Dosing and uses of Paxil, Paxil CR (paroxetine)
Adult dosage forms and strengths
tablet
- 10mg
- 20mg
- 30mg
- 40mg
capsule
- 7.5mg
tablet, extended-release
- 12.5mg
- 25mg
- 37.5mg
oral suspension
- 10mg/5mL
Depression
Conventional: 20 mg PO qDay initially; may increase by 10 mg/day qWeek not to exceed 50 mg/day
Paxil CR: 25 mg PO qDay initially; may increase by 12.5 mg/day qWeek not to exceed 62.5 mg/day
Obsessive-Compulsive Disorder
20 mg PO qDay initially; may increase by 10 mg qWeek, not to exceed 60 mg/day
Panic Disorder
10 mg PO qDay initially; may increase by 10 mg qWeek (target dose 40 mg/day), not to exceed 60 mg/day, Or
Paxil CR: 12.5 mg PO qDay initial, increase by 12.5 mg qWeek not to exceed 75 mg/day
Social Phobia
20 mg PO qDay Or
Paxil CR: 12.5 mg PO qDay initially; may increase by 12.5 mg qWeek, not to exceed 37.5 mg/day
Generalized Anxiety Disorder
20 mg PO qDay initially, may increase by 10 mg qWeek, up to 50 mg/day doses have been used but no increase in benefit seen at doses >20 mg/day
Posttraumatic Stress Disorder
20 mg PO qDay initially; may increase by 10 mg qWeek, up to 50 mg/day doses have been used but no increase in benefit seen at doses >20 mg/day
Premenstrual Dysphoric Disorder
Paxil CR: 12.5 mg PO qDay initially; may increase at 1 week intervals not to exceed 25 mg/day
Menopausal Vasomotor Symptoms
Brisdelle: Indicated to treat moderate-to-severe vasomotor symptoms associated with menopause
Brisdelle: 7.5 mg PO qHs
Paxil CR (Off-label): 12.5-25 mg PO qDay
Dosing Modifications
Severe renal impairment (CrCl <30 mL/min)
- Conventional: 10 mg PO qDay initially; may titrate; not to exceed 40 mg/day
- Paxil CR: 12.5 mg PO qDay initially; may titrate; not to exceed 50 mg/day
Stuttering (Off-label)
20 mg PO qDay
Vasovagal Syncope (Off-label)
20 mg/day PO
Diabetic Neuropathy (Off-label)
10 mg/day PO initially; may increase to 20-60 mg/day
Pediatric dosage forms and strengths
Safety and efficacy not established
Geriatric dosage forms and strengths
Caution should be used in the elderly because paroxetine is the most sedating and anticholinergic of the selective serotonin reuptake inhibitors
The elderly are prone to SSRI/SNRI-induced hyponatremia; monitor closely
Paxil, Paxil CR (paroxetine) adverse (side) effects
>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
Warnings
Black box warnings
In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for major depressive disorders and other psychiatric illnesses
This increase was not seen in patients aged >24 years; a slight decrease in suicidal thinking was seen in adults >65 years
In children and young adults, risks must be weighed against the benefits of taking antidepressants
Patients should be monitored closely for changes in behavior, clinical worsening, and suicidal tendencies; this should be done during the initial 1-2 months of therapy and dosage adjustments
The patient’s family should communicate any abrupt changes in behavior to the healthcare provider
Worsening behavior and suicidal tendencies that are not part of the presenting symptoms may require discontinuation of therapy
This drug is not approved for use in pediatric patients
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
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
Pregnancy and lactation
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.
Pharmacology of Paxil, Paxil CR (paroxetine)
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 (https://www.appliedbiosystems.com/)
- GenPath Diagnostics (https://www.genpathdiagnostics.com/)
