|ccpharma.gifMarch/April 1999In This IssueParoxetin (Paxil®): A Brief Review
                  *
                  Did You Know...*
                  Formulary Update
                  
                  Drug
                  Information Service
                  Pharmacy Department
                  Warren G. Magnuson Clinical Center
                  National Institutes of Health
                  Bethesda, Maryland 20892-1196
                  Charles E. Daniels, Ph.D.
                  Chief, Pharmacy DepartmentEditor-in-Chief
                  Karim Anton Calis, Pharm.D., M.P.H.
                  Coordinator, Drug Information Service, and
                  Endocrinology Clinical Pharmacy Specialist[email protected]Associate
                  EditorMaryam R.
                  Mohassel, Pharm.D.
                  Specialized Resident in Drug Information Practice
                  and Pharmacotherapy[email protected]
                  
                  Archives
               Paroxetine (Paxil®): A Brief Review
                  
                  Paroxetine hydrochloride is a phenylpiperidine antidepressant structurally unrelated 
to other available antidepressants, including other selective serotonin reuptake 
inhibitors (SSRIs). It was approved for use in the United States in 1992. SSRIs have surpassed tricyclic antidepressants (TCAs) 
as first-line therapy for the treatment of major 
depression. Numerous clinical trials in patients with depression have shown the SSRIs to be equivalent 
to TCAs in efficacy, but superior in tolerability and safety.IndicationsParoxetine is indicated for the treatment of depression, obsessive-compulsive disorder, 
and panic disorder.PharmacologyThe mechanism of action of paroxetine is serotonin (5HT) reuptake 
blockade via inhibition of the serotonin reuptake transporter. Blockade of this transporter initially leads 
to increased concentrations of 5HT in the synaptic cleft. In response to increased 5HT, 
5HT1A autoreceptors act to decrease serotonin neurotransmission (auto-feedback 
mechanism). Chronic 5HT transporter blockade, unlike acute blockade, leads to downregulation 
(desensitization) of 5HT1A and 
5HT1B/1D autoreceptors which results in enhanced 5HT 
neurotrans
mission. 5HT autoreceptor downregulation is thought to confer the antidepressant effects of 
the SSRIs evident with chronic dosing. Paroxetine's inhibitory effects on the reuptake of 
norepinephrine and dopamine are minimal. Of the available SSRIs, paroxetine is the 
most potent inhibitor of 5HT reuptake. Paroxetine is more selective for serotonin (vs. norepineph
rine) reuptake inhibition compared to fluvoxamine, sertraline, and fluoxetine. In 
contrast, citalopram has greater serotonin selectivity compared to paroxetine. The extent to which 
these differences in 5HT selectivity offer advantages in regards to efficacy remains to 
be determined. Paroxetine has negligible affinity for adrenergic, dopamine 
D2, histamine H1, 
and 5HT2 receptors and weak affinity for muscarinic cholinergic receptors.PharmacokineticsParoxetine is well absorbed from the gastrointestinal tract after oral administration. 
It undergoes extensive first-pass metabolism (partially saturable), estimated to be approximately 50 percent. Due to its highly lipophilic properties, paroxetine distributes widely 
in tissues including the central nervous system, with only one percent of the drug remaining in 
the systemic circulation. Paroxetine distributes into breast milk, with concentrations similar 
to those found in plasma. Advanced age and severe renal or hepatic impairment have 
been associated with increased paroxetine half-life and serum concentrations. Paroxetine is extensively metabolized in the liver by oxidation and methylation. Its glucuronide and 
sulfate metabolites are not pharmacologically active. Paroxetine is also partially metabolized by 
the cytochrome P450 (CYP) CYP2D6 isoenzyme. Saturation of this enzymatic pathway 
appears to account for the non-linearity of paroxetine's pharmacokinetics at high doses. 
Table 1 summarizes pharmacokinetic parameters (mean data only) of paroxetine com
pared to the other SSRIs.Selected Clinical StudiesIn general, paroxetine has shown superior efficacy compared to placebo and equal 
efficacy to TCAs and other SSRIs in the treatment of depression. Trials comparing paroxetine and TCAs have found similar efficacy (50 to 70 percent response) but better tolerability
with paroxetine.The rating scales widely used in depression clinical 
trials include the Hamilton Depression Rating Scale (HDRS) 
and the Montgomery Åsberg Depression Rating Scale 
(MADRS). Although rating scale endpoint scores can be compared 
to baseline scores to evaluate efficacy, a categorical 
response criterion of  50 percent decrease in rating scale score at 
end point is generally considered to reflect a clinically 
meaningful decrease in depressive symptoms. See Table 2 for a 
summary of treatment trials.Adverse EffectsCommon adverse effects associated with the use 
of paroxetine include headache, nervousness, tremors, 
insomnia, drowsiness, fatigue, nausea, and sexual dysfunction. 
Paroxetine has been associated with significantly more 
sedation compared to other SSRIs. To minimize daytime sedation, paroxetine 
is typically administered at bedtime.
One 12-week study evaluated paroxetine 20 
mg/day, fluoxetine 20 mg/day, and placebo in depressed 
outpatients. Among all adverse events evaluated, the only side 
effect which differed significantly between the SSRIs was 
sexual dysfunction. Twenty-five percent of 
paroxetine-treated patients, versus seven percent of fluoxetine-treated 
patients, reported this side effect.Sexual dysfunction, which includes loss of libido, 
inorgasmia, ejaculatory delay, and erectile dysfunction is 
a common side effect of SSRIs. Early clinical trials 
underestimated the incidence of sexual adverse 
effects because they relied on spontaneous reporting by trial participants. 
One descriptive study evaluating sexual dysfunction among 
344 patients receiving SSRIs found little difference in 
the incidence of sexual dysfunction for patients 
receiving paroxetine, fluvoxamine, fluoxetine, or sertraline.A discontinuation syndrome has also been described following 
cessation (usually abrupt) of SSRI therapy. The syndrome is characterized 
by dizziness or light-headedness, nausea, vomiting, headaches, 
lethargy, anxiety and/or agitation, 
tingling/numbness/"electric" shock-like sensations, trem
ors, sweating, insomnia, irritability, 
or diarrhea. These symptoms usually appear within 1 to 10 days of stopping 
the SSRI. For fluoxetine, the syndrome appears from 5 to 42 
days after discontinuation of the drug. 
One open-label SSRI discontinuation trial reported higher rates of 
adverse events after abrupt discontinuation 
of paroxetine and sertraline compared to fluoxetine. However, the discontinuation period was of 
short duration (5 to 8 days), thereby favoring the fluoxetine treatment group.Drug InteractionsConcomitant use of SSRI 
with monoamine oxidase inhibitors (MAOIs) may result in serotonin syndrome. 
SSRIs differ in their ability to inhibit various cytochrome P450 isoenzymes. Table 
3 lists the relative potencies with which the SSRIs inhibit specific CYP isoenzymes. 
Selected examples of substrates for these isoenzymes include 
theophylline and caffeine (CYP1A2); phenytoin and warfarin (CYP2C); TCAs 
and antipsychotics (CYP2D6); and cisapride, astemizole, 
and triazolobenzodiazepines (CYP3A4).
The mechanism for drug interactions involving 
SSRIs and warfarin is complicated. Alterations in 
the concentration of the inactive warfarin enantiomer 
can ultimately affect the active enantiomer. SSRIs most 
commonly associated with potential drug interactions 
with warfarin include fluoxetine, fluvoxamine, and 
paroxetine. One study evaluating a paroxetine-warfarin 
interaction found no significant increase in prothrombin time, but 
an increase in clinically significant bleeding was noted 
in 5 of 27 subjects when paroxetine 30 mg/day was added 
to warfarin 5 mg/day therapy. The exact mechanism of 
this interaction is unknown.PrecautionsDue to the wide safety index of the SSRIs, few 
serious adverse events have been reported with increased doses 
or plasma concentrations. Paroxetine's elimination
half-life appears to be prolonged in the geriatric population. 
For patients exhibiting renal (creatinine clearance <30 
mL/min) and/or hepatic dysfunction, paroxetine should be initiated 
at the lower dose of 10 mg/day and titrated to a maximum of 40 mg/day.ContraindicationsConcomitant use of paroxetine in patients taking MAOIs 
or other SSRIs  is contraindicated. These combinations 
can result in a serious, sometimes fatal, serotonin syndrome. 
This syndrome is characterized by hyperthermia, 
rigidity, myoclonus, and autonomic instability with possible fluctuations of vital signs and mental status changes. 
Paroxetine should not be used within 14 days of discontinuing an 
MAOI. Similarly, it is recommended that MAOI therapy 
not be initiated until 14 days have elapsed following paroxetine discontinuation.Dosage and AdministrationParoxetine is administered as a single daily dose, initi
ated at 20 mg/day. Although the package insert specifies 
drug administration in the morning, patients 
experiencing sedation may opt for nighttime administration. For patients 
not showing an adequate therapeutic response within 2 to 
3 weeks of paroxetine initiation, the dose may be increased in 
10 mg increments at weekly intervals. The usual dose range 
in the treatment of depression is 20 to 50 mg/day.  For 
elderly patients and those with renal and/or hepatic dys
function, doses are initiated at 10 mg/day and titrated to 
a maximum of 40 mg/day.ConclusionParoxetine is a selective and specific serotonin reup
take inhibitor with demonstrated efficacy and tolerability 
in the acute treatment of depressed patients. It is as effective 
as TCAs and other SSRIs in the acute treatment of depression. Paroxetine exhibits a favorable pharmacokinetic 
profile, including a relatively short half-life (compared 
to fluoxetine) and lack of active metabolites. The adverse event profile 
of paroxetine is similar to that of other antidepressants in 
this class, but paroxetine may be associated with more sedation. 
As with other SSRIs, a discontinuation syndrome is possible 
with abrupt cessation. When discontinuing paroxetine, 
tapering of the dose is suggested. Paroxetine potently 
inhibits CYP2D6, but it shows little clinically relevant 
inhibition of other cytochrome P450 isoenzymes. 
References available upon request.Up to TopDid You Know ...
vAn estradiol transdermal patch (Climara®) 
was recently approved for the prevention of 
postmenopausal osteoporosis. This is the only 
once-a-week transdermal estrogen product 
approved for osteoporosis prevention.vThe FDA recently approved alitretinoin 0.1% 
(Panretin®) for the topical treatment of cutaneous 
lesions in patients with AIDS-related Kaposi's 
sarcoma. This is the first topical agent approved 
for this condition.vCilastazol (Pletal®) has been approved for reduc
tion of symptoms associated with intermittent 
claudication. The dose of cilastazol may need to 
be decreased in patients receiving concomitant 
treatment with agents known to inhibit the cyto
chrome P450 3A4 isozyme (e.g., azole antifungals 
or certain macrolide antibiotics).vTelmisartan (Micardis®), a new angiotensin II 
receptor inhibitor, was recently approved for the treatment of hypertension.vLovastatin (Mevacor®) was approved for the 
primary prevention of coronary heart disease 
in patients diagnosed with hypercholesterolemia.Formulary Update:
The Pharmacy and Therapeutic Committee 
recently approved the following formulary actions:Additions:
vThyrotropin alfa (Thyrogen®), a highly 
purified recombinant form of human thyroid stimulating hormone 
(TSH) for use as an adjunctive diagnostic tool for serum thyroglobulin testing with or without radioiodine imaging.vParoxetine (Paxil®), a selective 
serotonin-reuptake inhibitor indicated for the treatment of 
depression, obsessive-compulsive disorder, and panic disorder.vOctreotide acetate (Sandostatin LAR® Depot), a 
long-acting octreotide formulation administered 
once monthly by intramuscular injection. It is indicated
for the treatment of acromegaly, and diarrhea and flushing associated with metastatic carcinoid tumors 
or vasoactive intestinal peptide tumors.vRopivacaine (Naropin®), a long-acting amide 
local anesthetic indicated for local or regional anesthesia 
for surgery, postoperative-pain management, and obstetrical procedures.vAbacavir (Ziagen®), a nucleoside reverse 
transcriptase inhibitor of HIV-1 for use in combination with 
other antiretroviral agents in the treatment of HIV infection.vTrastuzumab (Herceptin®), a recombinant 
humanized monoclonal antibody (rhuMab) indicated for 
the treatment of metastatic breast cancer in patients 
who present with an overexpression of the human 
epidermal growth factor receptor-2, c-erbB2.vBotulinum toxin type A (Botox®), a lyophilized form 
of purified botulinum toxin indicated for the treatment 
of strabismus and blepharospasm.vAbciximab (ReoPro®), a Fab fragment of the 
chimeric human murine monoclonal antibody 7E3 used as 
an adjunct to percutaneous transluminal coronary angioplasty for the 
prevention of acute cardiovascular ischemic complications.Up to TopDesigned by Richard Barnes, NCRR, MAPB.Comments or questions concerning this site? ContactPharmacy
         WebmasterNational Institutes of Health (NIH) , Warren Grant Magnuson
         Clinical Center (CC)
         Pharmacy Department, Bethesda, Maryland 20892
         Last updated: February 6, 1998NIH
         Home Page|Clinical
         Center Home Page|Pharmacy
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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                  | March/April 1999 | In This IssueParoxetin (Paxil®): A Brief Review
                  *
                  Did You Know...*
                  Formulary Update
                  
                  Drug
                  Information Service
                  Pharmacy Department
                  Warren G. Magnuson Clinical Center
                  National Institutes of Health
                  Bethesda, Maryland 20892-1196
                  Charles E. Daniels, Ph.D.
                  Chief, Pharmacy DepartmentEditor-in-Chief
                  Karim Anton Calis, Pharm.D., M.P.H.
                  Coordinator, Drug Information Service, and
                  Endocrinology Clinical Pharmacy Specialist[email protected]Associate
                  EditorMaryam R.
                  Mohassel, Pharm.D.
                  Specialized Resident in Drug Information Practice
                  and Pharmacotherapy[email protected]
                  
                  Archives | Paroxetine (Paxil®): A Brief Review
                  
                  Paroxetine hydrochloride is a phenylpiperidine antidepressant structurally unrelated 
to other available antidepressants, including other selective serotonin reuptake 
inhibitors (SSRIs). It was approved for use in the United States in 1992. SSRIs have surpassed tricyclic antidepressants (TCAs) 
as first-line therapy for the treatment of major 
depression. Numerous clinical trials in patients with depression have shown the SSRIs to be equivalent 
to TCAs in efficacy, but superior in tolerability and safety.IndicationsParoxetine is indicated for the treatment of depression, obsessive-compulsive disorder, 
and panic disorder.PharmacologyThe mechanism of action of paroxetine is serotonin (5HT) reuptake 
blockade via inhibition of the serotonin reuptake transporter. Blockade of this transporter initially leads 
to increased concentrations of 5HT in the synaptic cleft. In response to increased 5HT, 
5HT1A autoreceptors act to decrease serotonin neurotransmission (auto-feedback 
mechanism). Chronic 5HT transporter blockade, unlike acute blockade, leads to downregulation 
(desensitization) of 5HT1A and 
5HT1B/1D autoreceptors which results in enhanced 5HT 
neurotrans
mission. 5HT autoreceptor downregulation is thought to confer the antidepressant effects of 
the SSRIs evident with chronic dosing. Paroxetine's inhibitory effects on the reuptake of 
norepinephrine and dopamine are minimal. Of the available SSRIs, paroxetine is the 
most potent inhibitor of 5HT reuptake. Paroxetine is more selective for serotonin (vs. norepineph
rine) reuptake inhibition compared to fluvoxamine, sertraline, and fluoxetine. In 
contrast, citalopram has greater serotonin selectivity compared to paroxetine. The extent to which 
these differences in 5HT selectivity offer advantages in regards to efficacy remains to 
be determined. Paroxetine has negligible affinity for adrenergic, dopamine 
D2, histamine H1, 
and 5HT2 receptors and weak affinity for muscarinic cholinergic receptors.PharmacokineticsParoxetine is well absorbed from the gastrointestinal tract after oral administration. 
It undergoes extensive first-pass metabolism (partially saturable), estimated to be approximately 50 percent. Due to its highly lipophilic properties, paroxetine distributes widely 
in tissues including the central nervous system, with only one percent of the drug remaining in 
the systemic circulation. Paroxetine distributes into breast milk, with concentrations similar 
to those found in plasma. Advanced age and severe renal or hepatic impairment have 
been associated with increased paroxetine half-life and serum concentrations. Paroxetine is extensively metabolized in the liver by oxidation and methylation. Its glucuronide and 
sulfate metabolites are not pharmacologically active. Paroxetine is also partially metabolized by 
the cytochrome P450 (CYP) CYP2D6 isoenzyme. Saturation of this enzymatic pathway 
appears to account for the non-linearity of paroxetine's pharmacokinetics at high doses. 
Table 1 summarizes pharmacokinetic parameters (mean data only) of paroxetine com
pared to the other SSRIs.Selected Clinical StudiesIn general, paroxetine has shown superior efficacy compared to placebo and equal 
efficacy to TCAs and other SSRIs in the treatment of depression. Trials comparing paroxetine and TCAs have found similar efficacy (50 to 70 percent response) but better tolerability
with paroxetine.The rating scales widely used in depression clinical 
trials include the Hamilton Depression Rating Scale (HDRS) 
and the Montgomery Åsberg Depression Rating Scale 
(MADRS). Although rating scale endpoint scores can be compared 
to baseline scores to evaluate efficacy, a categorical 
response criterion of  50 percent decrease in rating scale score at 
end point is generally considered to reflect a clinically 
meaningful decrease in depressive symptoms. See Table 2 for a 
summary of treatment trials.Adverse EffectsCommon adverse effects associated with the use 
of paroxetine include headache, nervousness, tremors, 
insomnia, drowsiness, fatigue, nausea, and sexual dysfunction. 
Paroxetine has been associated with significantly more 
sedation compared to other SSRIs. To minimize daytime sedation, paroxetine 
is typically administered at bedtime.
One 12-week study evaluated paroxetine 20 
mg/day, fluoxetine 20 mg/day, and placebo in depressed 
outpatients. Among all adverse events evaluated, the only side 
effect which differed significantly between the SSRIs was 
sexual dysfunction. Twenty-five percent of 
paroxetine-treated patients, versus seven percent of fluoxetine-treated 
patients, reported this side effect.Sexual dysfunction, which includes loss of libido, 
inorgasmia, ejaculatory delay, and erectile dysfunction is 
a common side effect of SSRIs. Early clinical trials 
underestimated the incidence of sexual adverse 
effects because they relied on spontaneous reporting by trial participants. 
One descriptive study evaluating sexual dysfunction among 
344 patients receiving SSRIs found little difference in 
the incidence of sexual dysfunction for patients 
receiving paroxetine, fluvoxamine, fluoxetine, or sertraline.A discontinuation syndrome has also been described following 
cessation (usually abrupt) of SSRI therapy. The syndrome is characterized 
by dizziness or light-headedness, nausea, vomiting, headaches, 
lethargy, anxiety and/or agitation, 
tingling/numbness/"electric" shock-like sensations, trem
ors, sweating, insomnia, irritability, 
or diarrhea. These symptoms usually appear within 1 to 10 days of stopping 
the SSRI. For fluoxetine, the syndrome appears from 5 to 42 
days after discontinuation of the drug. 
One open-label SSRI discontinuation trial reported higher rates of 
adverse events after abrupt discontinuation 
of paroxetine and sertraline compared to fluoxetine. However, the discontinuation period was of 
short duration (5 to 8 days), thereby favoring the fluoxetine treatment group.Drug InteractionsConcomitant use of SSRI 
with monoamine oxidase inhibitors (MAOIs) may result in serotonin syndrome. 
SSRIs differ in their ability to inhibit various cytochrome P450 isoenzymes. Table 
3 lists the relative potencies with which the SSRIs inhibit specific CYP isoenzymes. 
Selected examples of substrates for these isoenzymes include 
theophylline and caffeine (CYP1A2); phenytoin and warfarin (CYP2C); TCAs 
and antipsychotics (CYP2D6); and cisapride, astemizole, 
and triazolobenzodiazepines (CYP3A4).
The mechanism for drug interactions involving 
SSRIs and warfarin is complicated. Alterations in 
the concentration of the inactive warfarin enantiomer 
can ultimately affect the active enantiomer. SSRIs most 
commonly associated with potential drug interactions 
with warfarin include fluoxetine, fluvoxamine, and 
paroxetine. One study evaluating a paroxetine-warfarin 
interaction found no significant increase in prothrombin time, but 
an increase in clinically significant bleeding was noted 
in 5 of 27 subjects when paroxetine 30 mg/day was added 
to warfarin 5 mg/day therapy. The exact mechanism of 
this interaction is unknown.PrecautionsDue to the wide safety index of the SSRIs, few 
serious adverse events have been reported with increased doses 
or plasma concentrations. Paroxetine's elimination
half-life appears to be prolonged in the geriatric population. 
For patients exhibiting renal (creatinine clearance <30 
mL/min) and/or hepatic dysfunction, paroxetine should be initiated 
at the lower dose of 10 mg/day and titrated to a maximum of 40 mg/day.ContraindicationsConcomitant use of paroxetine in patients taking MAOIs 
or other SSRIs  is contraindicated. These combinations 
can result in a serious, sometimes fatal, serotonin syndrome. 
This syndrome is characterized by hyperthermia, 
rigidity, myoclonus, and autonomic instability with possible fluctuations of vital signs and mental status changes. 
Paroxetine should not be used within 14 days of discontinuing an 
MAOI. Similarly, it is recommended that MAOI therapy 
not be initiated until 14 days have elapsed following paroxetine discontinuation.Dosage and AdministrationParoxetine is administered as a single daily dose, initi
ated at 20 mg/day. Although the package insert specifies 
drug administration in the morning, patients 
experiencing sedation may opt for nighttime administration. For patients 
not showing an adequate therapeutic response within 2 to 
3 weeks of paroxetine initiation, the dose may be increased in 
10 mg increments at weekly intervals. The usual dose range 
in the treatment of depression is 20 to 50 mg/day.  For 
elderly patients and those with renal and/or hepatic dys
function, doses are initiated at 10 mg/day and titrated to 
a maximum of 40 mg/day.ConclusionParoxetine is a selective and specific serotonin reup
take inhibitor with demonstrated efficacy and tolerability 
in the acute treatment of depressed patients. It is as effective 
as TCAs and other SSRIs in the acute treatment of depression. Paroxetine exhibits a favorable pharmacokinetic 
profile, including a relatively short half-life (compared 
to fluoxetine) and lack of active metabolites. The adverse event profile 
of paroxetine is similar to that of other antidepressants in 
this class, but paroxetine may be associated with more sedation. 
As with other SSRIs, a discontinuation syndrome is possible 
with abrupt cessation. When discontinuing paroxetine, 
tapering of the dose is suggested. Paroxetine potently 
inhibits CYP2D6, but it shows little clinically relevant 
inhibition of other cytochrome P450 isoenzymes. 
References available upon request. |  | Up to Top |  |  | Did You Know ...
vAn estradiol transdermal patch (Climara®) 
was recently approved for the prevention of 
postmenopausal osteoporosis. This is the only 
once-a-week transdermal estrogen product 
approved for osteoporosis prevention.vThe FDA recently approved alitretinoin 0.1% 
(Panretin®) for the topical treatment of cutaneous 
lesions in patients with AIDS-related Kaposi's 
sarcoma. This is the first topical agent approved 
for this condition.vCilastazol (Pletal®) has been approved for reduc
tion of symptoms associated with intermittent 
claudication. The dose of cilastazol may need to 
be decreased in patients receiving concomitant 
treatment with agents known to inhibit the cyto
chrome P450 3A4 isozyme (e.g., azole antifungals 
or certain macrolide antibiotics).vTelmisartan (Micardis®), a new angiotensin II 
receptor inhibitor, was recently approved for the treatment of hypertension.vLovastatin (Mevacor®) was approved for the 
primary prevention of coronary heart disease 
in patients diagnosed with hypercholesterolemia.Formulary Update:
The Pharmacy and Therapeutic Committee 
recently approved the following formulary actions:Additions:
vThyrotropin alfa (Thyrogen®), a highly 
purified recombinant form of human thyroid stimulating hormone 
(TSH) for use as an adjunctive diagnostic tool for serum thyroglobulin testing with or without radioiodine imaging.vParoxetine (Paxil®), a selective 
serotonin-reuptake inhibitor indicated for the treatment of 
depression, obsessive-compulsive disorder, and panic disorder.vOctreotide acetate (Sandostatin LAR® Depot), a 
long-acting octreotide formulation administered 
once monthly by intramuscular injection. It is indicated
for the treatment of acromegaly, and diarrhea and flushing associated with metastatic carcinoid tumors 
or vasoactive intestinal peptide tumors.vRopivacaine (Naropin®), a long-acting amide 
local anesthetic indicated for local or regional anesthesia 
for surgery, postoperative-pain management, and obstetrical procedures.vAbacavir (Ziagen®), a nucleoside reverse 
transcriptase inhibitor of HIV-1 for use in combination with 
other antiretroviral agents in the treatment of HIV infection.vTrastuzumab (Herceptin®), a recombinant 
humanized monoclonal antibody (rhuMab) indicated for 
the treatment of metastatic breast cancer in patients 
who present with an overexpression of the human 
epidermal growth factor receptor-2, c-erbB2.vBotulinum toxin type A (Botox®), a lyophilized form 
of purified botulinum toxin indicated for the treatment 
of strabismus and blepharospasm.vAbciximab (ReoPro®), a Fab fragment of the 
chimeric human murine monoclonal antibody 7E3 used as 
an adjunct to percutaneous transluminal coronary angioplasty for the 
prevention of acute cardiovascular ischemic complications. |  |  |  |  | Up to Top | 
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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | March/April 1999
|In This IssueParoxetin (Paxil®): A Brief Review
                  *
                  Did You Know...*
                  Formulary Update
                  
                  Drug
                  Information Service
                  Pharmacy Department
                  Warren G. Magnuson Clinical Center
                  National Institutes of Health
                  Bethesda, Maryland 20892-1196
                  Charles E. Daniels, Ph.D.
                  Chief, Pharmacy DepartmentEditor-in-Chief
                  Karim Anton Calis, Pharm.D., M.P.H.
                  Coordinator, Drug Information Service, and
                  Endocrinology Clinical Pharmacy Specialist[email protected]Associate
                  EditorMaryam R.
                  Mohassel, Pharm.D.
                  Specialized Resident in Drug Information Practice
                  and Pharmacotherapy[email protected]
                  
                  Archives                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Paroxetine (Paxil®): A Brief Review
                  
                  Paroxetine hydrochloride is a phenylpiperidine antidepressant structurally unrelated 
to other available antidepressants, including other selective serotonin reuptake 
inhibitors (SSRIs). It was approved for use in the United States in 1992. SSRIs have surpassed tricyclic antidepressants (TCAs) 
as first-line therapy for the treatment of major 
depression. Numerous clinical trials in patients with depression have shown the SSRIs to be equivalent 
to TCAs in efficacy, but superior in tolerability and safety.IndicationsParoxetine is indicated for the treatment of depression, obsessive-compulsive disorder, 
and panic disorder.PharmacologyThe mechanism of action of paroxetine is serotonin (5HT) reuptake 
blockade via inhibition of the serotonin reuptake transporter. Blockade of this transporter initially leads 
to increased concentrations of 5HT in the synaptic cleft. In response to increased 5HT, 
5HT1A autoreceptors act to decrease serotonin neurotransmission (auto-feedback 
mechanism). Chronic 5HT transporter blockade, unlike acute blockade, leads to downregulation 
(desensitization) of 5HT1A and 
5HT1B/1D autoreceptors which results in enhanced 5HT 
neurotrans
mission. 5HT autoreceptor downregulation is thought to confer the antidepressant effects of 
the SSRIs evident with chronic dosing. Paroxetine's inhibitory effects on the reuptake of 
norepinephrine and dopamine are minimal. Of the available SSRIs, paroxetine is the 
most potent inhibitor of 5HT reuptake. Paroxetine is more selective for serotonin (vs. norepineph
rine) reuptake inhibition compared to fluvoxamine, sertraline, and fluoxetine. In 
contrast, citalopram has greater serotonin selectivity compared to paroxetine. The extent to which 
these differences in 5HT selectivity offer advantages in regards to efficacy remains to 
be determined. Paroxetine has negligible affinity for adrenergic, dopamine 
D2, histamine H1, 
and 5HT2 receptors and weak affinity for muscarinic cholinergic receptors.PharmacokineticsParoxetine is well absorbed from the gastrointestinal tract after oral administration. 
It undergoes extensive first-pass metabolism (partially saturable), estimated to be approximately 50 percent. Due to its highly lipophilic properties, paroxetine distributes widely 
in tissues including the central nervous system, with only one percent of the drug remaining in 
the systemic circulation. Paroxetine distributes into breast milk, with concentrations similar 
to those found in plasma. Advanced age and severe renal or hepatic impairment have 
been associated with increased paroxetine half-life and serum concentrations. Paroxetine is extensively metabolized in the liver by oxidation and methylation. Its glucuronide and 
sulfate metabolites are not pharmacologically active. Paroxetine is also partially metabolized by 
the cytochrome P450 (CYP) CYP2D6 isoenzyme. Saturation of this enzymatic pathway 
appears to account for the non-linearity of paroxetine's pharmacokinetics at high doses. 
Table 1 summarizes pharmacokinetic parameters (mean data only) of paroxetine com
pared to the other SSRIs.Selected Clinical StudiesIn general, paroxetine has shown superior efficacy compared to placebo and equal 
efficacy to TCAs and other SSRIs in the treatment of depression. Trials comparing paroxetine and TCAs have found similar efficacy (50 to 70 percent response) but better tolerability
with paroxetine.The rating scales widely used in depression clinical 
trials include the Hamilton Depression Rating Scale (HDRS) 
and the Montgomery Åsberg Depression Rating Scale 
(MADRS). Although rating scale endpoint scores can be compared 
to baseline scores to evaluate efficacy, a categorical 
response criterion of  50 percent decrease in rating scale score at 
end point is generally considered to reflect a clinically 
meaningful decrease in depressive symptoms. See Table 2 for a 
summary of treatment trials.Adverse EffectsCommon adverse effects associated with the use 
of paroxetine include headache, nervousness, tremors, 
insomnia, drowsiness, fatigue, nausea, and sexual dysfunction. 
Paroxetine has been associated with significantly more 
sedation compared to other SSRIs. To minimize daytime sedation, paroxetine 
is typically administered at bedtime.
One 12-week study evaluated paroxetine 20 
mg/day, fluoxetine 20 mg/day, and placebo in depressed 
outpatients. Among all adverse events evaluated, the only side 
effect which differed significantly between the SSRIs was 
sexual dysfunction. Twenty-five percent of 
paroxetine-treated patients, versus seven percent of fluoxetine-treated 
patients, reported this side effect.Sexual dysfunction, which includes loss of libido, 
inorgasmia, ejaculatory delay, and erectile dysfunction is 
a common side effect of SSRIs. Early clinical trials 
underestimated the incidence of sexual adverse 
effects because they relied on spontaneous reporting by trial participants. 
One descriptive study evaluating sexual dysfunction among 
344 patients receiving SSRIs found little difference in 
the incidence of sexual dysfunction for patients 
receiving paroxetine, fluvoxamine, fluoxetine, or sertraline.A discontinuation syndrome has also been described following 
cessation (usually abrupt) of SSRI therapy. The syndrome is characterized 
by dizziness or light-headedness, nausea, vomiting, headaches, 
lethargy, anxiety and/or agitation, 
tingling/numbness/"electric" shock-like sensations, trem
ors, sweating, insomnia, irritability, 
or diarrhea. These symptoms usually appear within 1 to 10 days of stopping 
the SSRI. For fluoxetine, the syndrome appears from 5 to 42 
days after discontinuation of the drug. 
One open-label SSRI discontinuation trial reported higher rates of 
adverse events after abrupt discontinuation 
of paroxetine and sertraline compared to fluoxetine. However, the discontinuation period was of 
short duration (5 to 8 days), thereby favoring the fluoxetine treatment group.Drug InteractionsConcomitant use of SSRI 
with monoamine oxidase inhibitors (MAOIs) may result in serotonin syndrome. 
SSRIs differ in their ability to inhibit various cytochrome P450 isoenzymes. Table 
3 lists the relative potencies with which the SSRIs inhibit specific CYP isoenzymes. 
Selected examples of substrates for these isoenzymes include 
theophylline and caffeine (CYP1A2); phenytoin and warfarin (CYP2C); TCAs 
and antipsychotics (CYP2D6); and cisapride, astemizole, 
and triazolobenzodiazepines (CYP3A4).
The mechanism for drug interactions involving 
SSRIs and warfarin is complicated. Alterations in 
the concentration of the inactive warfarin enantiomer 
can ultimately affect the active enantiomer. SSRIs most 
commonly associated with potential drug interactions 
with warfarin include fluoxetine, fluvoxamine, and 
paroxetine. One study evaluating a paroxetine-warfarin 
interaction found no significant increase in prothrombin time, but 
an increase in clinically significant bleeding was noted 
in 5 of 27 subjects when paroxetine 30 mg/day was added 
to warfarin 5 mg/day therapy. The exact mechanism of 
this interaction is unknown.PrecautionsDue to the wide safety index of the SSRIs, few 
serious adverse events have been reported with increased doses 
or plasma concentrations. Paroxetine's elimination
half-life appears to be prolonged in the geriatric population. 
For patients exhibiting renal (creatinine clearance <30 
mL/min) and/or hepatic dysfunction, paroxetine should be initiated 
at the lower dose of 10 mg/day and titrated to a maximum of 40 mg/day.ContraindicationsConcomitant use of paroxetine in patients taking MAOIs 
or other SSRIs  is contraindicated. These combinations 
can result in a serious, sometimes fatal, serotonin syndrome. 
This syndrome is characterized by hyperthermia, 
rigidity, myoclonus, and autonomic instability with possible fluctuations of vital signs and mental status changes. 
Paroxetine should not be used within 14 days of discontinuing an 
MAOI. Similarly, it is recommended that MAOI therapy 
not be initiated until 14 days have elapsed following paroxetine discontinuation.Dosage and AdministrationParoxetine is administered as a single daily dose, initi
ated at 20 mg/day. Although the package insert specifies 
drug administration in the morning, patients 
experiencing sedation may opt for nighttime administration. For patients 
not showing an adequate therapeutic response within 2 to 
3 weeks of paroxetine initiation, the dose may be increased in 
10 mg increments at weekly intervals. The usual dose range 
in the treatment of depression is 20 to 50 mg/day.  For 
elderly patients and those with renal and/or hepatic dys
function, doses are initiated at 10 mg/day and titrated to 
a maximum of 40 mg/day.ConclusionParoxetine is a selective and specific serotonin reup
take inhibitor with demonstrated efficacy and tolerability 
in the acute treatment of depressed patients. It is as effective 
as TCAs and other SSRIs in the acute treatment of depression. Paroxetine exhibits a favorable pharmacokinetic 
profile, including a relatively short half-life (compared 
to fluoxetine) and lack of active metabolites. The adverse event profile 
of paroxetine is similar to that of other antidepressants in 
this class, but paroxetine may be associated with more sedation. 
As with other SSRIs, a discontinuation syndrome is possible 
with abrupt cessation. When discontinuing paroxetine, 
tapering of the dose is suggested. Paroxetine potently 
inhibits CYP2D6, but it shows little clinically relevant 
inhibition of other cytochrome P450 isoenzymes. 
References available upon request.
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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
|Up to Top                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | Did You Know ...
vAn estradiol transdermal patch (Climara®) 
was recently approved for the prevention of 
postmenopausal osteoporosis. This is the only 
once-a-week transdermal estrogen product 
approved for osteoporosis prevention.vThe FDA recently approved alitretinoin 0.1% 
(Panretin®) for the topical treatment of cutaneous 
lesions in patients with AIDS-related Kaposi's 
sarcoma. This is the first topical agent approved 
for this condition.vCilastazol (Pletal®) has been approved for reduc
tion of symptoms associated with intermittent 
claudication. The dose of cilastazol may need to 
be decreased in patients receiving concomitant 
treatment with agents known to inhibit the cyto
chrome P450 3A4 isozyme (e.g., azole antifungals 
or certain macrolide antibiotics).vTelmisartan (Micardis®), a new angiotensin II 
receptor inhibitor, was recently approved for the treatment of hypertension.vLovastatin (Mevacor®) was approved for the 
primary prevention of coronary heart disease 
in patients diagnosed with hypercholesterolemia.Formulary Update:
The Pharmacy and Therapeutic Committee 
recently approved the following formulary actions:Additions:
vThyrotropin alfa (Thyrogen®), a highly 
purified recombinant form of human thyroid stimulating hormone 
(TSH) for use as an adjunctive diagnostic tool for serum thyroglobulin testing with or without radioiodine imaging.vParoxetine (Paxil®), a selective 
serotonin-reuptake inhibitor indicated for the treatment of 
depression, obsessive-compulsive disorder, and panic disorder.vOctreotide acetate (Sandostatin LAR® Depot), a 
long-acting octreotide formulation administered 
once monthly by intramuscular injection. It is indicated
for the treatment of acromegaly, and diarrhea and flushing associated with metastatic carcinoid tumors 
or vasoactive intestinal peptide tumors.vRopivacaine (Naropin®), a long-acting amide 
local anesthetic indicated for local or regional anesthesia 
for surgery, postoperative-pain management, and obstetrical procedures.vAbacavir (Ziagen®), a nucleoside reverse 
transcriptase inhibitor of HIV-1 for use in combination with 
other antiretroviral agents in the treatment of HIV infection.vTrastuzumab (Herceptin®), a recombinant 
humanized monoclonal antibody (rhuMab) indicated for 
the treatment of metastatic breast cancer in patients 
who present with an overexpression of the human 
epidermal growth factor receptor-2, c-erbB2.vBotulinum toxin type A (Botox®), a lyophilized form 
of purified botulinum toxin indicated for the treatment 
of strabismus and blepharospasm.vAbciximab (ReoPro®), a Fab fragment of the 
chimeric human murine monoclonal antibody 7E3 used as 
an adjunct to percutaneous transluminal coronary angioplasty for the 
prevention of acute cardiovascular ischemic complications.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                  |                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            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