- Paroxetine in the treatment of premature ejaculation: a systematic review and meta-analysis
- Suicidal Thoughts And Behaviors In Adolescents And Young Adults
- Serotonin Syndrome
- Drug Interactions Leading To QT Prolongation
- Embryofetal And Neonatal Toxicity
- Increased Risk Of Bleeding
- Activation Of Mania Or Hypomania
- Discontinuation Syndrome
- Angle-Closure Glaucoma
- Reduction Of Efficacy Of Tamoxifen
- Bone Fracture
- Patient Counseling Information
- Suicidal Thoughts And Behaviors
- Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment Of Fertility
- Use In Specific Populations
- Nursing Mothers
- Pediatric Use
- Geriatric Use
- Renal And/Or Hepatic Impairment
- FDA Approves Paroxetine Controlled-Release Formulation For Social Anxiety Disorder
Subjects with mild-to-moderate DSM-IV major depressive disorder were recruited for this study of the prediction of antidepressant treatment response using paroxetine. Although personality disorders appear to be common among patients with depression, whether personality disorders influence the treatment response is not clear and often shows a complicated prognosis.6 We therefore excluded depressed patients with comorbid personality disorders.
Intensive research efforts have focused on the question of how to predict whether a given treatment will have a relatively favorable outcome.2 In depression treatment, clinical and psychopharmacologic aspects have been investigated to predict the response to antidepressants. The clinical benefit of having an early prediction method promises to be significant. Clinically, we encountered patients who quickly responded to antidepressants and those who did not. Research into when a drug effect becomes noticeable is rare.
If we can investigate the clinically important early effects of antidepressants, these findings will have considerable significance for clinical practice. Early improvement may be predictive of a positive outcome at the end of treatment. Generally, outpatients return to their psychiatrist 1 or 2 weeks after the first visit; therefore, primary care physicians and psychiatrists cannot determine effectiveness in the early stages of treatment.
Randomized controlled trials comparing antidepressant agents with a placebo showed statistically significant benefits of SSRIs after as little as 1 week of use.7,8 These studies were typically of a similar design and were often assessed weekly.7,8 To our knowledge, few studies have investigated the effect of SSRIs within 1 week (i.e., on the third day from therapy onset). Our results suggest that the therapeutic efficacy of paroxetine may be predicted within the first 3 days of therapy onset.
Considering the results of the subscale scores of the HAM-D, Dunbar et al.7 found that paroxetine improved retardation symptoms by 1 week and anxiety/somatization symptoms by 2 weeks when compared with placebo. However, recent studies indicate that SSRI treatment might be expected to improve, at least initially, the components of depression reflecting anxiety, agitation, and hostility.8 The earliest improvement in paroxetine responders was anxiety, and depressed mood and cognitive impairment improved somewhat later.10 In this study, the reduction rate of the core subscale decreased significantly earlier than that of the anxiety/somatization subscale on the third day. Although these findings suggest the earlier effect of paroxetine on core depressive symptoms, our results may have been insufficiently assessed because of smaller samples and because almost all subjects had mild-to-moderate depression.
A sufficient effect of antidepressants may be achieved in 2 to 4 weeks. Furthermore, some patients respond after 4 to 8 weeks following an appropriate increase in the anti-depressant dose; therefore, it may be difficult to predict the final reactivity/effectiveness based on the early response. In this study, we judged treatment efficacy in the second week using low doses of paroxetine (5–20 mg/day); therefore, nonresponsive patients might have improved if we had administered a higher dose of the anti-depressant over a longer period of time. Since we used a self-rating method to evaluate the patients, there might have been a problem in the precision of the assessment. However, in patients responding to antidepressants in the early stages of treatment, our results suggest that treatment response may be predicted in the first 3 days using a self-rated HAM-D questionnaire.
From here, it is necessary to increase the accuracy of evaluation of efficacy using other monitoring psychometries. Except for the preliminary study and the small patient samples, we did not examine the validity of the self-rated HAM-D. The validity of the instrument in rating the depressive state should be examined. Moreover, further study is needed of the coincidence-of-effect evaluation between patients and psychiatrists.
Drug name: paroxetine (Paxil, Pexeva, and others).
Paroxetine in the treatment of premature ejaculation: a systematic review and meta-analysis
Description of studies
Search results and reporting quality
After searching the 3 databases, a total of 512 relevant articles were retrieved. According to the titles and abstracts of publications, 492 records were excluded because of repeats, irrelevance or not being RCTs. The remaining 20 full-text articles were uploaded and assessed for eligibility, and 19 of 20 met our criteria. Thus, 19 RCTs were included for systematic review and meta-analysis. Table 1 shows their characteristics, and Fig. 1 summarizes the inclusion process. Comparators included placebo, dapoxetine, tramadol, sertraline, PDE5Is, fluoxetine, behaviour therapy, local lidocaine gel, duloxetine, escitalopram, and combined therapy. The majority of the included RCTs were 4–12 weeks in duration. Only Wang’s and Moudi’s trials lasted for 6 months . All of the articles reported similar outcomes involving IELT. Other diffused distribution outcomes included sexual satisfaction score, side effects, premature ejaculation diagnostic tool (PEDT), International Index of Erectile Function (IIEF), premature ejaculation profile (PEP), Arabic Index of Premature Ejaculation (AIPE), libido and frequency of intercourse, which rendered pooled meta-analysis difficult. The only method that we could use was to depict these outcomes. If study data were missing, we attempted to contact the corresponding authors.
Table 1 Characteristics of included stuides Fig. 1
Flow diagram of the study selection process. RCT = randomized controlled trail
Cochrane’s risk of bias tool was used to assess the quality of the articles on the basis of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcomes assessment, incomplete outcome data, selective report and other biases. Then, a risk of bias summary graph was successfully generated, as Fig. 2 shows. We can see that a large number of RCTs were considered to have an unclear risk of bias because of a lack of adequate information from the articles. Gameel’s and Abu’s trails were considered at high risk of performance bias due to single blinding. One RCT was considered at high risk of attrition due to incomplete outcome data: there were 1.67, 18.33 and 36.67% of patients in the sildenafil, paroxetine and squeeze therapy groups, respectively, who withdrew from the trial due to little efficacy or side effects .
Overall quality assessment for the selected articles
Paroxetine vs. placebo: A total of 7 RCTs met the condition . Two RCTs lacked relevant standard deviations . The quality of these articles were described,but they were not included in the meta-analysis. Thus,based on 5 pooled RCTs , the men treated with paroxetine 20 mg for 4–12 weeks had significantly increased IELT compared with placebo (p = 0.01). The MD in IELT was 2.96, in favour of paroxetine , 0.63 to 5.29; p = 0.01] (Fig. 3). Meta-analysis of these studies showed a high level of heterogeneity, which might have arisen from the difference in types of PE and treatment periods (Fig. 3). Seven RCTs favoured of paroxetine. One RCT showed PEP changes from the baseline significantly greater than placebo, and two RCTs showed that the change in satisfaction score from baseline was more significant. One RCT reported that paroxetine had a significantly stronger ejaculation-delaying effect than placebo (p < 0.05), and it decreased PEDT significantly more than placebo without any side effects . Safarinejad et al. reported that paroxetine had better ability to delay ejaculation than placebo at the end of 12 weeks of treatment. Not only was IELT increased from 31 and 34 to 370 and 55, respectively, with paroxetine (p < 0.05) and placebo (p > 0.05), but the mean number of coitus episodes and IIEF value improved significantly in the paroxetine group (p < 0.05). A similar finding was reported by Abu et al. . The IELT significantly improved from 38.66 to 173.86 in the paroxetine group, while the placebo group showed almost no change. The mean satisfaction score and PEDT in the paroxetine group improved more significant than with placebo. Therefore, paroxetine could have a significantly stronger ejaculation-delaying effect than placebo.
Forest plot of IELT between paroxetine and other drugs. Cl,confidence interval;IELT, intra-vaginal ejaculatory latency time; PDE-5, phosphodiesterase-5 inhibitor; SD, standard deviation
Where reported, side effects related to paroxetine included: headache, fatigue, nausea, dizziness, sleep disturbances, yawning, dry mouth, sweating, and constipation. The pooled relative risk of 3 RCTs was 1.23 , which indicated no difference between the paroxetine and placebo groups in terms of adverse events (Fig. 4). Our pooled estimate showed significant heterogeneity (I2 = 65%), which might have arisen from the treatment period, dosage and inclusion criteria. Four RCTs that followed up for 3–10 weeks showed no serious treatment-related side effects detected for paroxetine or placebo.
Pooled estimate of side effects of paroxetine vs. other medical therapy
Paroxetine vs. tramadol: Three RCTs provided evidence that suggested that the difference in IELT was not significant between the two groups , − 2.40 to 4.03; p = 0.62] (Fig. 3). One of 3 reported that on-demand tramadol more significantly improved PEP than paroxetine at 4 weeks. Another RCT reported that there was no difference in terms of sexual satisfaction score after one month of on-demand treatment . In addition, Alghobary et al. compared the efficacy of daily paroxetine and on-demand tramadol, paroxetine and tramadol increased IELT after 6 weeks by 11- and 7-fold, respectively. After 12 weeks, the tramadol group decreased IELT to fivefold, while the paroxetine group increased IELT to 22-fold. The tendency of the Arabic Index of PE (AIPE) was consistent with IELT in the two groups. Paroxetine increased libido significantly more than tramadol at 12 weeks. Therefore, a longer treatment time should be used to explore the efficacy and safety of tramadol and paroxetine.
Paroxetine vs. PDE5Is: Five RCTs compared the safety and efficacy of paroxetine with those of tramadol . Because 2 RCTs lacked relevant standard deviations ,3 other pooled RCTs showed that paroxetine had similar effects to PDE5Is,with between-group difference in IELT of − 0.59 , − 1.45 to 0.26;p = 0.17]. While there was a high level of heterogeneity (I2 = 88%) (Fig. 3), which may come from the difference type of PE and treatment period. One RCT showed that the on-demand sildenafil group has better sexual satisfaction scores than the daily paroxetine group. Wang et al. reported that 1.7 and 18.3% of patients withdrew from the study in the sildenafil and paroxetine groups, respectively, after 6 months. One RCT reported that there was no significant difference in PEDT or satisfaction score after 6 weeks of treatment between the two groups.
The relative risk of side effects between two groups pooled from 3 RCTs was 1.14 , as shown in Fig. 4. According to 5 RCTs, all side effects were well tolerated. One RCT showed that sleep disturbances, dry mouth, nausea, dizziness, fatigue, vomiting, sweating, headache, flushing, hypotension and nasal congestion were reported with paroxetine and sildenafil . One RCT reported that the most adverse effect in the paroxetine group was sleep disturbance, and in the sildenafil group, it was headache.
Paroxetine vs. dapoxetine: The IELT with treatment using paroxetine and dapoxetine increased from 38 and 31 to 37 and 179, respectively, at the end of 12 weeks in one RCT . Sexual satisfaction was also significantly higher with paroxetine than with dapoxetine (p = 0.04). According to analysis of variance with multiple comparisons, treatment with paroxetine caused a greater increase in mean weekly intercourse frequency than dapoxetine. Abu et al. reported that paroxetine resulted in higher satisfaction scores and IELT than dapoxetine, although the difference was not statistically significant.
Paroxetine vs. local lidocaine gel: A single RCT reported that paroxetine-treated patients had a longer IELT, of 3.25 min than had those treated with lidocaine gel , − 0.58 to 0.84,p = 0.72] (Fig. 3), and paroxetine was associated with better sexual satisfaction scores than the local anaesthetic of 3.25 and 2.97 points, respectively. The most common side effects were penile anaesthesia and headache in the lidocaine and paroxetine groups, respectively.
Paroxetine vs. escitalopram: Only one RCT compared IELT and adverse events between paroxetine and escitalopram groups. Treatment with paroxetine was found to be significantly more effective based on IELT than escitalopram , 0.08 to 0.32;p = 0.001] (Fig. 3). Both drugs were generally well tolerated.
Pooled estimate of IELT of paroxetine vs. combined therapy
Paroxetine combined with behaviour therapy vs. paroxetine: A single RCT reported that patients treated with paroxetine combined with behaviour therapy had a significantly longer IELT than had those treated with paroxetine alone , − 0.62 to − 0.18;p = 0.0003] (Fig. 5). The rates of occurrence of side effects were 10.0 and 40% in the paroxetine and combined groups, respectively, but all side effects, including dizziness, dry mouth, sleep disturbances and fatigue, were tolerable.
Included as part of the PRECAUTIONS section.
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 1000 patients treated are provided in Table 2.
Table 2: Risk Differences of the Number of Patients of 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 of Suicidal Thoughts and Behaviors per 1,000 Patients Treated|
|Increases Compared to Placebo|
|<18 years old||14 additional patients|
|18-24 years old||5 additional patients|
|Decreases Compared to Placebo|
|25-64 years old||1 fewer patient|
|≥65 years old||6 fewer 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 PAXIL CR, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including PAXIL CR, 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, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs . Serotonin syndrome can also occur when these drugs are used alone.
The concomitant use of PAXIL CR with MAOIs is contraindicated. In addition, do not initiate PAXIL CR 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). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PAXIL CR, discontinue PAXIL CR before initiating treatment with the MAOI .
Monitor all patients taking PAXIL CR for the emergence of serotonin syndrome. Discontinue treatment with PAXIL CR and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of PAXIL CR with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
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 PAXIL CR is contraindicated in combination with thioridazine and pimozide .
Embryofetal And Neonatal Toxicity
PAXIL CR can cause fetal harm when administered to a pregnant woman. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of cardiovascular malformations. Exposure to paroxetine in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn (PPNH) and/or neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.
If PAXIL CR is used during pregnancy, or if the patient becomes pregnant while taking PAXIL CR, the patient should be apprised of the potential hazard to the fetus .
Increased Risk Of Bleeding
Drugs that interfere with serotonin reuptake inhibition, including PAXIL CR, 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. 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 PAXIL CR and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.
Activation Of Mania Or Hypomania
In patients with bipolar disorder, treating a depressive episode with PAXIL CR or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of immediate-release paroxetine hydrochloride, hypomania or mania occurred in approximately 1% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with PAXIL CR, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.
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 .
Adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of PAXIL CR in pediatric patients have not been established .
PAXIL CR has not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. PAXIL CR should be prescribed with caution in patients with a seizure disorder and should be discontinued in any patient who develops seizures.
The pupillary dilation that occurs following use of many antidepressant drugs including PAXIL CR 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 hydrochloride tablets have been reported. Avoid use of antidepressants, including PAXIL CR, in patients with untreated anatomically narrow angles.
Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including PAXIL CR. 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 PAXIL CR 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 SNRIs and SSRIs. .
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 as a result of paroxetineÃ¢â¬™s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen . 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.
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts And Behaviors
Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider .
Important Administration Instructions
Instruct patients to swallow PAXIL CR whole and to not chew or crush the tablets .
Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of PAXIL CR with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. JohnÃ¢â¬™s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid). Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome .
Advise patients to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for drug-drug interactions .
Inform patients about the concomitant use of PAXIL CR with aspirin, NSAIDs, other antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or planning to take any prescription or over-the counter medications that increase the risk of bleeding .
Activation Of Mania/Hypomania
Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider .
Advise patients not to abruptly discontinue PAXIL CR and to discuss any tapering regimen with their healthcare provider. Inform patients that adverse reactions can occur when PAXIL CR is discontinued .
Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing .
Advise women of the potential risk to the fetus . Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy because of the risk to the fetus.
Advise women to notify their healthcare provider if they are breastfeeding an infant .
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to approximately 1.6 (mouse) and 2.5 (rat) times the MRHD on an mg/m² basis. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.
Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats.
Impairment Of Fertility
Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is approximately twice the MRHD on an mg/m² basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (approximately 6 and 3 times the MRHD on an mg/m² basis).
Use In Specific Populations
Pregnancy Category D
Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. If paroxetine is used during pregnancy, or if the patient becomes pregnant while taking paroxetine, advise the patient of the potential hazard to the fetus.
- A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery.
- A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).
- Two large case-control studies using separate databases, each with >9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2-to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the OR was 2.5 (95% confidence interval, 1.0 to 6.0, 7 exposed infants) and in the other study the OR was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).
Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations.
Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant . For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options .
Treatment Of Pregnant Women During Their Third Trimester
Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), including PAXIL CR, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome .
Exposure to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 Ã¢â¬“ 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy.
There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs.
When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment . A prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy. The women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 6 (rat) and less than 2 (rabbit) times the maximum recommended human dose (MRHD Ã¢â¬“ 75 mg) on an mg/m² basis. These studies have revealed no evidence of malformations. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-thirteens of the MRHD on an mg/m² basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known.
Like many other drugs, paroxetine is secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from PAXIL CR, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of PAXIL CR in pediatric patients have not been established .
Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with immediate-release paroxetine, and effectiveness was not established in pediatric patients.
Decreased appetite and weight loss have been observed in association with the use of SSRIs.
In placebo-controlled clinical trials conducted with pediatric patients, the following adverse reactions were reported in at least 2% of pediatric patients treated with immediate-release paroxetine hydrochloride and at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.
Adverse reactions upon discontinuation of treatment with immediate-release paroxetine hydrochloride in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients and at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain.
SSRIs and SNRIs, including PAXIL CR, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction .
In premarketing clinical trials with immediate-release paroxetine hydrochloride, 17% of paroxetine treated patients (approximately 700) were 65 years or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; however, no overall differences in safety or effectiveness were observed between these subjects and younger subjects .
Renal And/Or Hepatic Impairment
Increased plasma concentrations of paroxetine occur in patients with renal and hepatic impairment. The initial dosage should be reduced in patients with severe renal impairment and patients with severe hepatic impairment .
FDA Approves Paroxetine Controlled-Release Formulation For Social Anxiety Disorder
Philadelphia, PA, October 17, 2003 – GlaxoSmithKline (NYSE: GSK) today announced the U.S. Food and Drug Administration (FDA) approved Paxil CRTM (paroxetine HCl) Controlled-Release Tablets for the treatment of social anxiety disorder. Paxil CR is the first and only controlled-release SSRI (selective serotonin reuptake inhibitor) approved for social anxiety disorder, a highly debilitating condition that affects more than 10 million Americans. Furthermore, Paxil CR was generally well tolerated, with a low patient drop out rate due to adverse events that was comparable to placebo (3% vs. 2% respectively). Paxil CR is also indicated for the treatment of depression, panic disorder and premenstrual dysphoric disorder (PMDD).
“Adverse events and poor compliance are often stumbling blocks in treating disorders like social anxiety disorder. As a result, many patients continue to suffer the debilitating symptoms of their condition, which often severely limits their social, home and work relationships,” said Dr. Murray Stein, Professor of Psychiatry, University of California San Diego. “The low rate of drop outs due to adverse events seen with the Paxil CR social anxiety disorder study may offer new hope to patients.”
Treatment with Paxil CR
The tolerability and efficacy of Paxil CR (paroxetine HCl) Controlled-Release Tablets in the treatment of social anxiety disorder were established in a 12-week, multi-center, placebo-controlled study of 370 patients with social anxiety disorder. Patients were randomized to receive either a flexible dose regimen of Paxil CR (12.5 mg – 37.5 mg per day) or placebo. Patients given Paxil CR showed statistically significant and clinically meaningful differences versus placebo in the two primary efficacy variables: mean change from baseline in the Liebowitz Social Anxiety Scale (LSAS) and percent of responders defined by a CGI-Global Improvement score of one (very much improved) or two (much improved).
“We are pleased to offer physicians and patients a new option in the treatment of social anxiety disorder,” said Bonnie Rossello, Vice President, Cardiovascular/Neuroscience, GlaxoSmithKline. “As one of the most popular treatments for depression and anxiety disorders, Paxil has been successful in helping people treat their condition, and now, as the first controlled-release SSRI approved to treat social anxiety disorder, Paxil CR builds on the heritage of Paxil and has a favorable tolerability profile.”
Social Anxiety Disorder
Social anxiety disorder, also known as social phobia, is the most common type of anxiety disorder, with more sufferers than general anxiety disorder, which currently ranks second. People with social anxiety disorder have an intense fear of being scrutinized by other people in social or performance situations. When exposed to “everyday” social situations such as meetings, classes, parties, speaking in public and talking to strangers or authority figures, people with social anxiety disorder literally become “sick with fear” and often develop symptoms including rapid heartbeat, sweating, shaking and upset stomach. Some people with social anxiety disorder avoid these situations altogether, severely limiting their life, work and social relationships.
Controlled-Release Paxil Tablets
Paxil CR offers the proven efficacy of paroxetine in a Geomatrix oral drug delivery system. The tablet is a multi-layered formulation that controls dissolution and absorption of the drug in the body. Paxil CR offers flexible dosing with three dosing strengths: 12.5 mg, 25 mg, and 37.5 mg. Geomatrix technology is licensed from SkyePharma PLC (Nasdaq: SKYE/LSE:SKP). Most common adverse events (incidence of 5% or greater and incidence for Paxil CR and at least twice that for placebo) in studies for major depressive disorder, panic disorder, PMDD and social anxiety disorder include infection, trauma, nausea, diarrhea, dry mouth, constipation, decreased appetite, somnolence, dizziness, decreased libido, tremor, yawn, sweating, abnormal vision, asthenia, insomnia, abnormal ejaculation, female genital disorders and impotence. Patients should not be abruptly discontinued from antidepressant medication, including Paxil CR. Concomitant use of Paxil CR in patients taking monoamine oxidase inhibitors (MAOIs) or thioridazine is contraindicated.
For more information on Paxil CR log on to www.paxilcr.com, or for patients who are being treated with Paxil CR, visit www.CRBalance.com.
As many of you probably know, last year, I had a bit of a breakdown. My personal and health problems became too much for me to handle. I became paralyzed by anxiety, fear, and physical pain. I couldn’t sleep. I couldn’t eat. I couldn’t enjoy the little things that make life worth living: a challenging, sweaty workout that you hope never ends, a leisurely stroll on a crowded city street, the simple pleasure of just holding your husband in your arms, laughing with friends, SEX, dressing up and looking damn good on a Friday night. The list could go on for days.
All of the above situations made me anxious and nervous. I often couldn’t breathe, let alone find enjoyment in anything. Damn, I was a mess. I have never felt that low in my entire life. EVER. I sought help from a doctor. That part most of you know. I was thrown a lifeline and I took it.
That lifeline was Paxil.
I have never talked about the Paxil part of my recovery until now.
I don’t know why I haven’t discussed taking an antidepressant on here before. My family has a great deal of experience with mental illness, and I am well aware of the stigma surrounding it. But all of that knowledge didn’t stop me from hiding it from you guys. I disliked seeing new doctors because under the section for “medications you are currently taking” I always had to write in Paxil. I hated that. It was painful to have to describe to inquisitive doctors why a seemingly level-headed girl was on meds. “Well, let’s see. I’m a super easy going person. Nothing bothers me, and that’s why I’m on anti-anxiety medication.” I was a walking contradiction.
I think it has more to do with my pride than anything else. I have always been too proud to ask for help. Before, during, and after my breakdown, I continued to feverishly clutch to my pride in a pathetic, self-defeating sort of way.
I was too strong, too sane, too “normal” to need help. In my mind, taking medication was a sign of weakness.
Well, I’m here to say that even the coolest, most put together, smartest, whatever-est people need help sometimes. It’s not weakness. It’s being human. If I’ve learned anything throughout this ordeal, I have learned that. I leaned on my husband and my family like no other. I lost friends. I’m still processing what it means to go through such a bad time in your life, and to never get a call from people, who for a long time, you called dear friends. Best friends, even. When I think about it, it’s like an open sore that won’t heal. But, I’m rifting.
Anywho, back to the Paxil.
I started taking it in September 2010, and I instantly felt better. My chest loosened, and I could take deep breaths again. My mind was clearing, and things began to make sense. Within months, I was seeing glimpses of the old me. I scheduled an appointment to see a new gynecologist, and I got the surgery I desperately needed.
I got my life back, and that was such a good feeling.
After surgery, I became consumed by my recovery. We went back to trying to conceive again, and I was afraid to go off Paxil for fear that my nerves would come back with a vengeance. So I stayed on it a bit longer. A few doctors warned me that I shouldn’t be on Paxil while pregnant. Yes, I’ve seen the scary commercials where they talk about Paxil, birth defects, and class action lawsuits. I know the risks, but at the time, I felt like I couldn’t go off of it. I was frightened by the withdrawals, but more importantly, scared to death of relapsing into a state of constant, out of control anxiety.
Since then I have made the decision that I do not want to be pregnant and on it. I think it is an individual choice that needs to be made with your mental and physical health prioritized first. I’m not telling anyone what they should or shouldn’t do. I will say that Paxil saved me right as I was about to break in half. I took a low dose, and fortunately, it was enough for me to get back on track.
As of this week, I am happy to report that I am taking half of my prescribed dose. Hopefully next week I will be completely drug free. I don’t know for sure how this will affect me, but I think I am ready to let go of Paxil’s hand and face life on my own.
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Tags: fertility, health, personal