paroxetine (Rx)

>10% (Based on 40 mg Dose)

Nausea (15-24%)

Insomnia (11-24%)

Dry mouth (9-18%)

Headache (17%)

Asthenia (10-15%)

Constipation (10-15%)

Diarrhea (9-12%)

Dizziness (6-14%)

Ejaculation disorder (10-15%)

Tremor (4-11%)

1-10% (Based on 40 mg Dose)

Anxiety (5-10%)

Blurred vision (5-10%)

Decreased appetite (5-10%)

Impotence (2-9%)

Nervousness (2-5%)

Paresthesia (2-5%)

Hypomania (0.3 to 2.2%)

Frequency Not Defined (Based on 40 mg Dose)

Hypertension

Tachycardia

Emotional lability

Pruritus

Weight gain

Arthralgia

Tinnitus

Vertigo

Angle clossure glaucoma

Serious

• Depression exacerbation
• Mania (rare)
• Serotonin syndrome
• Suicidal thoughts (rare)
• Suicide (rare)
• Seizure (rare)
• Toxic epidermal necrolysis
• Hyponatremia (rare)
• Bleeding, abnormal (rare)
• Acute hepatitis (rare)
• Stevens-Johnson Syndrome
• Bone fracture
• Akathisia

Contraindications

Hypersensitivity

Concomitant pimozide

Coadministration with serotonergic drugs

• Concomitant use or within 14 days of MAOIs increases risk of serotonin syndrome
• Reactions to concomitant administration with MAOIs include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma
• Starting paroxetine in a patient who is being treated with linezolid or IV methylene blue is contraindicated because of an increased risk of serotonin syndrome
• If linezolid or IV methylene blue must be administered, discontinue SSRI immediately and monitor for CNS toxicity; may resume 24 hr after last linezolid or methylene blue dose, or after 2 weeks of monitoring (5 weeks for fluoxetine), whichever comes first

Cautions

Clinical worsening and suicidal ideation may occur despite medication in adolescents and young adults (18-24 years)

Use caution in patients with bipolar disorder, seizure disorder, history of suicidal thought/behavior

Life-threatening serotonin syndrome reported with SNRIs and SSRIs alone; also with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort)

Risk of mydriasis; may trigger angle closure attack in patients with angle closure glaucoma with anatomically narrow angles without a patent iridectomy

Conflicting evidence regarding use of SSRIs during pregnancy and increased risk of persistent pulmonary hypertension of the newborn (see Pregnancy)

Risk of complications such as feeding difficulties, irritability, and respiratory problems reported in neonates exposed to SNRIs/SSRIs late in third trimester

Risk of cardiovascular defects in infants whose mothers took drug during early pregnancy

Withdraw gradually

Use lower starting dose in renal impairment (CrCl <30 mL/min) or severe hepatic impairment

Increases risk of hyponatremia and impairment of cognitive and motor functions in the elderly

May cause or exacerbate sexual dysfunction

Inability to remain still due to feelings of agitation or restlessness reported; may occur within first few weeks of therapy

May impair platelet aggregation especially when used in combination with aspirin or NSAIDs; increases risk of bleeding in patients taking anticoagulants/antiplatelets concomitantly

Epidemiologic studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures; there are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment

Bone fractures reported to be associated with antidepresant use

Consider risk of serotonin syndrome if administered concomitantly with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort

Pregnancy

Pregnancy category: D

Teratogenic effects: Epidemiologic studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations

Use late in the third trimester associated with complications in newborns and may require prolonged hospitalization, respiratory support, and tube feeding

A study of nearly 28,000 women taking SSRIs confirmed 5 previously reported birth defercts associated with paroxetine, including heart defects, anencephaly, and abdominal wall defects (BMJ 2015; 351:h3190)

Persistent pulmonary hypertension of the newborn

• Potential risk of persistent pulmonary hypertension of the newborn (PPHN) when used during pregnancy
• Initial public health advisory in 2006 was based on a single published study; since then, there have been conflicting findings from new studies, making it unclear whether use of SSRIs during pregnancy can cause PPHN
• FDA has reviewed the additional new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN
• FDA recommendation: FDA advises health care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program
• A meta-analysis of 7 observational studies, found exposure to SSRIs in late pregnancy (ie, >20 weeks' gestation) more than doubled the risk of PPHN that could not be explained by other etiologies (eg, congenital malformations, meconium aspiration) (BMJ 2014;348:f6932)

Lactation

Excreted in breast milk; use caution (AAP states effect on nursing infants is unknown but may be of concern)

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

SSRI; little or no affinity for alpha-adrenergic histamine or cholinergic receptor

Absorption

Peak plasma time: 5.2-8.1 hr (immediate-release); 6-10 hr (controlled-release)

Peak plasma concentration: 61.7 ng/mL

Distribution

Protein bound: 93-95%

Vd: 8.7 L/kg

Metabolism

Metabolism: Hepatic P450 enzyme CYP2D6

Enzymes inhibited: CYP2D6

Metabolites: Inactive

Elimination

Half-life: 21 hr

Dialyzable: No

Excretion: Urine (64%); feces (36%)

Pharmacogenomics

Several SSRIs (eg, fluoxetine, fluvoxamine, paroxetine, sertraline) are metabolized by CYP2D6

CYP2D6 is involved in the metabolism of approximately 20% of drugs in clinical use, and it displays large individual-to-individual variability in activity due to genetic polymorphisms

More than 80 CYP2D6 variant alleles have been identified; however, 4 of the most prevalent alleles, CYP2D6*3, *4, *5, and *6, account for 93-97% of CYP2D6 poor metabolizers (PMs)

CYP2D6*4, the most common variant (~25% frequency in whites), causes a splicing defect; CYP2D6*3 (2.7% frequency) causes a frameshift mutation; and CYP3D6*5 (2.6%) is an entire deletion of the CYP2D6 gene; individuals homozygous for these alleles have no CYP2D6 activity

The impact of CYP2D6 activity is further complicated in some SSRIs (eg, fluoxetine, fluvoxamine, paroxetine, sertraline) that in addition to being substrates for CYP2D6, are also known to moderately inhibit CYP2D6 activity

Genetic testing laboratories

• Genotyping tests for CYP2D6 variants are commercially available through the following companies
• Applied Biosystems (http://www.appliedbiosystems.com/)
• GenPath Diagnostics (http://www.genpathdiagnostics.com/)