} {79}} (trembling or shaking)
    
urinary frequency or retention ^{{56} {79}} (problems in urinating)
    
vomiting ^{{12} {37} {58} {68}}

Note: Dryness of mouth is probably due to a direct effect on the serotonin system rather than cholinergic blockade ^{{44} {71} {77}}.


Incidence less frequent
    
Anxiety or nervousness ^{{31} {57} {65} {77}}
    
blurred vision ^{{35} {79}{100}{101}}
    
decreased libido ^{{34} {56} {71} {79}} (decreased sexual desire)
    
decreased ^{{33} {56} {68} {79}{100}{101}} or increased ^{01} appetite
    
paresthesia ^{79} (tingling, burning, or prickling sensations)
    
taste perversion ^{79} (change in sense of taste)
    
weight loss ^{01} or gain ^{{01} {12}}

Note: Paroxetine may cause less weight loss than fluoxetine or sertraline ^{33}; also, it may cause less weight gain than imipramine, especially in females ^{76}. Long-term paroxetine treatment may cause increased appetite and weight gain ^{62}.




Those indicating the need for medical attention if they occur after medication is discontinued
    
Agitation ^{{01} {87}} , confusion ^{{81} {82}} , or restlessness ^{04}
    
diarrhea ^{69}
    
dizziness ^{{81} {82} {87}} , vertigo ^{69} , or lightheadedness ^{{69} {87}}
    
headache ^{87}
    
increased sweating ^{{01} {81} {82}}
    
insomnia ^{{69} {81} {82} {87}} (trouble in sleeping)
    
migraine-like visual disturbances ^{69} (vision changes )
    
myalgia ^{69} (muscle pain)
    
nausea ^{{69} {81} {82}} or vomiting ^{69}
    
rhinorrhea ^{69} (runny nose)
    
tremor ^{{81} {82}} (trembling or shaking)
    
unusual tiredness or weakness ^{69}

Note: Discontinuation symptoms, if they occur, usually start 1 to 4 days after stopping paroxetine ^{81}; however, some patients may experience effects immediately ^{04}. Instances of withdrawal symptoms occurring in patients after paroxetine dosage was tapered over 7 to 10 days have been reported ^{69}. Although most effects are generally mild and transient ^{82}, some patients may experience more severe symptoms ^{69}.





Overdose
For specific information on the agents used in the management of paroxetine overdose, see Charcoal, Activated (Oral-Local) monograph.

For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
    
Dilated pupils ^{87} (large pupils)
    
dizziness ^{{01}{100}{101}}
    
drowsiness ^{{01} {87}{100}{101}}
    
dryness of mouth ^{87}
    
flushing of face ^{{01}{100}{101}}
    
irritability ^{87}
    
nausea ^{{01} {87}{100}{101}}
    
sinus tachycardia ^{87} ( racing heartbeat)
    
tremor ^{87} (trembling or shaking)
    
vomiting ^{{01} {87}{100}{101}}


Treatment of overdose
There is no specific antidote for paroxetine ^{87}. Treatment is essentially symptomatic and supportive ^{03}.

To decrease absorption—Decontaminating gastrointestinal tract ^{03} by, gastric lavage ^{87}{101}, followed by administration of 20 to 30 grams ^{87} of activated charcoal ^{{03} {20} {39}} every 4 to 6 hours during the first 24 to 48 hours following ingestion ^{87}.

Monitoring—Taking an electrocardiogram (ECG) and monitoring cardiac function if there is any sign of abnormality ^{{01} {87}{100}{101}}. Monitoring vital signs ^{{01} {87}{101}}.

Supportive care—Establishing and monitoring airway ^{{01} {87}{100}{101}}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Note: Due to the large volume of distribution of paroxetine ^{42}, forced diuresis ^{{01} {87}{100}{101}}, hemodialysis ^{{01} {42} {87}{100}{101}}, hemoperfusion ^{{01} {87}{100}{101}}, or exchange transfusions ^{{01} {87}{100}{101}} are not likely to be of benefit.
If a tricyclic antidepressant has been coingested, the tricyclic toxicity may be prolonged due to inhibition of metabolism by paroxetine ^{01}{101}.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Paroxetine (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to paroxetine

Pregnancy—No difference in birth outcome was found between 267 SSRI-exposed pregnancies (97 to paroxetine) and 267 pregnancies exposed to known nonteratogenic medications or procedures; behavioral effects were not studied





Breast-feeding—Distributed into breast milk



Contraindicated medications
Monoamine oxidase (MAO) inhibitors
Other medications, especially astemizole, moclobemide, serotonergics or other medications or substances with serotonergic activity, tricyclic antidepressants, and warfarin
Other medical problems, especially severe hepatic or renal function impairment

Proper use of this medication
» Compliance with therapy; not taking more or less medicine than prescribed

Taking with or without food, on a full or empty stomach, as directed by physician

» Four or more weeks of therapy may be required before antidepressant effects are achieved; antiobsessional and antipanic effects may require several weeks to achieve

For patients taking oral suspension dosage form—Shaking well before measuring dose; measuring dose with a calibrated measuring device

For patients taking extended-release tablet dosage form—Swallowing tablet whole; not chewing or crushing

» Proper dosing
Taking as soon as possible ^{87}; continuing on regular schedule with next dose ^{87}; not doubling doses

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress of therapy

Checking with physician before discontinuing medication; gradual dosage reduction may be recommended ^{87}

» Not taking paroxetine within 2 weeks of taking a monoamine oxidase (MAO) inhibitor; not starting an MAO inhibitor within 2 weeks of discontinuing paroxetine

Avoiding use of alcoholic beverages

» Possible blurred vision, drowsiness, impairment of judgment, thinking, or motor skills; caution when driving or doing jobs requiring alertness until effects of medication are known


Side/adverse effects
Possibility of discontinuation symptoms

Signs of potential side effects, especially agitation; myalgia, myasthenia, or myopathy; palpitation; skin rash; abnormal bleeding; extrapyramidal symptoms; hyponatremia; mania or hypomania; serotonin syndrome


General Dosing Information
Paroxetine may be administered once daily ^{{03} {43} {62}}, usually in the morning ^{{03} {43} {55} {62}}, to diminish sleep disturbances and other adverse effects ^{03}.

Potentially suicidal patients, particularly those who may use alcohol excessively, should not have access to large quantities of this medication ^{{01} {87}}. Some clinicians recommend that the patient have immediate access to the smallest total amount of medication necessary for satisfactory patient management ^{{01} {07} {87}}.

Abrupt discontinuation of paroxetine may result in discontinuation symptoms ^{81}. It is not known whether tapering the dose will prevent or reduce discontinuation symptoms ^{87}.

Diet/Nutrition
Paroxetine may be taken with or without food ^{{03} {20} {28} {42} {43}{100}{101}}. Some clinicians advise their patients to take this medication with food to lessen gastrointestinal side effects ^{{03} {05} {06}}.

For treatment of adverse effects
Serotonin syndrome—Serotonergic medications should be discontinued ^{84}. Treatment is essentially symptomatic and supportive ^{84}. The nonspecific serotonergic receptor antagonists cyproheptadine and methysergide have been reported to be of some use in shortening the duration of the syndrome ^{84}.


Oral Dosage Forms

PAROXETINE HYDROCHLORIDE ORAL SUSPENSION

Note: The dosing and strength of the available dosage forms are expressed in terms of paroxetine base (not the hydrochloride salt) ^{01}.


Usual adult dose
Antianxiety or
Antidepressant or
Antiobsessional agent
Oral, initially 20 mg (base) once a day, usually in the morning ^{{01} {43} {87}}. The dosage may be increased, as needed and tolerated, by 10 mg a day ^{{01} {43} {87}} at intervals of at least seven days ^{{01} {87}}.

Antipanic agent
Oral, initially 10 mg (base) once a day, usually in the morning ^{{01} {87}}. The dosage may be increased, as needed and tolerated, by 10 mg a day ^{{87} {92}} at intervals of at least seven days ^{{01} {87}}.


Note: For most patients, 20 mg a day is the optimal dosage for treatment of depression ^{{11} {43} {62}}. For treatment of obsessive-compulsive disorder and panic disorder, 40 mg a day is the recommended dosage ^{{01} {87}}.
For all indications, debilitated patients and patients with severe renal or hepatic function impairment should receive an initial dosage of 10 mg (base) a day, with upward titration as needed, up to a maximum of 40 mg a day ^{{01} {08} {64}}. Longer intervals should be allowed between dosage increases in patients with renal or hepatic function impairment ^{01}.


Usual adult prescribing limits
Antidepressant
50 mg (base) per day ^{{01} {43} {62} {87}}.

Antianxiety agent or
Antiobsessional agent or
Antipanic agent
60 mg (base) per day ^{{01} {87}}.


Usual pediatric dose
Safety and efficacy have not been established ^{{01} {87}}.

Usual geriatric dose
Antianxiety or
Antidepressant or
Antiobsessional agent or
Antipanic agent
Oral, initially 10 mg (base) once a day ^{{01} {08} {64} {85}}, usually in the morning ^{87}. The dosage may be increased as needed and tolerated ^{{01} {92}}.


Usual geriatric prescribing limits
Antianxiety or
Antidepressant or
Antiobsessional agent or
Antipanic agent
40 mg (base) a day ^{{01} {03} {62} {64} {87}}.


Strength(s) usually available
U.S.—


10 mg (base) per 5 mL (Rx) [Paxil (citric acid anhydrate ) (FD&C Yellow No. 6) ( flavorings) (glycerin) ( methylparaben) (microcrystalline cellulose) (polacrilin potassium) (propylparaben ) (propylene glycol) ( Simethicone Emulsion USP) (sodium citrate dihydrate ) (sodium saccharin) ( sorbitol)]^{01}

Canada—
Not commercially available.

Packaging and storage:
Store at or below 25 °C (77 °F) ^{01}, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Shake well before using.

Additional information:
Paroxetine hydrochloride oral suspension is orange flavored ^{01}.


PAROXETINE HYDROCHLORIDE TABLETS

Note: The dosing and strength of the available dosage forms are expressed in terms of paroxetine base (not the hydrochloride salt) ^{{01} {87}}.


Usual adult dose
See Paroxetine Hydrochloride Oral Suspension

Usual adult prescribing limits
See Paroxetine Hydrochloride Oral Suspension

Usual pediatric dose
See Paroxetine Hydrochloride Oral Suspension

Usual geriatric dose
See Paroxetine Hydrochloride Oral Suspension

Usual geriatric prescribing limits
See Paroxetine Hydrochloride Oral Suspension

Strength(s) usually available
U.S.—


10 mg (base) (Rx) [Paxil (dibasic calcium phosphate dihydrate ) (hydroxypropyl methylcellulose) (magnesium stearate) (polyethylene glycols) (polysorbate 80) ( sodium starch glycolate) (titanium dioxide) (D&C Red No. 30) ( and/or D&C Yellow No. 10) ( and/or FD&C Blue No. 2) ( and/or FD&C Yellow No. 6)]^{01}


20 mg (base) (Rx) [Paxil (scored) ( dibasic calcium phosphate dihydrate) (hydroxypropyl methylcellulose) (magnesium stearate) (polyethylene glycols) (polysorbate 80) (sodium starch glycolate) ( titanium dioxide) (D&C Red No. 30) ( and/or D&C Yellow No. 10) ( and/or FD&C Blue No. 2) ( and/or FD&C Yellow No. 6)]^{01}


30 mg (base) (Rx) [Paxil (dibasic calcium phosphate dihydrate ) (hydroxypropyl methylcellulose) (magnesium stearate) (polyethylene glycols) (polysorbate 80) ( sodium starch glycolate) (titanium dioxide) (D&C Red No. 30) ( and/or D&C Yellow No. 10) ( and/or FD&C Blue No. 2) ( and/or FD&C Yellow No. 6)]^{01}


40 mg (base) (Rx) [Paxil (dibasic calcium phosphate dihydrate ) (hydroxypropyl methylcellulose) (magnesium stearate) (polyethylene glycols) (polysorbate 80) ( sodium starch glycolate) (titanium dioxide) (D&C Red No. 30) ( and/or D&C Yellow No. 10) ( and/or FD&C Blue No. 2) ( and/or FD&C Yellow No. 6)]^{01}

Canada—


10 mg (base) (Rx) [Paxil (scored) ( dibasic calcium phosphate dihydrate USP) (sodium starch glycolate NF) (hydroxypropyl methylcellulose USP) (magnesium stearate NF) ( opadry yellow) (opadry clear)^{27}]


20 mg (base) (Rx) [Paxil (scored) ( dibasic calcium phosphate dihydrate USP) (sodium starch glycolate NF) (hydroxypropyl methylcellulose USP) (magnesium stearate NF) ( opadry pink) (opadry clear)^{87}]


30 mg (base) (Rx) [Paxil (dibasic calcium phosphate dihydrate USP) (sodium starch glycolate NF) (hydroxypropyl methylcellulose USP) ( magnesium stearate NF) (opadry blue) (opadry clear)^{87}]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F) ^{{01} {87}}, unless otherwise specified by manufacturer.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.


PAROXETINE HYDROCHLORIDE EXTENDED-RELEASE TABLETS

Usual adult dose
Antidepressant
Oral, initially 25 milligrams (mg) once a day, usually in the morning. The dosage may be increased, as needed and tolerated, by 12.5 mg a day at intervals of at least seven days.^{101}


Note: Debilitated patients and patients with severe renal or hepatic function impairment should receive an initial dosage of 12.5 mg a day, with upward titration as needed, to a maximum of 50 mg a day^{101}.


Usual adult prescribing limits
Antidepressant
62.5 milligrams a day^{101}.


Usual pediatric dose
Safety and efficacy have not been established^{101}.

Usual geriatric dose
See Usual adult dose.

Usual geriatric prescribing limits
Antidepressant
50 milligrams a day ^{101}.


Strength(s) usually available
U.S.—


12.5 milligrams (Rx) [Paxil CR (hydroxypropyl methylcellulose ) ( polyvinylpyrrolidone) ( lactose monohydrate) (magnesium stearate) (colloidal silicon dioxide) (glyceryl behenate) (methacrylic acid copolymer type C) (sodium lauryl sulfate) (polysorbate 80) (talc) (triethyl citrate ) (yellow ferric oxide and/or red ferric oxide)]


25 milligrams (Rx) [Paxil CR (hydroxypropyl methylcellulose ) ( polyvinylpyrrolidone) ( lactose monohydrate) (magnesium stearate) (colloidal silicon dioxide) (glyceryl behenate) (methacrylic acid copolymer type C) (sodium lauryl sulfate) (polysorbate 80) (talc) (triethyl citrate ) ( yellow ferric oxide and/or red ferric oxide )]

Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F)^{101}.

Auxiliary labeling:
   • Avoid alcoholic beverages.
   • May cause drowsiness.
   • Swallow whole. Do not crush or chew the tablets.

Developed: 11/02/1999
Revised: 08/22/2001

References

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2. Personal communication, SmithKline Beecham—US, 1/20/93.
   

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37. Kuhs H, Rudolf GAE. A double-blind study of the comparative antidepressant effect of paroxetine and amitriptyline. Acta Psychiatr Scand 1989; 80 Suppl 350: 145-6.
    

38. Tasker TCG, Kaye CM, Zussman BD, et al. Paroxetine plasma levels: lack of correlation with efficacy or adverse events. Acta Psychiatr Scand 1989; 80 Suppl 350: 152-5.
    

39. Greb WH, Buscher G, Dierdorf H-D, et al. Ability of charcoal to prevent absorption of paroxetine. Acta Psychiatr Scand 1989; 80 Suppl 350: 156-7.
    

40. Boyer WF, Feighner JP. An overview of paroxetine. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 3-6.
    

41. Tulloch IF, Johnson AM. The pharmacologic profile of paroxetine, a new selective serotonin reuptake inhibitor. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 7-12.
    

42. DeVane CL. Pharmacokinetics of the selective serotonin reuptake inhibitors. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 13-20.
    

43. Dunner DL, Dunbar GC. Optimal dose regimen for paroxetine. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 21-6.
    

44. Kiev A. A double-blind, placebo-controlled study of paroxetine in depressed outpatients. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 27-9.
    

45. Rickels K, Amsterdam J, Clary C, et al. The efficacy and safety of paroxetine compared with placebo in outpatients with major depression. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 30-2.
    

46. Claghorn J. The safety and efficacy of paroxetine compared with placebo in a double-blind trial of depressed outpatients. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 33-5.
    

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48. Fabre LF. A 6-week, double-blind trial of paroxetine, imipramine, and placebo in depressed outpatients. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 40-3.
    

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50. Shrivastava RK, Patel Shrivastava SH, Overweg N, et al. A double-blind comparison of paroxetine, imipramine, and placebo in major depression. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 48-51.
    

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52. Dunner DL, Cohn JB, Walshe III, T, et al. Two combined, multicenter double-blind studies of paroxetine and doxepin in geriatric patients with major depression. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 57-60.
    

53. Boyer WF, Blumhardt CL. The safety profile of paroxetine. J Clin Psychiatry 1992 Feb; 53(2 Suppl): 61-6.
    

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62. Jenner PN. Paroxetine: an overview of dosage, tolerability, and safety. Int Clin Psychopharmacol 1992 Jun; 6 Suppl 4: 69-80.
    

63. Panel comment, 3/31/97.
    

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73. Lisi DM. Comment: paroxetine-associated hyponatremia. Ann Pharmacother 1993 Dec; 27: 1547-8.
    

74. Panel comment, 4/14/97.
    

75. Kuhs H, Schlake H-P, Rolf LH, et al. Relationship between parameters of serotonin transport and antidepressant plasma levels or therapeutic response in depressive patients treated with paroxetine and amitriptyline. Acta Psychiatr Scand 1992; 85: 364-9.
    

76. Ohrberg S, Christiansen PE, Severin B, et al. Paroxetine and imipramine in the treatment of depressive patients in psychiatric practice. Acta Psychiatr Scand 1992; 86: 437-44.
    

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85. Reviewers" consensus on monograph revision of 06/94.
    

86. Reviewers" consensus on Sertraline monograph revision of 7/98.
    

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88. Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1996. p. 538.
    

89. Ottervanger JP, Stricker BHCh, Huls J, et al. Bleeding attributed to the intake of paroxetine [letter]. Am J Psychiatry 1994 May; 151(5): 781-2.
    

90. Spigset O, Carleborg L, Norström Å, et al. Paroxetine level in breast milk [letter]. J Clin Psychiatry 1996 Jan; 57(1): 39.
    

91. Psychiatric Disease Advisory Panel Meeting, 11/7/94.
    

92. Personal communication, SmithKline Beecham—US, 1/16/97.
    

93. von Moltke LL, Greenblatt DJ, Court MH, et al. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995 Apr; 15(2): 125-31.
    

94. Brøsen K, Hansen JG, Nielsen KK, et al. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur J Clin Pharmacol 1993; 44: 349-55.
    

95. Leinonen E, Koponen HJ, Lepola U. Paroxetine increases serum trimipramine concentration: a report of two cases. Hum Psychopharmacol Clin Exp 1995 Jul-Aug; 10: 345-7.
    

96. Albers LJ, Reist C, Helmeste D, et al. Paroxetine shifts imipramine metabolism. Psychiatry Res 1996; 59: 189-96.
    

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