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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If occurs, discontinue paroxetine tablets and serotonergic agents and initiate supportive measures. ( 5.2 ) • Embryofetal Toxicity: May cause fetal harm. Meta-analyses of epidemiological studies have shown increased risk (less than 2-fold) of cardiovascular malformations with exposure during the first trimester. ( 5.4 , 8.1 ) • Increased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory • drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. ( 5.5 ) • Activation of Mania/Hypomania : Screen patients for bipolar disorder. ( 5.6 ) • Seizures : Use with caution in patients with seizure disorders. ( 5.8 ) • Angle-Closure Glaucoma : Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9 ) • Sexual Dysfunction: Paroxetine tablets may cause symptoms of sexual dysfunction. ( 5.13 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 2. Table 2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional cases 18-24 years old 5 additional cases Decreases Compared to Placebo 25-64 years old 1 fewer case ≥65 years old 6 fewer cases Paroxetine tablets are not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing paroxetine tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome SSRIs, including paroxetine tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of paroxetine tablets with MAOIs is contraindicated. In addition, do not initiate paroxetine tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine tablets discontinue paroxetine tablets before initiating treatment with the MAOI [see Contraindications ( 4 ), Drug Interactions ( 7 )] . Monitor all patients taking paroxetine tablets for the emergence of serotonin syndrome. Discontinue treatment with paroxetine tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of paroxetine tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Drug Interactions Leading to QT Prolongation The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of paroxetine tablets is contraindicated in combination with thioridazine and pimozide [see Contraindications ( 4 ), Drug Interactions ( 7 ),Clinical Pharmacology ( 12.3 )]. 5.4 Embryofetal Toxicity Based on meta-analyses of epidemiological studies, exposure to paroxetine in the first trimester of pregnancy is associated with a less than 2-fold increase in the rate of cardiovascular malformations among infants. For women who intend to become pregnant or who are in their first trimester of pregnancy, paroxetine tablets, should be initiated only after consideration of the other available treatment options [see Use in Specific Populations ( 8.1 )]. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including paroxetine tablets, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )] . Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of paroxetine tablets and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. 5.6 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with paroxetine tablets or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of paroxetine tablets, hypomania or mania occurred in approximately 1% of paroxetine tablets-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with paroxetine tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.7 Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [seeDosage and Administration ( 2.7 )]. During clinical trials of GAD and PTSD, gradual decreases in the daily dose by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for paroxetine tablets and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness adverse reactions have been reported upon discontinuation of treatment with paroxetine tablets in pediatric patients. The safety and effectiveness of paroxetine tablets in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions ( 5.1 ), Use in Specific Populations ( 8.4 )]. 5.8 Seizures Paroxetine tablets have not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies, seizures occurred in 0.1% of patients treated with paroxetine tablets. Paroxetine tablets should be prescribed with caution in patients with a seizure disorder. Discontinue paroxetine tablets in any patient who develops seizures. 5.9 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine tablets may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of paroxetine tablets have been reported. Avoid use of antidepressants, including paroxetine tablets in patients with untreated anatomically narrow angles. 5.10 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including paroxetine tablets. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue paroxetine tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations ( 8.5 )]. 5.11 Reduction of Efficacy of Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of paroxetine tablets as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions( 7 )] . One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. 5.12 Bone Fracture Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation, and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. 5.13 Sexual Dysfunction Use of SSRIs, including paroxetine tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of paroxetine tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.