Date of approval.
Date of revision.
Paroxetine Hydrochloride Enteric Extended Release Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warning: Suicidal ideation and antidepressants
Depression and certain psychiatric disorders are inherently associated with an increased risk of suicide. Results of short-term clinical trials of depression (MDD) and other psychiatric disorders have shown that antidepressant medications increase the risk of suicidal ideation (suicidal ideation and suicidal behavior) in adolescents and young adults (≤ 24 years of age) compared to placebo. Anyone considering the use of paroxetine hydrochloride or other antidepressants in adolescents and young adults (≤24 years of age) must weigh the risks against clinical need. Short-term clinical trials have not shown an increased risk of suicidal ideation with antidepressant use in adults aged >24 years compared with placebo; and in adults aged 65 years and older, the risk of suicidal ideation was reduced with antidepressant use. Patients of all ages must be closely monitored for worsening clinical symptoms, suicidal ideation, and abnormal changes in behavior after initiation of treatment with antidepressants. Families and caregivers should be advised that they must closely observe and communicate with their physicians. Paroxetine hydrochloride enteric extended-release tablets are not approved for use in pediatric patients (see [Precautions] – Warnings, worsening of clinical symptoms and risk of suicide)
Drug Name]
Generic Name: Paroxetine Hydrochloride Enteric-Coated Sustained-Release Tablets English Name: Yansuan Paluoxiting Changrong Huanshipian
Ingredients
The main ingredient of this product is paroxetine hydrochloride.
Chemical name: (-)-(3S,4R)-4-(4-fluorophenyl)-3-[[(3,4-methylenedioxy)phenoxy]methyl]piperidine hydrochloride hemihydrate compound.
Chemical structure formula.
Molecular formula: C19H20FNO3-HCl -1/2H2O
Molecular weight: 374.8 (free group is 329.3)
【Properties】.
It is a yellow film-coated tablet, after removing the coating, it is a white and light yellow double layer tablet (12.5mg specification) or a pink film-coated tablet, after removing the coating, it is a white and pink double layer tablet (25mg specification).
Indications
For the treatment of depression in adults.
The effectiveness of paroxetine hydrochloride enteric extended-release tablets for the treatment of depressive episodes was established in two 12-week controlled clinical trials in depressed outpatients meeting the criteria of the American Diagnostic Statistical Manual of Mental Disorders (4th edition). The antidepressant effect of paroxetine in hospitalized depressed patients has not been adequately studied.
The safety of the efficacy of paroxetine enteral extended-release tablets beyond 12 weeks has not been systematically evaluated in controlled clinical trials; however, the effectiveness of paroxetine immediate-release tablets for up to 1 year of maintenance treatment in patients with depression has been confirmed in controlled clinical trials (see [Clinical Trials]). Physicians who choose paroxetine enteral extended-release tablets for long-term treatment should periodically reevaluate the long-term effectiveness of the drug for individual patients.
【Specifications】.
According to C19H20FNO3 (1) 12.5mg (2) 25mg
Dosage]
Common initial dose: Paroxetine hydrochloride enteric extended-release tablets are generally administered once in the morning, before and after meals. The recommended initial dose is 25mg/day. In clinical trials, patients received doses ranging from 25 mg/day to 62.5 mg/day, and the results showed the effectiveness of paroxetine enteric-coated extended-release tablets in the treatment of depression. As with all medications effective for depression, there is a time delay in the full onset of action of paroxetine hydrochloride enteral extended-release tablets. Some patients for whom the 25 mg/day dose is ineffective may achieve efficacy with dose increases in increments of 12.5 mg daily, with at least 1 week between each dose increase. The maximum dose administered is 62.5 mg/day.
Patients should be cautioned that paroxetine enteral extended-release tablets should be swallowed whole and not chewed or crushed.
Maintenance therapy: There is no definitive basis for how long patients treated with paroxetine hydrochloride enteral extended-release tablets need to be maintained on the medication. It is generally accepted that acute episodes of depression require several months or even longer of medication maintenance therapy. It is uncertain whether the dose of this product used for maintenance therapy should be the same as the dose used for the acute phase of treatment.
Systematic evaluation of the effectiveness of paroxetine hydrochloride immediate-release tablets has shown that an average dose of 30 mg/day for more than 1 year of continuous treatment maintains effectiveness, which is equivalent to 37.5 mg/day of paroxetine hydrochloride enteric extended-release tablets, as measured by relative bioavailability (see [Pharmacokinetics]).
Special Populations:
Pregnant women in late pregnancy (second trimester): Newborns exposed to paroxetine enteral extended-release tablets and other selective 5-hydroxytryptamine reuptake inhibitors or selective norepinephrine reuptake inhibitors in late pregnancy (second trimester) have developed comorbidities that have necessitated extended hospitalization, respiratory support, and tube feeding (see WARNINGS). When treating pregnant women in late pregnancy (second trimester) with paroxetine, physicians should carefully consider the potential risks and benefits of treatment. Your doctor may consider tapering the dose of paroxetine in the second trimester of pregnancy.
Elderly or debilitated patients and patients with severe hepatic or renal impairment: The recommended initial dose is 12.5 mg/day for elderly patients, debilitated patients and/or patients with severe hepatic or renal impairment. The dose may be increased if an increase in dose is indicated. The maximum dose should not exceed 50 mg/day.
Interchangeable Applications with Monoamine Oxidase Inhibitors: Discontinue monoamine oxidase inhibitors for at least 14 days before initiating treatment with paroxetine enteral extended-release tablets. Similarly, discontinue paroxetine hydrochloride enteral extended-release tablets for at least 14 days before initiating treatment with monoamine oxidase inhibitors.
Discontinuation of paroxetine enteral extended-release tablets: Some of the symptoms associated with discontinuation of treatment with paroxetine hydrochloride immediate-release tablets or paroxetine hydrochloride enteral extended-release tablets have been summarized (see [Precautions]). Patients should be monitored for changes in these symptoms after stopping treatment, regardless of the indication for treatment with paroxetine hydrochloride enteral extended-release tablets. The dose of the drug should be tapered as gradually as possible rather than stopped abruptly. If intolerable symptoms occur during the dose reduction process, consider resuming the previous dose followed by a more gradual dose reduction.
Adverse Reactions
Information on “Adverse Events Observed in Short-Term Controlled Clinical Studies of Paroxetine Hydrochloride Enteric Extended-Release Tablets” was obtained from data from three placebo-controlled clinical trials. In the analysis, information from two depression clinical trials enrolling patients in the age range of 18 to 65 years was summarized, and information from a third geriatric depression clinical trial (age 60 to 88 years) was summarized separately.
Additional adverse event information was obtained from additional adverse event information associated with paroxetine enteral extended-release tablets and paroxetine hydrochloride immediate-release tablets (see Other Adverse Events).
Adverse events observed in short-term controlled clinical trials with paroxetine hydrochloride enteral extended-release tablets.
Adverse events leading to treatment discontinuation: In the two clinical trials pooled for depression, 10% (21/212) of patients discontinued paroxetine enteric-coated extended-release tablets due to adverse events. The most common (≥1%) and considered drug-related (e.g., events in which the discontinuation rate of paroxetine hydrochloride enteral extended-release tablets was two or more times higher than in the placebo group) adverse events are shown in the following table.
Paroxetine Hydrochloride Enteric Extended-Release Tablets
(n = 212) Placebo
(n = 211) Nausea 3.7% 0.5% Debilitation 1.9% 0.5% Dizziness 1.4% 0.0% Drowsiness 1.4% 0.0% In a controlled clinical trial of elderly patients with depression, 13% (13/ 104) of patients using paroxetine hydrochloride enteral extended-release tablets discontinued treatment due to adverse events. Adverse events that met the above criteria are shown in the following table.
Paroxetine Hydrochloride Enteric Extended-Release Tablets
(n = 104) Placebo
(n = 109) Nausea 2.9% 0.0% Headache 1.9% 0.9% Depression 1.9% 0.0% Liver function abnormalities 1.9% 0.0% Common adverse events:The pooled data from two clinical trials documenting common adverse events (incidence higher than 5% and at least two times higher than the placebo group, see Table 1 below) for paroxetine hydrochloride enteral extended-release tablets for depression were: abnormal ejaculation, abnormal visualization, constipation, decreased libido, diarrhea, dizziness, female sexual dysfunction, nausea, drowsiness, hyperhidrosis, trauma, tremor, and yawning.
Using the same criteria, adverse events associated with the use of paroxetine hydrochloride enteric extended-release tablets in clinical trials in elderly patients with depression were: abnormal ejaculation, constipation, decreased appetite, dry mouth, impotence, infection, decreased libido, excessive sweating, and tremor.
Incidence of Adverse Events in Controlled Clinical Trials: Table 1 summarizes the incidence of adverse events in two short-term (12-week) placebo-controlled clinical trials with an incidence of 1% or greater in depressed patients in the paroxetine hydrochloride enteral extended-release tablet treatment group, with patients ranging in age from 18 to 65 years and a dose range of 25 – 62.5 mg/day of paroxetine hydrochloride enteral extended-release tablets. Table 2 summarizes adverse events with an incidence of 5% or more in the paroxetine enteral extended-release tablet group in older (60-88 years of age) depressed patients in a short-term (12-week) placebo-controlled clinical trial with a dose range of 12.5 – 50 mg/day of paroxetine hydrochloride enteral extended-release tablets.
Physicians are cautioned that the above adverse events are not intended to predict the incidence of adverse events in routine clinical practice because clinical patient characteristics and other factors differ from those of patients in clinical trials. Similarly, the frequency of occurrence figures obtained from other clinical studies involving different treatments, different uses and investigators are not comparable. Data are cited to show the degree of correlation between estimated drug and non-drug factors on the incidence of adverse events in population trials for physician prescribing purposes.
Table 1. Adverse events during treatment with an incidence of ≥1% in two clinical trials of paroxetine hydrochloride enteric extended-release tablets for depression1, 2
Human systems/adverse events Adverse event incidence (%) Paroxetine hydrochloride enteral extended-release tablets
(n = 212) Placebo
(n = 211) Systemic headache 27%20% debilitating 14%9% infection 38%5% abdominal pain 7%4% back pain 5%3% trauma 45%1% pain 53%1% allergic reactions 62%1% cardiovascular system palpitations 1% 0% vasodilation 72% 0% digestive system nausea 22%10% diarrhea 18%7% dry mouth 15%8% constipation 10%4% bloating 6%4% loss of appetite 4%2% vomiting2%1% nervous system drowsiness22%8% insomnia17%9% dizziness14%4% hypoactive sexual desire7%3% tremor7%1% increased muscle tone3%1% sensory abnormalities3%1% agitation2%1% disorders1%0% respiratory system yawning5%0% rhinitis4%1% aggravated cough2%1% bronchitis1%0% skin and peripheral tissues hyperhidrosis6%2% photosensitivity2%0% Special sensations Visual abnormalities 85%1% Taste abnormalities 2% 0% Genitourinary system Ejaculatory abnormalities 9,1026%1% Female sexual abnormalities 9,1110%<1% Impotence 95%3% Urinary tract infections 3%1% Menstrual disorders 92%<1% Vaginitis 92% 0% 1. Adverse events that occurred at a lower rate in the paroxetine hydrochloride enteric extended-release tablet group than or equal to the placebo group were not included. events. These adverse events included: abnormal dreaming, anxiety, arthralgia, depersonalization, dysmenorrhea, dyspepsia, hyperkinesia, hyperphagia, myalgia, neuroticism, pharyngitis, purpura, rash, respiratory disease, sinusitis, dysuria, and weight gain.
2. <1% is defined as greater than 0 and less than 1%.
3. Mostly influenza.
4. Inconspicuous multiple injuries.
Insignificant multiple sites of pain.
Most commonly seasonal allergic symptoms.
Commonly flushing.
Mainly blurred vision.
Depending on the number of men or women.
Primarily sexual pleasure deficit and delayed ejaculation.
Predominantly sexual pleasure deficit and delayed orgasm.
Table 2. Adverse events during treatment with an incidence of ≥5% in a clinical trial of paroxetine hydrochloride enteric extended-release tablets for depression in the elderly1,2
Human system/adverse events % Adverse events reported Paroxetine hydrochloride
Enteric extended-release tablets
(n = 104) Placebo
(n = 109) Systemic headache 17%13% debilitation 15%14% trauma 8%5% infection 6%2% digestive system dry mouth 18%7% diarrhea 15%9% constipation 13%5% dyspepsia 13%10% decreased appetite 12%5% bloating 8%7% nervous system drowsiness 21%12% insomnia 10%8% dizziness 9%5% decreased sex drive 8%<1% tremor 7% 0% excessive sweating of skin and peripheral tissues10%<1% genitourinary abnormal ejaculation3,417%3% impotence39%3%1. Adverse events not included with paroxetine hydrochloride enteric extended-release tablets were lower than or equivalent to the incidence in the placebo group. These events included nausea and respiratory disease.
2. <1% is defined as above 0 and below 1%.
3. Based on the number of male patients.
4. primarily lack of sexual pleasure or delayed ejaculation.
Dose Dependence of Adverse Events: Comparisons of the incidence of adverse events in placebo-controlled trials of fixed-dose paroxetine hydrochloride immediate-release tablets for depression showed clear dose dependence in the adverse events more commonly associated with paroxetine hydrochloride immediate-release tablets.
Male and female dysfunction and selective 5-hydroxytryptamine reuptake inhibitors: Although libido, sexual performance and sexual satisfaction are often clinical manifestations of psychiatric disorders, they may also be the result of pharmacological treatment. In specific cases, some evidence suggests that selective 5-hydroxytryptamine reuptake inhibitors may contribute to these sexual dysfunctions.
Physicians are cautioned that the incidence provided in the instructions may be lower than the actual incidence because patients and physicians may be less likely to discuss sexual experiences.
The following summarizes the incidence of symptoms of abnormal sexual function in two placebo-controlled clinical trials in patients with depression.
Paroxetine hydrochloride enteric extended-release tablets placebo n (men) 7878 decreased libido 10% 5% ejaculatory disorders 26% 1% impotence 5% 3% n (women) 134133 decreased libido 4% 2% orgasmic disorders 10% <1% There are no adequate, controlled design clinical trials examining abnormal sexual function with paroxetine hydrochloride treatment.
Paroxetine hydrochloride treatment was associated with several cases of abnormal penile erections, but all of these patients recovered with no sequelae.
Although the precise risk of sexual abnormalities associated with selective 5-hydroxytryptamine reuptake inhibitor therapy is difficult to know, physicians should routinely ask about these possible side effects.
Changes in weight and vital signs: Some patients experienced significant weight loss during treatment with paroxetine hydrochloride enteral extended-release tablets; however, patients in controlled clinical trials with paroxetine hydrochloride enteral extended-release tablets or immediate-release tablets experienced only a mild average weight loss (approximately 1 pound). There were no significant changes in vital signs (systolic blood pressure, diastolic blood pressure, pulse, or temperature) in controlled clinical trials with paroxetine hydrochloride enteral extended-release or immediate-release tablets.
ECG changes: The ECGs of 682 patients in the paroxetine hydrochloride immediate-release tablet treatment group and 415 patients in the placebo group in controlled trials were analyzed, and no clinically meaningful changes in the ECGs were observed.
Liver function: In a pooled analysis of two controlled clinical trials of paroxetine hydrochloride enteric extended-release tablets, the incidence of abnormal liver function was similar in patients in the paroxetine hydrochloride enteric extended-release tablet and placebo groups. There was no difference in the percentage of patients with significant abnormalities of alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin in the paroxetine hydrochloride enteral slow-release tablets treatment group compared with placebo.
In a clinical trial in elderly patients with depression, three of 104 patients in the paroxetine enteral extended-release tablet treatment group had potentially clinically significant aminotransferase elevations; two of these patients withdrew from the trial due to abnormal liver function, and one patient returned to normal aminotransferase on continued treatment. None of the 109 patients in the placebo group had potentially clinically significant aminotransferase elevations.
In the pooled analysis of placebo-controlled clinical trials of paroxetine hydrochloride immediate-release tablets, the incidence of abnormal liver function was not higher in patients in the treatment group than in the placebo group.
Hallucinations: In a pooled analysis of clinical trials of paroxetine hydrochloride immediate-release tablets, 22 of 9,089 patients in the drug treatment group and 4 of 3,187 patients in the placebo group experienced hallucinations.
Other adverse events observed in the clinical development of paroxetine.
Adverse events reported during the clinical development of paroxetine hydrochloride enteral extended-release tablets and/or paroxetine hydrochloride immediate-release tablets are listed below and include only those adverse events for paroxetine hydrochloride enteral extended-release tablets not listed previously, whether these adverse events were associated with paroxetine hydrochloride enteral extended-release tablets is unclear.
Adverse events are listed in alphabetical order within the human system, and major adverse events of clinical importance are listed in the [Precautions] section.
Systemic: uncommonly, chills, facial edema, fever, flu-like syndrome, malaise; rarely, abscesses, anaphylactic reactions, anticholinergic syndrome, decreased body temperature; also seen with adrenergic syndrome, cervical tonicity, and sepsis.
Cardiovascular system: uncommonly, angina pectoris, bradycardia, hematoma, hypertension, hypotension, palpitations, upright hypotension, supraventricular tachycardia, syncope; rarely, bundle branch block; also, sinus arrhythmia, atrial fibrillation, cerebrovascular accident, congestive heart failure, decreased cardiac output, myocardial infarction, myocardial ischemia, pallor, phlebitis, pulmonary embolism, premature supraventricular beats, thrombotic phlebitis, thrombosis, vascular headache, and premature ventricular contractions.
Digestive system: uncommonly, nocturnal teeth grinding, dysphagia, belching, gastritis, gastroenteritis, gastroesophageal reflux, gingivitis, hemorrhoids, abnormal liver function tests, black stools, pancreatitis, rectal bleeding, toothache, and ulcerative stomatitis; rarely, colitis, tongue inflammation, gingival hyperplasia, hepatomegaly, splenomegaly, salivation disorder, intestinal obstruction, peptic ulcers, gastric ulcers, and pharyngeal spasm; also seen are stomatitis like stomatitis, hematochezia, hyperphagia, pancreatic spasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impaction, fecal incontinence, bleeding gums, vomiting blood, hepatitis, ileitis, intestinal obstruction, jaundice, oral ulcer, salivary gland enlargement, salivary gland inflammation, stomatitis, tongue discoloration, tongue edema.
Endocrine system: uncommonly, ovarian cysts, testicular pain; rarely, diabetes mellitus, goiter, hyperthyroidism; also seen as hypothyroidism, thyroiditis.
Hematologic and lymphatic system: uncommonly, anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, purpura; rarely, thrombocytopenia; also seen are unequal red blood cell size, basophilia, prolonged bleeding time, lymphoedema, lymphocytosis, microcytic anemia, mononucleosis, normocytic anemia, and thrombocytosis.
Immune system: very rare with severe allergic reactions (including tachyphylaxis and angioedema).
Metabolic and nutritional disorders: uncommonly, generalized edema, hyperglycemia, hypokalemia, peripheral edema, elevated AST, elevated ALT, and thirst; rarely, bilirubinemia, dehydration, hyperkalemia, and obesity; elevated alkaline phosphatase, elevated urea nitrogen, and elevated creatine phosphokinase may also occur. calciumemia, hypoglycemia, hyponatremia, ketosis, elevated lactate dehydrogenase, and elevated non-protein nitrogen (NPN).
Skeletal-muscular system: uncommon include arthritis, bursitis, tendonitis; rare include: muscle weakness, myopathy, myositis; also seen are: generalized spasticity, osteoporosis, tenosynovitis, and torsades de pointes.
Neurological: common is depression. Uncommon include amnesia, convulsions, depersonalization, dystonia, emotional instability, hallucinations, hyperalgesia, hyperkinesia, dyskinesia, increased libido, neuralgia, neuropathy, nystagmus, paresthesia, and vertigo. Rarely, these include: ataxia, coma, diplopia, dyskinesia, hostility, paranoid reactions, slanting neck, withdrawal syndrome. Also seen are: gait abnormalities, sedentary inability, motor inability, aphasia, choreoathetosis, perioral sensory abnormalities, delirium, delusions, dysphonia, euphoria, extrapyramidal syndrome, fasciculus tremens, grand mal convulsions, nociceptive hypersensitivity, irritability, manic response, manic-depressive response, meningitis, myelitis, peripheral neuritis, psychosis, psychotic depression, hyporeflexia, hyperreflexia, xylopia , clenching of teeth.
Respiratory system: common is pharyngitis. Uncommon are asthma, dyspnea, epistaxis, laryngitis, pneumonia; dysphonia, emphysema, hemoptysis, eruption, hyperventilation, pulmonary fibrosis, pulmonary edema, influenza, and increased sputum volume.
Rarely, these include: exfoliative dermatitis, boils, pustules, seborrheic dermatitis; also seen as: angioedema, petechiae, erythema multiforme, erythema nodosum, hirsutism, maculopapular rash, skin pigmentation changes, skin hyperplasia, skin ulcers, decreased sweating, and maculopapular rash. Very rare: severe cutaneous adverse reactions (including erythema multiforme, Stevens-Johnson syndrome and toxic epidermolysis bullosa), urticaria, photosensitivity reactions.
Special sensations: uncommonly, conjunctivitis, otalgia, keratoconjunctivitis, astigmatism, photophobia, retinal hemorrhage, tinnitus; rarely, blepharitis, visual field defects; also amblyopia, unequal pupils, blurred vision, cataracts, conjunctival edema, corneal ulcers, deafness, ocular proptosis, glaucoma, auditory hypersensitivity, night blindness, olfactory abnormalities, ptosis, and loss of taste.
Genitourinary system: common is dysmenorrhea; uncommon are proteinuria, breast pain, cystitis, prostatitis, dyspareunia, urinary retention; rare: breast enlargement, mammary neoplasia, female lactation, hematuria, kidney stones, nephritis, nocturnal polyuria, abnormalities after pregnancy and childbirth, tubal inflammation, urinary incontinence, enlarged uterine fibroids, menstrual irregularities (including excessive menstruation, uterine bleeding and amenorrhea); visible breast atrophy, ejaculation abnormalities, endometrial lesions, epididymitis, mammary fibrocysts, leucorrhoea abnormalities, mastitis, oliguria, polyuria, pyuria, urethritis, ductal pattern, urinary urgency, urinary calculi, uterine cramps and vaginal bleeding.
POST-MARKETING REPORTS: Since marketing, a number of spontaneous reports of adverse events have been received from patients taking paroxetine hydrochloride immediate-release tablets and not listed above; adverse events that may not be causally related to the drug include: acute pancreatitis, elevated liver function assay values (the most severe cases died from hepatic necrosis, significant elevation of aminotransferases associated with hepatic impairment), Guillain-Barre syndrome toxic epidermolysis bullosa, abnormal penile erection, antidiuretic dysregulation syndrome, prolactinoma suggestive symptoms and overflow, malignant syndrome-like events, 5-hydroxytryptamine syndrome; extrapyramidal symptoms include: sedentary inability, bradykinesia, cogwheel ankylosis, dystonia, hypertonia, kinetic eye crisis associated with pimozide combination; tremor and dental closure; persistent epilepsy, acute renal failure, pulmonary hypertension, allergic alveolitis, allergic reactions, convulsions, laryngospasm, optic neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including tip-twist), thrombocytopenia, hemolytic anemia, events associated with hematopoietic impairment (including: aplastic anemia, pancytopenia, myelodysplasia, and agranulocytosis), and vasculitis syndromes (e.g., allergic purpura). One case of paroxetine hydrochloride combined with phenytoin for 4 weeks has been reported, resulting in increased blood levels of phenytoin. One case of severe hypotension was reported in a patient taking metoprolol for a long time.
[Contraindications].
This product should not be used in combination with monoamine oxidase inhibitors (including the antibiotic linezolid, a reversible, non-selective monoamine oxidase inhibitor, and methylene blue (hypomethylene blue)) or within two weeks of the end of treatment with monoamine oxidase inhibitors. Similarly, monoamine oxidase inhibitors should not be used within two weeks of the end of treatment with this product (see [Drug Interactions] for details).
This product should not be used in combination with methiodiazine. Because, like other drugs that inhibit the hepatic cytochrome P450 isoenzyme CYP450 2D6, this product can cause an increase in plasma concentrations of methiodiazine (see [Drug Interactions]). The use of methiodiazide alone may result in prolonged QTc intervals with severe ventricular arrhythmias, such as tip-twisting ventricular tachycardia and sudden death.
Combination with pimozide is contraindicated (see [Precautions]).
Paroxetine Hydrochloride Enteric Extended-Release Tablets are contraindicated in patients with hypersensitivity to paroxetine hydrochloride or other components of paroxetine hydrochloride Enteric Extended-Release Tablets.
[Precautions].
Warnings
Clinical deterioration and risk of suicide:
Patients with adult or pediatric depression (MDD) with or without antidepressants may experience worsening of depressive symptoms and/or suicidal ideation and suicidal behavior (suicidal ideation), and this risk persists during illness until significant remission is achieved. Suicide is a known risk for depression and certain other psychiatric disorders, which are themselves the strongest predictors of the occurrence of suicide. It has long been thought that the early stages of antidepressant treatment induce deterioration and suicidal ideation in some patients. A comprehensive analysis of data from short-term, placebo-controlled clinical trials of antidepressant medications (SSRIs and other classes) has shown that these medications increase suicidal ideation and suicidal behavior (suicidal ideation) in children, adolescents, and young adults (18-24 years of age) with depression and other psychiatric disorders. Short-term clinical trials of antidepressants have shown no elevated risk of suicide in adult patients over 24 years of age compared to placebo, and instead a decreased risk of suicide in adult patients over 65 years of age.
In children and adolescents with depression, obsessive-compulsive disorder, or other psychiatric disorders, a comprehensive analysis of data from placebo-controlled clinical trials included 24 short-term clinical trials of nine antidepressants in 4,400 patients. In adults with depression or other psychiatric disorders, the pooled analysis of placebo-controlled clinical trials included 295 short-term clinical trials (median duration of 2 months) of 11 antidepressants in more than 77,000 patients. Suicide risk varied between drugs, but almost all drugs tested showed a trend toward increased suicide risk in younger patients; absolute suicide risk also varied between indications, with the highest incidence in depression.
The differences in risk (between drug and placebo) were relatively stable across age strata and across indications, and these differences are detailed in Table 3 (drug-placebo differences in the number of suicides per 1000 treated patients).
Table 3
Drug-placebo differences in the number of suicides per 1000 treated patients for age range Number of cases increased compared with placebo<18 14 more cases 18-24 5 more cases Decreased compared with placebo 25-64 1 less case ≥65 6 less cases For this product, there were no suicides in any pediatric-related clinical trials and suicides in adult clinical trials, but these data are not yet are not sufficient to evaluate the effect of the drug on suicide.
It is not known whether the risk of suicide increases with longer-term medication use (e.g., more than a few months). However, data from a placebo-controlled maintenance treatment clinical trial in adults with depression demonstrate that the use of antidepressants delays the reignition of depression.
All patients receiving antidepressant medication should be monitored appropriately and closely for worsening, suicidal ideation, and abnormal behavioral changes, especially during the first few months of therapy or when the dose of medication is changed (increased or decreased).
In adult and pediatric patients treated with antidepressants for depression as well as for other indications, regardless of psychiatric illness, subjects have reported the following symptoms: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, impulsivity, inability to sit still (difficulty sitting still), hypomania, and mania. Although a causal relationship between these symptoms and clinical worsening of depression and/or risk of suicide has not been proven, these symptoms may be precursors to suicidal behavior.
If a patient’s depression continues to worsen, suicidal ideation/behavior develops, signs of exacerbation of depression, or precursors to suicide, especially if these symptoms are severe, emergent, or new, a change in treatment regimen should be considered, including the possible need to discontinue medication.
If a decision is made to discontinue treatment, the dose should be tapered as rapidly as possible due to the risk of discontinuation, being aware that certain symptoms may occur with abrupt discontinuation (see [DOSAGE]).
During treatment with antidepressants for depression or other indications (whether psychiatric or not), family members or caregivers are cautioned that the patient should be closely monitored for excitement, irritability, abnormal changes in behavior or other symptoms as described above, and suicidal ideation, and that these symptoms should be reported promptly to medical personnel or providers. Family members or caregivers should monitor the condition on a daily basis.
To reduce the risk of overdose, the smallest dose of tablets should be selected when prescribing this product, and should be accompanied by good patient management practices.
Screening Patients for Bipolar Disorder: Depressive episodes may be the initial manifestation of bipolar disorder and it is generally believed (although not confirmed by controlled clinical trials) that treatment of depressive episodes with antidepressants alone in patients at risk for bipolar disorder may increase the likelihood of exacerbation of their mixed/manic episodes. It is not clear whether this shift in symptoms also occurs as described above. Prior to initiating antidepressant therapy, patients should be adequately screened to determine if they are at risk for bipolar disorder; this screening should include a detailed psychiatric history, as well as a family history of suicide, bipolar disorder, and depression. It should be noted that this product is not approved for the treatment of bipolar disorder.
Possible interactions with monoamine oxidase inhibitors: Serious, even fatal, reactions have been reported with the combination of monoamine oxidase inhibitors (MAOI) in patients receiving one 5-hydroxytryptamine reuptake inhibitor, and these include hyperthermia, rigidity, myoclonus, autonomic instability with rapid fluctuations in vital signs, altered mental status (including extreme euphoria progressing to delirium and coma). These reactions have also been reported in patients who have recently discontinued such drugs and started treatment with a monoamine oxidase inhibitor. Some cases exhibit features similar to the malignant syndrome of nerve blockers. There are no data from human trials on the interaction of monoamine oxidase inhibitors with this product, and limited data from animal studies suggest that the combination of paroxetine hydrochloride and monoamine oxidase inhibitor analogues can exert a synergistic effect in raising blood pressure and inducing behavioral arousal. Therefore, combining this product with monoamine oxidase inhibitors (including the antibiotic linezolid, a reversible, nonselective monoamine oxidase inhibitor) is not recommended, nor is using this product within two weeks of discontinuing monoamine oxidase inhibitors (see [Contraindications]); monoamine oxidase inhibitors should not be used until at least two weeks after discontinuation of this product.
5-hydroxytryptamine syndrome or neuroblocker malignant syndrome-like reactions: Potentially fatal 5-hydroxytryptamine syndrome or neuroblocker malignant syndrome-like reactions may occur with selective norepinephrine reuptake inhibitors and selective 5-hydroxytryptamine reuptake inhibitors, including paroxetine, particularly 5-hydroxytryptaminergic drugs (including tretinoin) with drugs that decrease 5-hydroxytryptamine metabolism (including monoamine oxidase inhibitors). Symptoms of 5-hydroxytryptamine syndrome may include altered mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, fluctuating blood pressure, elevated body temperature), neuromuscular abnormalities (e.g., hyperreflexia, ataxia), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Severe cases of 5-hydroxytryptamine syndrome are similar to those of neuroblocker malignant syndrome and include fever, myotonia, autonomic disturbances with rapid fluctuations in vital signs, and altered mental status. Patients should be closely monitored for the development of signs and symptoms associated with 5-hydroxytryptamine syndrome or nerve blocker malignant syndrome.
Combination of paroxetine enteral extended-release tablets with monoamine oxidase inhibitor classes for the treatment of depression is contraindicated.
Caution and close clinical monitoring are required when this product is combined with a 5-hydroxytryptamine receptor agonist (treprostin), especially at the beginning of treatment and when increasing the dose.
Combination with 5-hydroxytryptamine precursor substances (e.g. tryptophan) is not recommended.
If any of these events occur, treatment with paroxetine hydrochloride enteral extended-release tablets and any combination 5-hydroxytryptaminergic or anti-dopaminergic medications, including antipsychotic medications, should be discontinued immediately and supportive symptomatic therapy initiated.
Possible interactions with methiodiazine: Methiodiazine alone prolongs the QTc interval and presents with severe ventricular arrhythmias such as tip-twisting ventricular tachycardia as well as sudden death. This effect appears to be dose dependent. An in vivo trial showed that CYP2D6-inhibiting drugs (e.g., paroxetine) can increase plasma levels of methiodiazine, so the combination of paroxetine and methiodiazine is not recommended (see [Contraindications]).
General Precautions.
Induction of Mania/Mild Mania: Pre-marketing studies showed that mania or mild mania occurred in approximately 1% of patients when paroxetine hydrochloride immediate-release tablets were used for the treatment of non-bipolar depressive disorder, compared with 1.1% in positive drug controls and only 0.3% in placebo controls. Among patients in the bipolar disorder subgroup, the rate of manic episodes was 2.2% in the paroxetine immediate-release tablet group compared to 11.6% in the positive control group. In controlled clinical trials of paroxetine hydrochloride enteric extended-release tablets for depression, no manic or hypomanic episodes were reported in any of the patients. As with all effective medications for the treatment of depression, paroxetine hydrochloride enteric extended-release tablets should be used with caution in patients with a history of mania.
Epilepsy: Pre-marketing trials of paroxetine hydrochloride immediate-release tablets showed that 0.1% of paroxetine-treated patients had seizures, a rate similar to other effective drugs for depression. In controlled clinical trials of paroxetine hydrochloride enteral extended-release tablets for depression, panic disorder, social anxiety disorder, or premenstrual dysphoric disorder, 1 patient out of 1627 had a seizure (approximately 0.1%). Paroxetine hydrochloride enteric extended-release tablets should be used with caution in patients with a history of epilepsy. Paroxetine Enteric Extended-Release Tablets should be discontinued when seizures occur in any patient.
Discontinuation of paroxetine hydrochloride enteral extended-release tablets: Adverse events upon discontinuation of paroxetine hydrochloride enteral extended-release tablets therapy have not been systematically evaluated in most clinical trials; however, in recent placebo-controlled clinical trials of paroxetine hydrochloride enteral extended-release tablets at doses up to 37.5 mg/day, spontaneous adverse events were evaluated after patients discontinued therapy. Patients receiving 37.5 mg/day continued treatment for 1 week at a dose of 25 mg/day by subtracting 12.5 mg/day before discontinuing treatment. For patients receiving 25 mg/day or 12.5 mg/day, the dose was not reduced prior to discontinuation of treatment. With this dosing regimen in the trial, adverse events with an incidence of 2% or more on treatment with paroxetine hydrochloride enteral extended-release tablets and at least two times higher than in the placebo group were reported as follows: including the presence of dizziness, nausea, nervousness and other symptoms associated with dose taper or discontinuation of paroxetine hydrochloride enteral extended-release tablets as described by the investigator (e.g., mood swings, headache, agitation, electroshock sensation, fatigue and sleep abnormalities ). 0.3% of these events reported by patients after discontinuation of paroxetine enteral extended-release tablets were serious adverse events.
During the marketing of paroxetine hydrochloride enteral extended-release tablets and other selective 5-hydroxytryptamine reuptake inhibitors and selective norepinephrine reuptake inhibitors, spontaneous adverse events reported upon discontinuation of treatment with these drugs (especially abruptly) included the following symptoms: anxiety, irritability, agitation, dizziness, sensory abnormalities (e.g., sensory confusion such as electroconvulsive sensation and tinnitus), anxiety, confusion, headache, drowsiness, mood swings, and loss of sleep. drowsiness, mood swings, insomnia, and hypomania. Although these symptoms are usually self-limiting, severe withdrawal symptoms have been reported.
Patients should be monitored for these symptoms when discontinuing treatment with paroxetine hydrochloride enteral extended-release tablets. Whenever possible, gradual dose reductions are recommended rather than abrupt discontinuation. If intolerable symptoms occur at the time of dose reduction or discontinuation of therapy, consider resuming the previously prescribed dose. Subsequently, dose reductions may be continued at a more gradual rate of dose reduction (see [DOSAGE]).
Tamoxifen: Some clinical studies suggest that the combination with paroxetine may reduce the efficacy of paroxetine in terms of risk of breast cancer recurrence/mortality due to its irreversible inhibition of CYP2D6 (see Interactions). This risk may increase with longer duration of combined drug use. When tamoxifen is used to combat breast cancer, prescribers should consider using antidepressants that have little or no inhibitory effect on CYP2D6.
Sedentary inability: Sedentary inability may occur with the use of this or other selective 5-hydroxytryptamine reuptake inhibitors and is characterized by irritable internal feelings and psychomotor excitement, such as the inability to sit still or stand quietly, and is usually accompanied by subjective distress. This condition is most likely to occur within the first few weeks of treatment.
Hyponatremia: Selective 5-hydroxytryptamine reuptake inhibitors and selective norepinephrine reuptake inhibitors (including paroxetine hydrochloride enteral extended-release tablets) may cause hyponatremia following treatment. In many cases, hyponatremia occurs as a result of an abnormal antidiuretic hormone secretion syndrome. Cases of serum sodium below 110 mmol/L have been reported. The risk of hyponatremia is higher in elderly patients when treated with selective 5-hydroxytryptamine reuptake inhibitors and selective norepinephrine reuptake inhibitors. Patients on diuretics or patients with reduced volume are also at higher risk of hyponatremia (see [Geriatric Use]). In patients with symptomatic hyponatremia, discontinuation of paroxetine hydrochloride enteral extended-release tablet therapy should be considered and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness in standing, with the potential for falls from unsteadiness in standing. More severe or/and urgent signs and symptoms include: hallucinations, syncope, seizures, coma, respiratory arrest, and death.
Abnormal bleeding: 5-hydroxytryptamine reuptake inhibitors and selective noradrenaline reuptake inhibitors, including paroxetine, may increase the risk of bleeding events. Skin and mucosal bleeding (including gastrointestinal and gynecologic bleeding) has been reported following administration of this product. Combination with aspirin, NSAIDs, warfarin, and other anticoagulants may similarly increase the risk of bleeding. Case reports and epidemiologic trials (both case-control and cohort designs) have confirmed the association between drugs that interfere with 5-hydroxytryptamine reuptake and the occurrence of upper gastrointestinal bleeding. Bleeding events associated with the use of 5-hydroxytryptamine reuptake inhibitors and selective norepinephrine reuptake inhibitors can manifest as petechiae, hematomas, epistaxis, petechiae up to life-threatening bleeding. Patients should be warned about the risk of concomitant hemorrhage when paroxetine is combined with NSAIDs, aspirin, or other drugs that affect coagulation mechanisms (see [Adverse Reactions]).
Use in patients with co-morbidities: Clinical experience with paroxetine hydrochloride immediate-release tablets in some patients with concomitant other systemic diseases is limited. Caution should be advised in the use of paroxetine hydrochloride enteric extended-release tablets in patients with diseases or conditions that affect metabolism or affect hemodynamic responses.
As with other selective 5-hydroxytryptamine reuptake inhibitors, dilated pupils have been reported infrequently in premarketing trials of paroxetine hydrochloride. There are very few reports in the literature of acute angle-closure glaucoma associated with paroxetine immediate-release tablets. Because pupil dilation can cause acute angle-closure glaucoma in patients with narrow-angle glaucoma, paroxetine enteric extended-release tablets should be used with caution in patients with narrow-angle glaucoma.
Paroxetine hydrochloride enteric extended-release or immediate-release tablets have not been evaluated in any patients with recent myocardial infarction or unstable heart disease. Patients with these conditions were not included in premarketing clinical trials. In double-blind, placebo-controlled clinical trials, ECG analysis of 682 patients who received paroxetine hydrochloride immediate-release tablets showed no correlation between paroxetine hydrochloride application and significant abnormalities of the ECG. Similarly, paroxetine hydrochloride did not cause clinically meaningful changes in heart rate or blood pressure.
Patients with severe renal impairment (creatinine clearance <30 ml/min) or severe hepatic impairment may present with elevated plasma paroxetine concentrations. A lower initial dose should be used in such patients (see [DOSAGE]).
NOTE TO PATIENTS: Paroxetine Hydrochloride Enteric Extended-Release Tablets should be swallowed whole and not chewed or crushed.
Patients should be cautioned about the risk of 5-hydroxytryptamine syndrome associated with the combination of paroxetine hydrochloride enteral extended-release tablets with trimetazidine, tramadol, or other 5-hydroxytryptaminergic drugs.
The prescribing physician or other health care provider should inform the patient, the patient’s family, and the patient’s caregiver about the benefits and risks associated with the use of paroxetine hydrochloride and should instruct them on its appropriate use. Guidelines have been prepared and printed for the use of paroxetine in patients: “Antidepressants, Depressive Disorders, and Other Serious Mental Illnesses and Suicidal Ideation or Behavior. The prescriber or provider should inform the patient, the patient’s family, and the patient’s caregiver to read the medication guide and should help them understand its contents. The contents of the medication guide should be discussed with the patient and the patient’s questions should be answered. The full text of the Medication Guide is attached to this leaflet.
When taking Paroxetine Hydrochloride Enteric Extended-Release Tablets patients should be advised to ask their doctor promptly if they have any of the following problems
Risk of clinical deterioration and suicide: Patients, their families, and the patient’s caregivers should be encouraged to be alert for the onset of some symptoms, especially early in the course of antidepressant therapy or when the medication dose is increased or decreased. These symptoms include anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggression, hyperactivity, inability to sit still (psychomotor hyperactivity), hypomania, mania, other behavioral abnormalities, worsening depression, and suicidal ideation. It is essential to caution the patient’s family and the patient’s caregivers to observe these symptoms daily, as the condition can change suddenly. Report these symptoms to the patient’s physician when they occur, especially if they are severe, occur suddenly, or are new. The appearance of these symptoms may be associated with an increased risk of suicidal ideation and suicidal behavior and suggests the need for very close observation and possible adjustment of medication.
Drugs affecting coagulation (NSAIDs, aspirin, warfarin, etc.): Patients should be cautioned to use paroxetine in combination with NSAIDs, aspirin, or other drugs affecting coagulation, as psychiatric drugs that interfere with 5-hydroxytryptamine reuptake can increase the risk of bleeding when combined with these drugs.
Cognitive and motor effects: Any psychiatric drug may affect judgment, thinking, and motor skills. Although controlled trials have not shown significant impairment of psychomotor performance with paroxetine hydrochloride immediate-release tablets, patients should be cautioned not to operate dangerous mechanical devices (including driving) until they are confident that paroxetine hydrochloride enteral extended-release tablets do not affect their psychomotor performance.
Completion of treatment course: Although patients may show clinical improvement by 1-4 weeks of treatment with paroxetine hydrochloride enteral extended-release tablets, patients should be advised to continue treatment as prescribed.
Combination of medications: Because there are potential drug interactions with combination medications, patients should be advised to inform their physician of any prescription or over-the-counter medications they are currently using or intend to use.
Alcohol: Although paroxetine hydrochloride immediate-release tablets do not exacerbate alcohol-induced impairment of mental and motor function, patients should be advised to avoid alcohol while using paroxetine hydrochloride enteric-coated extended-release tablets.
Substance Abuse and Dependence.
Drug Control Level: paroxetine enteral extended-release tablets is not a controlled substance.
Somatic and Psychiatric Dependence: Studies related to the potential abuse risk, tolerance and somatic dependence of paroxetine in animals and humans have not been systematically conducted. Also, clinical trials have not shown any tendency for patients to engage in drug foraging behavior, and these study observations are not systematic or sufficient to predict the potential for misuse or conversion to abuse once the CNS-active drug is available. Therefore, the patient’s history of drug abuse should be evaluated in detail, and patients with a history of drug abuse should be closely monitored for signs of paroxetine enteral extended-release tablet misuse and abuse (e.g., development of tolerance, increased dosage, and foraging behavior).
The following applies only to Paroxetine Hydrochloride Enteric Extended-Release Tablets 12.5 mg size.
Paroxetine Hydrochloride Enteric Extended-Release Tablets 12.5 mg is coated (Obadiah Yellow: YS-1-2007) with an azo dye colorant sunset yellow aluminum precipitate (FD&C Yellow No. 6 aluminum precipitate) that may cause allergic-type reactions.
[For use during pregnancy and lactation].
Teratogenic effects.
Epidemiological studies have demonstrated an increased risk of cardiovascular malformations, primarily septal and atrial septal defects, in infants born to mothers exposed to paroxetine during the first trimester of pregnancy. In general, septal defects can be symptomatic and may require surgical treatment, or they can be asymptomatic and recover on their own. If a patient becomes pregnant while taking paroxetine, she should be informed of the potential hazards to the fetus. Consideration should be given to discontinuing paroxetine therapy or changing to another antidepressant unless it is demonstrated that continued paroxetine therapy is beneficial to the mother (see [Precautions] – Discontinuing Treatment with Paroxetine Hydrochloride Enteric Extended-Release Tablets). In women who are planning to become pregnant or in the first trimester of pregnancy, paroxetine treatment should be initiated only after other treatment options have been considered.
A study based on information from the Swedish National Registry evaluated 6,896 infants born to women exposed to antidepressants in early pregnancy (5,123 women exposed to selective 5-hydroxytryptamine reuptake inhibitors, including 815 exposed to paroxetine). Infants exposed to paroxetine in early gestation had an increased risk of cardiovascular malformations (particularly ventricular septal and atrial septal defects) compared with the overall registry population (hazard ratio 1.8; 95% confidence interval 1.1-2.8). The incidence of cardiovascular malformations after early exposure to paroxetine was 2%, relative to 1% in the overall enrolled population. In infants also exposed to paroxetine, examination of the data showed no increased risk of overall congenital malformations.
In another retrospective cohort study, the infants of 5,956 women who were prescribed paroxetine or other antidepressants in the first trimester of pregnancy (n = 815 for paroxetine) were evaluated using the US Medicare data. The study demonstrated an increased risk of cardiovascular malformations with paroxetine compared with other antidepressants (hazard ratio 1.5; 95% confidence interval 0.8-2.9). The incidence of cardiovascular malformations after exposure to paroxetine in the first trimester of pregnancy was 1.5% compared with 1% for other antidepressants. Of the 12 infants born to mothers prescribed paroxetine in the first trimester, 9 had ventricular septal defects. The study suggested an increased risk of major congenital malformations (including cardiovascular malformations) overall with paroxetine compared with other antidepressants (hazard ratio 1.8; 95% confidence interval 1.2-2.8). The incidence of all congenital malformations after early exposure to paroxetine was 4% compared with 2% for other antidepressants.
Non-teratogenic effects :
Neonates exposed in the second trimester to paroxetine hydrochloride enteral extended-release tablets or other selective
5-hydroxytryptamine reuptake inhibitors, or 5-hydroxytryptamine and norepinephrine reuptake inhibitors can present with comorbidities requiring extended hospitalization, respiratory support, and tube feeding. These comorbidities can occur immediately after birth. Reported clinical findings include: respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, hypersensitivity, irritability, and frequent crying. These manifestations are consistent with the direct toxic effects of selective 5-hydroxytryptamine reuptake inhibitors or selective norepinephrine reuptake inhibitors, or drug withdrawal syndrome. It should be noted that in some cases the clinical manifestations are consistent with 5-hydroxytryptamine syndrome (see [Precautions] – Potential Interactions with Monoamine Oxidase Inhibitors).
Exposure to selective 5-hydroxytryptamine reuptake inhibitors in late pregnancy may increase the risk of persistent pulmonary hypertension in the newborn. Persistent neonatal pulmonary hypertension has an incidence of 1 to 2 per 1,000 in the overall population of surviving neonates and is associated with neonatal morbidity and mortality. In a case-control retrospective study, 377 newborns had persistent pulmonary hypertension and 836 were normal, and exposure to selective 5-hydroxytryptamine reuptake inhibitors after the 20th week of gestation resulted in a 6-fold increased risk of persistent pulmonary hypertension in newborns compared with no exposure to antidepressants during gestation. This is the first study of this risk, and there is no conclusive evidence of the risk of persistent neonatal pulmonary hypertension following exposure to selective 5-hydroxytryptamine reuptake inhibitors during pregnancy. The study did not include enough cases of exposure to a single selective 5-hydroxytryptamine reuptake inhibitor to determine whether all selective 5-hydroxytryptamine reuptake inhibitors have similar levels of risk of persistent neonatal pulmonary hypertension.
Patients should be advised to inform their physician of their pregnancy if they become pregnant or plan to become pregnant during treatment.
There have also been post-marketing reports of preterm delivery in pregnant women exposed to paroxetine or other selective 5-hydroxytryptamine reuptake inhibitors. Physicians should carefully consider the potential risks and benefits of treatment in women receiving paroxetine in the second trimester of pregnancy (see [DOSAGE AND ADMINISTRATION]). Physicians should note that in a prospective study of 201 patients with a history of depression who were normal at the start of pregnancy, women who stopped taking antidepressants during pregnancy were more likely to experience a recurrence of depression compared with women who continued taking antidepressants.
Fertility: Some clinical trials have shown that SSRIs (including paroxetine) may affect sperm quality. This effect has been shown to be reversible after treatment discontinuation. Changes in sperm quality may affect fertility in some men.
Labor and delivery: The effects of paroxetine on labor and delivery in humans are not known.
Lactation: As with many other drugs, paroxetine is secreted with breast milk and therefore paroxetine should be used with caution in nursing women. If patients are breastfeeding their infants, they should be advised to inform their physicians about the breastfeeding.
Pediatric Use]
Safety and efficacy in pediatric populations have not been established (see [Precautions] – Clinical Deterioration and Risk of Suicide). Data from three placebo-controlled clinical trials in which 752 children with depression were enrolled in clinical trials of paroxetine do not adequately support the use of this product in children.
In placebo-controlled clinical trials of paroxetine in pediatric patients, adverse events that occurred in children receiving paroxetine hydrochloride immediate-release tablets at a rate of at least 2% and at least twice the rate of children in the placebo group included mood instability (including suicidal ideation, suicide attempts, mood changes, and crying), nervousness, dizziness, nausea, and abdominal pain (see [PRECAUTIONS] – Discontinuation of Paroxetine Hydrochloride Therapy).
[Geriatric use].
Clinically significant hyponatremia may occur with selective 5-hydroxytryptamine reuptake inhibitors and selective norepinephrine reuptake inhibitors, including paroxetine, in elderly patients at greater risk for hyponatremia (see [Precautions] – Hyponatremia).
In pre-marketing, global clinical trials of paroxetine hydrochloride immediate-release tablets, 17% of patients treated with paroxetine hydrochloride immediate-release tablets (approximately 700 patients) were 65 years of age or older. Pharmacokinetic trials showed reduced clearance of paroxetine hydrochloride immediate-release tablets in older patients, and a lower initial dose was recommended; however, there was no overall difference in adverse events between older and non-older patients, and effectiveness was similar in younger and older patients (see [DOSAGE]).
Drug Interactions]
In vitro drug interaction tests have shown that paroxetine inhibits cytochrome P450 2D6. In clinical drug interaction tests with cytochrome P450 2D6 substrates, paroxetine was observed to inhibit the metabolism of drugs that are metabolized by cytochrome P450 2D6, including desipramine, risperidone, and atoxetine.
Tryptophan: As with other 5-hydroxytryptamine reuptake inhibitors, there may be an interaction between paroxetine and tryptophan when they are combined. Adverse events have been reported when tryptophan and paroxetine hydrochloride immediate-release tablets are combined, manifesting as: headache, nausea, excessive sweating, and dizziness. Therefore, the combination of paroxetine hydrochloride enteric extended-release tablets and tryptophan is not recommended. (See [Precautions]-5-hydroxytryptamine syndrome)
Monoamine oxidase inhibitors: See [Contraindications] and [Precautions].
Pimozide: In a controlled clinical trial in healthy volunteers, after paroxetine hydrochloride immediate-release tablets were incremented to 60 mg daily, a single dose of 2 mg pimozide in combination with paroxetine increased the AUC and Cmax of pimozide by 151% and 62%, respectively, compared to the pimozide alone group. the increase in AUC and Cmax was attributed to paroxetine’s effect on cytochrome P450 2D6 inhibition. The combination of pimozide with this product is contraindicated because of its treatment of index stenosis and its effect on prolonging the QT interval (see [Contraindications]).
5-hydroxytryptaminergic drugs: Based on the mechanism of action of selective norepinephrine reuptake inhibitors and 5-hydroxytryptamine reuptake inhibitors (including paroxetine hydrochloride), and the potential for 5-hydroxytryptamine syndrome, caution is advised in combining paroxetine hydrochloride enteric extended-release tablets with other drugs that may affect the 5-hydroxytryptaminergic neurotransmitter system, e.g., trimetazidine, linezolid (a reversible non-selective monoamine oxidase inhibiting antibiotic), lithium, tramadol, or St. John’s Wort preparations (Guangyelian preparation) (see [Precautions]-5-hydroxytryptamine syndrome). The combination of paroxetine hydrochloride enteric extended-release tablets with monoamine oxidase inhibitors (including linezolid) is contraindicated. The combination of paroxetine hydrochloride enteral extended-release tablets with other selective 5-hydroxytryptamine reuptake inhibitors, selective norepinephrine reuptake inhibitors, or tryptophan is not recommended. Combination with monoamine oxidase inhibitors (including the antibiotic linezolid, a reversible, non-selective monoamine oxidase inhibitor, and methylene blue (hypromellose)) is strictly prohibited. (See [Precautions] – [Drug Interactions], Tryptophan)
Thioridazine: See [Contraindications] and [Precautions].
Warfarin: Preliminary data suggest a pharmacodynamic interaction between paroxetine and warfarin in combination (bleeding tendency even if prothrombin time is unchanged). Due to the lack of clinical experience, caution should be exercised when combining paroxetine hydrochloride enteric-coated extended-release tablets with warfarin (see
Drugs affecting coagulation mechanisms).
Tretinoin: Rare post-marketing reports of 5-hydroxytryptamine syndrome following the combination of selective 5-hydroxytryptamine reuptake inhibitors with tretinoin. If paroxetine is clinically indicated in combination with a tretinoin, patients are advised to monitor carefully, especially at the beginning of treatment and at increasing doses (see [Precautions] – 5-hydroxytryptamine syndrome).
Drugs affecting hepatic metabolism: Inducers or inhibitors of drug metabolizing enzymes can affect the metabolism and pharmacokinetics of paroxetine.
Cimetidine: Cimetidine inhibits a variety of cytochrome P450 (oxidative) enzymes. In a clinical trial, oral paroxetine hydrochloride immediate-release tablets (30 mg once daily) for 4 weeks, combined with oral cimetidine (300 mg three times daily) for the last week, increased steady-state paroxetine plasma concentrations by approximately 50%. Therefore, when these two drugs are combined, the dose of paroxetine enteric-coated extended-release tablets should be adjusted according to clinical efficacy after the initial dose. Studies on the effect of paroxetine on the pharmacokinetics of cimetidine have not been performed.
Phenobarbital: Phenobarbital can induce a variety of cytochrome P450 (oxidative) enzymes. When phenobarbital (100 mg once daily for 14 days) reached steady state with a single oral dose of 30 mg of paroxetine hydrochloride immediate-release tablets; paroxetine AUC was reduced and T1/2 was shortened (mean 25% and 38%, respectively) compared to a single oral dose of paroxetine hydrochloride only. Studies on the pharmacokinetic effects of paroxetine on phenobarbital have not been performed. Because of the nonlinear pharmacokinetic characteristics of paroxetine, the results of this trial do not reflect the long-term combined application of these two drugs. No initial dose adjustment is required when paroxetine hydrochloride enteral extended-release tablets and phenobarbital are combined, with subsequent dose adjustment based on clinical effects.
Phenytoin: When oral phenytoin (300 mg once daily for 14 days) reached steady state with a single dose of 30 mg of oral paroxetine hydrochloride immediate-release tablets; a reduction in AUC and a shortening of T1/2 was observed with paroxetine compared with a single dose of oral paroxetine hydrochloride immediate-release tablets only (mean of 50% and 35%, respectively). In another study, oral administration of a single dose of phenytoin 300 mg at the time oral paroxetine hydrochloride (30 mg once daily for 14 days) reached steady state resulted in a mild decrease in AUC for phenytoin (mean 12%) compared with oral administration of a single dose of phenytoin only. Considering the nonlinear pharmacokinetic characteristics of these two drugs, the above findings do not reflect the long-term combined application of these two drugs. No initial dose adjustment is required for the combination of paroxetine hydrochloride enteral extended-release tablets and phenytoin, with subsequent dose adjustment based on clinical effects (see [Adverse Reactions] – Postmarketing Reports).
Neuromuscular blocking agents: SSRIs may decrease plasma cholinesterase activity, resulting in prolonged neuromuscular blocking effects of mevisone and scrim.
Drugs metabolized by cytochrome CYP 2D6: Most effective antidepressants (paroxetine, other selective 5-hydroxytryptamine reuptake inhibitors, and many tricyclic antidepressants) are metabolized by CYP 2D6, an isoenzyme of cytochrome enzyme P As with other drugs metabolized by CYP 2D6, paroxetine significantly inhibits the activity of these isoenzymes, and in most patients (>90%), these CYP 2D6 enzymes are saturated soon after paroxetine administration. In a study in which daily oral paroxetine 20 mg was administered to reach steady state followed by a single oral dose of desipramine 100 mg, the Cmax, AUC, and T½ of paroxetine were approximately 2-fold, 5-fold, and 3-fold higher, respectively.
The combination of paroxetine with risperidone (a substrate of cytochrome CYP 2D6) was likewise evaluated. In Trial 1, the combination of risperidone (4-8 mg/day) increased mean plasma concentrations of risperidone by approximately 4-fold, decreased 9-hydroxyrisperidone concentrations by approximately 10% and increased active ingredient concentrations (sum of risperidone and 9-hydroxyrisperidone) by approximately 1.4-fold when patients were taking 20 mg of oral paroxetine daily to reach steady state.
The effect of paroxetine on the pharmacokinetics of atoxetine was evaluated when paroxetine was combined with atoxetine and steady state was achieved. In healthy volunteers with extensive cytochrome P450 metabolism, daily paroxetine 20 mg was combined with atoxetine 20 mg every 12 hours. The combination resulted in a 6- to 8-fold increase in atoxetine steady-state AUC values and a 3- to 4-fold increase in atoxetine Cmax values compared with atoxetine alone. Atoxetine dose adjustment is required when paroxetine is administered, and a lower initial dose of atoxetine is recommended.
Formal trials of the combination of paroxetine hydrochloride enteric extended-release tablets with other drugs metabolized via cytochrome CYP 2D6 have not been performed, but may require lower doses of paroxetine hydrochloride or other drugs than the conventional dose.
Therefore, paroxetine hydrochloride enteral extended-release tablets should be used with caution in combination with drugs metabolized by the CYP 2D6 enzyme, including drugs effective in the treatment of depression (e.g., nortriptyline, amitriptyline, promethazine, desipramine, and fluoxetine), phenothiazines, risperidone, tamoxifen, class IC antiarrhythmic drugs (e.g., propafenone, flecainide, and encainide), or CYP 2D6 enzyme inhibitors (e.g., quinidine).
However, the combination of paroxetine with methotrexate is contraindicated given the potential risk of severe ventricular arrhythmias and sudden death due to the elevated plasma concentrations of methotrexate (see [Contraindications] and [Precautions]).
Tamoxifen is metabolized by CYP2D6 to produce an important active metabolite, endoxifen (4-hydroxy-n-demethyltamoxifen), which has a major role in the efficacy of tamoxifen. Irreversible inhibition of CYP2D6 by paroxetine leads to a decrease in blood levels of endoxifen (4-hydroxy-n-demethyltamoxifen) (see [Precautions]).
At steady state, when the CYP 2D6 enzymatic metabolic pathway is largely saturated, paroxetine clearance is dependent on alternative P450 isozymes, unlike CYP 2D6, for which there is no evidence of saturation (see [Precautions] – Tricyclic Antidepressants).
Drugs metabolized by cytochrome CYP3A4: In an in vivo trial of drug-drug interactions between paroxetine and terfenadine (a substrate of the CYP3A4 enzyme) upon reaching steady state, the results showed no effect of paroxetine on the pharmacokinetics of terfenadine. Another in vitro study showed that ketoconazole, a potent inhibitor of CYP3A4 activity, inhibited the metabolism of several CYP3A4 substrates (e.g., terfenadine, astemizole, cisapride, triazolam, and cyclosporine) at least 100 times more than paroxetine. Based on the Ki of in vitro experiments with paroxetine and the lack of effect of in vivo tests on terfenadine clearance, the metabolic effects of paroxetine on other CYP3A4 substrates are presumed, and the inhibitory effect of paroxetine on CYP3A4 enzyme activity is unlikely to be clinically significant.
Tricyclic antidepressants: Because paroxetine may inhibit the metabolism of tricyclic antidepressants, paroxetine enteric extended-release tablets should be used with caution in combination with tricyclic antidepressants. If tricyclic antidepressants are used in combination with paroxetine hydrochloride enteral extended-release tablets, the blood levels of tricyclic antidepressants should be monitored and the dose of tricyclic antidepressants may need to be reduced (see [Precautions] – Drugs Metabolized by CYP2D6).
Drugs with high plasma protein binding: Because paroxetine has a high binding rate to plasma proteins, oral paroxetine hydrochloride enteral extended-release tablets may increase the free concentration of other drugs when the patient is taking other drugs with a high protein binding rate, leading to the potential for adverse events. Conversely, when protein-bound paroxetine is replaced by other drugs, this may also lead to the potential for adverse events.
Drugs affecting coagulation mechanisms (NSAIDs, aspirin, warfarin, etc.): 5-hydroxytryptamine released by platelets has an important hemostatic effect. Psychiatric drugs that interfere with 5-hydroxytryptamine reuptake have been shown to be associated with the occurrence of upper gastrointestinal bleeding in case-control and cohort-designed epidemiological trials, as well as a potential risk of bleeding when combined with NSAIDs or aspirin. Altered anticoagulant effects, including bleeding, have been reported with selective norepinephrine reuptake inhibitors or selective 5-hydroxytryptamine reuptake inhibitors in combination with warfarin. Patients receiving warfarin therapy should be closely monitored when starting or discontinuing paroxetine.
Alcohol: Although paroxetine does not exacerbate alcohol-induced psychiatric and motor disorders, patients are advised to avoid alcohol while taking paroxetine.
Lithium salts: Multi-dose studies have shown no pharmacokinetic interaction between paroxetine hydrochloride immediate-release tablets and lithium carbonate. However, due to the potential for 5-hydroxytryptamine syndrome, paroxetine hydrochloride immediate-release tablets should be used with caution in combination with lithium salts.
Digoxin: Under steady-state conditions, digoxin has no effect on the steady-state pharmacokinetics of paroxetine. In the presence of paroxetine, the mean steady-state AUC of digoxin decreased by 15%. Due to little clinical experience, paroxetine hydrochloride enteric extended-release tablets should be used with caution in combination with digoxin.
Diazepam: Under steady-state conditions, diazepam does not affect the pharmacokinetics of paroxetine. The effect of paroxetine on the pharmacokinetics of diazepam has not been evaluated.
Procyclidine: Oral paroxetine hydrochloride immediate-release tablets (30 mg once daily) increased the steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg once daily orally) by 35%, 37%, and 67%, respectively, compared with procyclidine alone under steady-state conditions. If an anticholinergic effect is observed, the dose of procyclidine should be reduced.
Beta-blockers: In one study, oral propranolol (80 mg twice daily) for 18 days, combined with oral paroxetine hydrochloride immediate-release tablets (30 mg once daily) for the second 10 days did not affect the steady-state plasma concentration of propranolol. The effect of propranolol on the pharmacokinetics of paroxetine has not been evaluated (see [Adverse Reactions] – Postmarketing Reports).
Theophylline: Elevated theophylline concentrations have been reported with paroxetine hydrochloride immediate-release tablets. Because formal drug interaction trials have not been performed, monitoring of theophylline blood concentrations is recommended when these two drugs are combined.
Furosemivir/ritonavir: The combination of furosemivir/ritonavir and paroxetine significantly reduces paroxetine plasma concentrations. Dose adjustments should be made based on clinical effects (tolerability and efficacy).
Electroconvulsive therapy (ECT): There are no studies on the combined application of paroxetine hydrochloride enteric extended-release tablets and ECT.
[Drug overdose].
Since the introduction of paroxetine hydrochloride immediate-release tablets in the United States and their widespread use worldwide (around 1999), there have been 342 reported cases of intentional or accidental overdose. These include overdoses of paroxetine alone or in combination with other drugs. Of these, 48 deaths occurred, 17 with paroxetine alone. 8 confirmed deaths on paroxetine were extensively interfered with by other conditions, including the combination of other medications or the presence of alcohol or apparent co-morbidities. The majority of the 145 non-fatal cases with known clinical outcomes recovered without residual sequelae. The maximum intake in patients with known recovery was 2000 mg (equivalent to 33 times the maximum recommended daily dose).
Common adverse events associated with paroxetine overdose include drowsiness, coma, nausea, tremor, palpitations, confusion, vomiting, and vertigo. Other notable signs and symptoms of paroxetine overdose alone (or in combination with other substances) are: dilated pupils, convulsions (including status epilepticus), ventricular arrhythmias (including tip-twisting ventricular tachycardia), hypertension, aggressive behavior, syncope, hypotension, coma, bradycardia, dystonia, rhabdomyolysis, signs of hepatic impairment (including: hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis). jaundice, hepatitis, and hepatic steatosis), 5-hydroxytryptamine syndrome, manic reaction, myoclonus, acute renal failure, and urinary retention.
Management of drug overdose.
This includes general management of drug overdose in the treatment of depression.
Ensure patency of the airway, oxygenation and ventilation. Monitor heart rate and vital signs, supportive therapy and symptomatic management. The use of emetic therapy is not recommended. If needed, gastric lavage is indicated for patients who have ingested the drug for a short time or are symptomatic, and care should be taken to keep the airway open when using a large-bore gastric lavage tube.
Activated charcoal therapy should be given. The use of diuresis, dialysis, volume expansion and blood replacement is unlikely to be beneficial due to the large volume of distribution of the drug. There is no specific antidote for paroxetine.
Be especially wary of patients who may have ingested an overdose of tricyclic antidepressants and who have taken or are currently taking paroxetine. In such cases, accumulation of tricyclic prodrugs and their active metabolites increases the likelihood of sequelae and prolongs the time required for close medical observation (see [Precautions] – Drugs Metabolized by Cytochrome CYP2D6).
In the management of overdose, the possibility of multiple drug combinations should be taken into account.
Clinical trials]
Two 12-week, dose-adjustable, placebo-controlled clinical trials in patients meeting the American Diagnostic Statistical Manual of Mental Disorders (4th edition) criteria for depression have been conducted to evaluate the effectiveness of paroxetine hydrochloride enteral extended-release tablets in the treatment of depression. Patients in one clinical trial ranged in age from 18 to 65 years, while patients in the other trial were aged 60 to 88 years old. The results of the two clinical trials showed that paroxetine hydrochloride enteral extended-release tablets were significantly more effective than placebo in the treatment of depression, as measured by the Hamilton Depression Rating Scale (HDRS), Hamilton Depressive Mood Phase, and Clinical General Impression Inventory (CGI)-severity of illness scores.
In another completed clinical trial, outpatients with depression (HDRS total score <8) who were given paroxetine hydrochloride immediate-release tablets effective during an 8-week open treatment period and subsequently randomized to paroxetine hydrochloride immediate-release tablets or placebo for one year demonstrated a significantly lower relapse rate in the paroxetine hydrochloride immediate-release group (15%) than in the placebo group (39%), and a similar effectiveness in male and The effectiveness was similar in female patients.
There was not enough information in these clinical trials to determine the effect of race or age on the results.
Pharmacology and Toxicology
Pharmacological effects
Paroxetine hydrochloride is a potent, highly selective 5-hydroxytryptamine reuptake inhibitor. The mechanism of action of paroxetine hydrochloride is to increase the concentration of 5-hydroxytryptamine in the synaptic gap and to enhance central 5-hydroxytryptamine neurological function. It only weakly inhibits the reuptake of norepinephrine and dopamine and has little or no affinity for muscarinic receptors, adrenergic α1, α2, and β receptors, dopamine 2 (D2) receptors, 5-hydroxytryptamine 1 and 2 (5-HT1 and 5-HT2) receptors, and histamine H1 receptors. No inhibitory effect on monoamine oxidase.
Toxicological studies
Genotoxicity: Paroxetine bacterial reversion mutation test, mouse lymphoma test, in-program DNA synthesis test, human lymphocyte chromosome aberration test, mouse bone marrow micronucleus test and rat dominant lethality test all showed negative results.
Reproductive toxicity: In the reproductive toxicity test, the conception rate was decreased in rats given paroxetine 15 mg/kg/day [approximately twice the recommended maximum human dose (MRHD) in mg/m2]. Irreversible damage to the reproductive tract of male rats (epithelial vacuole formation in the epididymal duct visible at 50 mg/kg/day and testicular vas deferens atrophy accompanied by spermatogenesis inhibition at 25 mg/kg/day) was observed in toxicity tests from 2 to 52 weeks. No teratogenic effects were observed in rats and rabbits given paroxetine up to 50 mg/kg/day and 6 mg/kg/day (8 and 2 times the MRHD in mg/m2), respectively, during the organogenesis phase. However, in rats administered continuously during late gestation and throughout lactation, pup mortality increased during the first 4 days of lactation, which occurred at 1 mg/kg/day (equivalent to approximately 1/6 of MRHD in mg/m2), the cause of mortality is unknown, and a no-effect dose for pup mortality could not be determined.
Carcinogenicity: In a two-year carcinogenicity test in rodents administered by adulteration, mice and rats were given paroxetine at doses up to 25 mg/kg/day and 20 mg/kg/day (equivalent to 2 and 3 times the MRHD in mg/m2, respectively). The incidence of reticulocytoma was significantly increased in male rats in the high dose group (1/100, 0/50, 0/50, 4/50 in the control, low, medium and high dose groups, respectively), with a dose-dependent increase in the incidence of lymphoreticular endothelial cell tumors. No effect was seen in female rats. A dose-related increase in the number of tumors was observed in mice, but no drug-related increase was seen in the number of mice that developed tumors. The relevance of these findings to humans is unclear.
[Pharmacokinetics].
Paroxetine hydrochloride solution is completely absorbed after oral administration. The clearance half-life after a single oral dose of paroxetine hydrochloride enteric extended-release tablets is approximately 15 to 20 hours. Paroxetine is completely metabolizable and its metabolites are inactive. A non-linear expression of pharmacokinetic parameters with increasing dose was observed. Paroxetine is partially metabolized by cytochrome P450 2D6-mediated metabolism, and the metabolites are excreted mainly by the kidneys and to a lesser extent by the feces. The pharmacokinetic behavior of paroxetine has not been evaluated in cytochrome P450 2D6-deficient subjects (those with poor metabolism).
Absorption and Distribution: Paroxetine hydrochloride enteric extended-release tablets contain a biodegradable polymer matrix (Geomatrix™) that is used to control the rate of dissolution of paroxetine over a period of approximately 4 to 5 hours. In addition to controlling the rate of drug release in the body, the enteric coating delays the onset of drug release in the body, pending the release of paroxetine hydrochloride enteric extended release tablets into the intestine.
Following oral administration of the hydrochloride solution, paroxetine hydrochloride can be completely absorbed. In a pharmacokinetic trial of a single dose of oral paroxetine hydrochloride enteric extended-release tablets (test doses included: 12.5 mg, 25 mg, 37.5 mg, and 50 mg) in healthy male and female subjects (n = 23), the peak concentrations (Cmax) and AUC0-inf of paroxetine were nonlinearly related to drug dose (which is similar to that observed in the immediate-release form of paroxetine hydrochloride The time to peak (Tmax) was generally between 6 and 10 h after dosing, indicating a reduced absorption rate of enteric extended-release tablets compared with the immediate-release form. The bioavailability of paroxetine hydrochloride enteric extended-release tablets (25 mg) is not affected by food.
Paroxetine is widely distributed throughout the body, including the central nervous system, with only 1% present in plasma.
At concentrations of 100ng/ml and 400ng/ml, paroxetine binds to plasma proteins at approximately 95% and 93%, respectively. In vitro, paroxetine does not affect the binding of phenytoin or warfarin to plasma proteins.
Metabolism and excretion: The mean clearance half-life after a single oral dose of paroxetine hydrochloride enteric extended-release tablets (doses of 12.5 mg, 25 mg, 37.5 mg, and 50 mg) is 15 to 20 hours. Continuous oral administration of 25 mg/day of paroxetine hydrochloride enteric extended-release tablets resulted in steady-state blood concentrations (which were comparable to immediate-release dosage forms) within 2 weeks. In a multiple dosing trial in healthy male and female subjects (N=23): the mean Cmax, Cmin, and AUC0-24 values at steady-state were 30ng/mL, 20ng/mL, and 550ng.hr./mL, respectively, when paroxetine hydrochloride enteral extended-release tablets (25mg/day) were administered orally.
The corresponding study for the immediate-release form of paroxetine: the steady-state drug exposure (based on AUC0-24) was several times higher compared to the presumed values from single-dose data. This excessive accumulation is due to the ease of saturation of an enzyme involved in paroxetine metabolism.
In steady-state dose-equivalent trials in elderly and adult patients, who received 20-40 mg/day and 20-50 mg/day of paroxetine hydrochloride immediate-release tablets orally, respectively, it was found that both doses and blood concentrations in these two populations exhibited nonlinear characteristics, again reflecting saturation of the metabolic pathway. The Cmin values for 40 mg daily were even 4-6 times higher than those for 20 mg daily.
Paroxetine is completely metabolized after oral administration. The main metabolites are oxidized and methylated polar conjugates that are easily cleared. The major metabolites are mainly glucuronide and sulfate conjugates, which have been isolated and identified. Paroxetine is partially metabolized by cytochrome P450 2D6. At clinical doses, the saturation of this enzyme shows a non-linear paroxetine pharmacokinetic profile with increasing dose and duration of treatment. The same enzymatic effects in the metabolism of paroxetine suggest potential drug interactions (see [Precautions]).
Within 10 days after a single oral dose of paroxetine solution 30 mg, approximately 64% of the drug is excreted in the urine, of which 2% is the prodrug and 62% is the metabolite. Within 10 days after administration, approximately 36% is excreted via feces (possibly via bile), most of which is metabolites and less than 1% is prodrugs.
Storage
Store below 25℃.
Package
Aluminum-plastic blister package. 10 tablets/box, 30 tablets/box.
Expiration date
12 months
【Execution standard
Approval number】
【Drug marketing license holder
Name: Shenzhen Xinlitai Pharmaceutical Co.
Registered address: 37th Floor, Main Building, Chegongmiao Greenview Plaza, No. 6009 Shennan Avenue, Futian District, Shenzhen
Manufacturer
Company Name: Shenzhen Xinlitai Pharmaceutical Co.
Production Address: No. 1, Planning Road 5, Longtian Street Industrial Zone, Pingshan District, Shenzhen
Zip code: 518118
Contact: (0755) 83867888
Fax: (0755) 83867338
Website: www.salubris.com