Paroxetine

Paroxetine is an Antidepressant agent belonging to the Serotonin Reuptake Inhibitor class.

Paroxetine is a selective serotonin reuptake inhibitor used to treat major depressive disorder, panic disorder, OCD, social phobia, generalized anxiety disorder, the vasomotor symptoms of menopause, and premenstrual dysphoric disorder.

Readily and completely absorbed from the gastrointestinal tract. Time to peak plasma concentration: 5.2-8.1 hours (immediate-release tab, suspension); 6 hours (range: 3-8 hours [cap]); 6-10 hours (modified-release tab). It is widely distributed throughout body tissues and crosses placenta and enters breast milk. The Volume of distribution is about 8.7 L/kg (3-28 L/kg). The Plasma protein binding is approximately 93-95%. Paroxetine undergoes extensive first-pass metabolism in the liver mainly via oxidation and methylation by CYP2D6 isoenzyme to form polar glucuronide and sulfate conjugates. Paroxetine mainly via urine (approx. 64% as metabolites, 2% as unchanged drug); faeces (approx. 36% as metabolites, <1% as unchanged drug). The Elimination half-life is approximately 21 hours (immediate release tab); 15-20 hours (modified-release tab).

Paroxetine shows side effects like Nausea and Vomiting, Dry mouth and lips, Constipation, Muscle stiffness, decreased sexual urge, Difficulty passing urine, etc.

Paroxetine is available as an Oral Tablet, Oral capsule, and Oral solution.

Paroxetine is available in India, Canada, US, China, France, Italy, Belgium, U.K, Holland, South Africa and Nigeria.

Paroxetine belongs to the Serotonin Reuptake Inhibitor class and acts as Antidepressant Agent.

The mechanism of action of Paroxetine in the treatment of MDD, SAD, OCD\, PD, GAD, and PTSD is unknown but is presumed to be linked to the potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT).

The Onset of action of Paroxetine is not clinically established.

The Time to peak plasma concentration of Paroxetine is approximately 5.2-8.1 hours (immediate-release tab, suspension); 6 hours (range: 3-8 hours [cap]); 6-10 hours (modified-release tab).

Paroxetine is available in the form of an Oral Tablet, Oral capsule, and Oral solution.

Paroxetine tablet, capsule and solution are taken orally, usually in divided dose.

For oral Tablet: Do not rush, break, or chew.

For oral solution: Shake well before use.

Paroxetine belongs to the selective serotonin reuptake inhibitors (SSRI) group. It is used to treat depression, obsessive-compulsive disorder (OCD), panic disorder, and other anxiety disorders.

Paroxetine is an Antidepressant agent belonging to the Serotonin Reuptake Inhibitor class.

Paroxetine is a selective serotonin reuptake inhibitor, chemically unrelated to tricyclic, tetracyclic, or other antidepressants; presumably, the inhibition of serotonin reuptake from brain synapse stimulated serotonin activity in the brain.

Paroxetine is approved for use in the following clinical indications

• Body dysmorphic disorder
• Generalized anxiety disorder
• Major depressive disorder
• Obsessive-compulsive disorder
• Panic disorder
• Posttraumatic stress disorder
• Premenstrual dysphoric disorder
• Social anxiety disorder
• Vasomotor symptoms associated with menopause

• Body dysmorphic disorder

Immediate release: Oral: Initial: 20 mg once daily; may increase dose gradually based on response and tolerability in increments of 20 mg/day at intervals of every 2 to 3 weeks to a usual dose of 60 mg/day; doses up to 100 mg/day may be necessary in some patients for optimal response, typically under specialist care.

• Generalized anxiety disorder

Immediate release: Oral: Initial: 10 mg once daily; may increase dose based on response and tolerability in 10 mg/day increments at intervals ≥1 week up to 50 mg/day.

• Major depressive disorder

Immediate release: Oral: Initial: 20 mg once daily; may increase dose based on response and tolerability in increments of 10 to 20 mg/day at intervals ≥1 week to a maximum of 50 mg/day.

Extended release: Oral: Initial: 25 mg once daily; may increase dose based on response and tolerability in increments of 12.5 mg/day at intervals ≥1 week to a maximum of 62.5 mg/day.

• Obsessive-compulsive disorder

Immediate release: Oral: Initial: 20 mg once daily; may increase the dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week up to a recommended dose of 40 to 60 mg/day; maximum dose: 60 mg/day.

• Panic disorder

Immediate release: Oral: Initial: 10 mg once daily for 3 to 7 days; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week up to a usual dose of 20 to 40 mg/day; maximum dose: 60 mg/day.

Extended-release: Oral: Initial: 12.5 mg once daily; may increase dose based on response and tolerability in increments of 12.5 mg/day at intervals ≥1 week up to a maximum of 75 mg/day.

• Posttraumatic stress disorder

Immediate release: Oral: Initial: 20 mg once daily; may increase dose based on response and tolerability in increments of 10 to 20 mg/day at intervals ≥1 week up to 60 mg/day.

• Premature ejaculation

Immediate release: Oral: Initial: 10 mg once daily; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week to a usual dosage of 20 mg/day. Some patients may require up to 40 mg/day for optimal response; some experts suggest 3- to 4-week titration intervals.

• Social anxiety disorder

Immediate release: Oral: Initial: 10 mg once daily; may increase dose based on response and tolerability in increments of 10 mg/day at intervals ≥1 week to a maximum of 60 mg/day.

Extended release: Oral: Initial: 12.5 mg once daily; may increase dose based on response and tolerability in increments of 12.5 mg/day at intervals ≥1 week up to a maximum of 37.5 mg/day.

• Vasomotor symptoms associated with menopause

Immediate release:

Capsule: Oral: 7.5 mg once daily at bedtime.

Tablet (off-label): Oral: 10 to 20 mg once daily at bedtime.

Extended release (off-label): Oral: 12.5 to 25 mg once daily at bedtime.

Paroxetine is available in various strengths as 7.5mg, 10mg, 12.5mg, 20mg, 25mg, 30mg, 37.5mg, 40mg, and 10 mg/5mL.

Paroxetine is available as Oral Tablet, Oral capsule, and Oral solution.

• Dosage Adjustment in Kidney Patient

CrCl >60 mL/minute: No dosage adjustment is necessary.

CrCl 30 to 60 mL/minute: There are no dosage adjustments provided.

CrCl <30 mL/minute: AUCs after a single paroxetine dose were ~3.5 times that of patients with normal kidney function.

• Dosage Adjustment in Hepatic impairment Patient

Mild to moderate impairment: There are no dosage adjustments provided.

Severe impairment:

Immediate release: Initial: 10 mg/day; increase if needed by 10 mg/day increments at intervals of at least one week; maximum dose: 40 mg/day.

Extended release: Initial: 12.5 mg/day; increase if needed by 12.5 mg/day increments at intervals of at least one week to a maximum of 37.5 mg/day (social anxiety disorder) or 50 mg/day (major depressive disorder, panic disorder).

Paroxetine is contraindicated in patients with

• Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome.
• Taking thioridazine because of the risk of QT prolongation.
• Taking pimozide because of the risk of QT prolongation.
• With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or any inactive ingredients in Paroxetine.

• Akathisia: Inability to remain still due to agitation or restlessness has been observed with paroxetine and other selective serotonin reuptake inhibitors (SSRIs). Usually occurs within the first few weeks of therapy.
• Anticholinergic effects: Has a low potential for sedation and anticholinergic effects relative to cyclic antidepressants; however, among the SSRI class, these effects are relatively higher.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).

Avoid or limit the uptake of alcohol while using Paroxetine. It is advised to refrain from driving vehicles and operating heavy machinery while using Paroxetine.

Like many other drugs, paroxetine is secreted in human milk. Because of the potential for severe adverse reactions in nursing infants from Paroxetine, a decision should be made whether to discontinue nursing infants or to discontinue the drug, considering the importance of the drug to the mother.

Infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. If paroxetine is used during pregnancy, or if the patient becomes pregnant while taking paroxetine, advise the patient of the potential hazard to the fetus.

• Common

Headache, dizziness, Weakness, difficulty concentrating, Nervousness, forgetfulness, Confusion, sleepiness, Nausea, vomiting, Diarrhea, constipation, Gas, stomach pain, heartburn, changes in ability to taste food, decreased appetite, weight loss or gain, sexual problems in males; decreased sex drive, inability to get or keep an erection, or delayed or absent ejaculation, sexual problems in females; decreased sex drive, or delayed orgasm or unable to have an orgasm, dry mouth, sweating, yawning, pain in the back, muscles, bones, or anywhere in the body, tenderness or swelling of joints.

• Rare

Fainting, rapid, pounding, or irregular heartbeat, chest pain, difficulty breathing, seizures, agitation, fever, sweating, confusion, fast or irregular heartbeat, and severe muscle stiffness or twitching, hallucinations, loss of coordination, nausea, vomiting, or diarrhea, abnormal bleeding or bruising, tiny red spots directly under the skin, peeling or blistering of skin, sore throat, fever, chills, cough, and other signs of infection, uncontrollable shaking of a part of the body, unsteady walking that may cause falling, numbness or tingling in your hands, feet, arms, or legs, painful erection that lasts for hours, sudden nausea, vomiting, weakness, cramping, bloating, swelling, tightness in hands and feet, dizziness, headache and/or confusion, hives, rash.

• Monoamine Oxidase Inhibitors (MAOIs): The concomitant use of SSRIs, including PAXIL, and MAOIs increases the risk of serotonin syndrome.
• Pimozide and Thioridazine: Increased plasma concentrations of pimozide and thioridazine, drugs with a narrow therapeutic index, may increase the risk of QTc prolongation and ventricular arrhythmias.
• Other Serotonergic Drugs: The concomitant use of serotonergic drugs with Paroxetine increases the risk of serotonin syndrome.
• Drugs Metabolized by CYP2D6: Paroxetine is a CYP2D6 inhibitor. The concomitant use of Paroxetine with a CYP2D6 substrate may increase the exposure of the CYP2D6 substrate.
• Tamoxifen: Concomitant use of tamoxifen with Paroxetine may lead to reduced plasma concentrations of the active metabolite (endoxifen) and reduced efficacy of tamoxifen.
• Fosamprenavir/Ritonavir: Co-administration of fosamprenavir/ritonavir with Paroxetine significantly decreased plasma levels of Paroxetine.

The common side effects of Paroxetine include the following:

• Common side effects

Nausea and Vomiting, Dry mouth and lips, Constipation, Muscle stiffness, decreased sexual urge, Difficulty in passing urine, Rapid weight gain/loss, Photosensitivity, Unusual bleeding or bruising, Racing thoughts, and weakness.

• Rare side effects

Suicidal thinking and behavior, Serotonin syndrome (agitation, hallucinations, seizures, nausea), Irregular heartbeat, Shaking of the hands or feet, Dizziness when getting up suddenly from a sitting position, Chills or cold sweats, Blurred vision, Reckless behavior, Unusual tiredness.

• Pregnancy

Pregnancy Category D

Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. If paroxetine is used during pregnancy, or if the patient becomes pregnant while taking paroxetine, advise the patient of the potential hazard to the fetus.

• Nursing Mothers

Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from Paroxetine, a decision should be made whether to discontinue nursing infants or to discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

The safety and effectiveness of Paroxetine in pediatric patients have not been established.

• Geriatric Use

In premarketing clinical trials with Paroxetine, 17% of patients treated with Paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; however, no overall differences in safety or effectiveness were observed between elderly and younger patients.

Symptoms: Somnolence, dizziness, nausea, tremor, tachycardia, confusion, vomiting, fever, involuntary muscle contractions, ECG changes, mydriasis, convulsions, ventricular dysrhythmias, hypertension, aggressiveness, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, hepatic dysfunction, manic reactions, myoclonus, acute renal failure, urinary retention, serotonin syndrome and coma.

Management: Symptomatic and supportive treatment. Ensure adequate airway, oxygenation, and ventilation. Administer 20-30 g activated charcoal within a few hours of ingestion to decrease absorption. Frequently monitor cardiac rhythm and vital signs.

• Pharmacodynamic

Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake (SSRI) and has only very weak effects on norepinephrine and dopamine neuronal reuptake.

• Pharmacokinetics

Absorption

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. At steady state, mean values of Cmax, Tmax, Cmin, and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. AUC was only slightly increased (6%) when drug was administered with food, but the Cmax was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.

Distribution

Paroxetine is distributed throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

Metabolism and Excretion

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of Paroxetine. Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.

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