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治療オプション:
Fedorchenko Olga Valeryevna 、薬局による医学的評価、 最終更新日:29.03.2022
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同じ成分を持つトップ20の薬:
大うつ病性障害。
Xetanorは大うつ病性障害の治療に適応されます。.
大うつ病エピソードの治療におけるXetanorの有効性は、診断が大うつ病性障害のDSM-IIIカテゴリに最も密接に対応している外来患者の6週間の対照試験で確立されました(参照)。 臨床試験。)。. 大うつ病エピソードは、通常、毎日の機能を妨げる、顕著で比較的持続的なうつ病または不快感を意味します。 (少なくとも2週間はほぼ毎日。) 次の8つの症状のうち少なくとも4つを含める必要があります。食欲の変化。, 睡眠の変化。, 精神運動興奮または遅滞。, 通常の活動への関心の喪失または性的欲求の減少。, 疲労の増加。, 罪悪感や無価値の感情。, 思考の鈍化または集中力の低下。, そして自殺未遂または自殺念慮。.
入院中のうつ病患者におけるゼタノールの影響は十分に研究されていません。.
大うつ病性障害の反応を最大1年間維持する上でのXetanorの有効性は、プラセボ対照試験で実証されました(参照)。 臨床試験。)。. それにもかかわらず、Xetanorを長期間使用することを選択した医師は、個々の患者に対する薬物の長期的な有用性を定期的に再評価する必要があります。.
強迫性障害。
Xetanorは、DSM-IVで定義されている強迫性障害(OCD)患者の強迫および強迫の治療に適応されます。強迫観念または強迫は、著しい苦痛を引き起こし、時間がかかり、社会的または職業的機能に著しく干渉します。.
Xetanorの有効性は、強迫性外来患者を対象とした2つの12週間の試験で確立され、その診断は強迫性障害のDSM-IIIRカテゴリに最も密接に対応していました(参照)。 臨床試験。).
強迫性障害は、自我的、および/または反復的、意図的、および意図的な行動(衝動)であり、過度または不合理であると認識されている、再発的で永続的なアイデア、思考、衝動、または画像(執着)によって特徴付けられます。.
有効性の長期維持は、6か月の再発防止試験で実証されました。. この試験では、パロキセチンに割り当てられた患者は、プラセボの患者と比較して再発率が低かった(参照)。 臨床試験。)。. それにもかかわらず、Xetanorを長期間使用することを選択した医師は、個々の患者に対する薬物の長期的な有用性を定期的に再評価する必要があります(参照)。 投与量と投与。).
パニック障害。
Xetanorはパニック障害の治療に使用されます。, 広場恐怖症の有無にかかわらず。, DSM-IVで定義されています。パニック障害は、予期しないパニック発作の発生と、追加の攻撃に対する関連する懸念によって特徴付けられます。, 攻撃の影響や結果を心配します。, および/または攻撃に関連する行動の大幅な変化。.
Xetanorの有効性は、診断がパニック障害のDSM-IIIRカテゴリーに対応するパニック障害患者を対象とした3つの10〜12週間の試験で確立されました(参照)。 臨床試験。).
パニック障害(DSM-IV)は、予期しないパニック発作の再発、つまり. 激しい恐怖または不快感の離散期間4。 (以上。) 以下の症状のうち、突然発症し、10分以内にピークに達します。 (1。) 動 ⁇ 。, ドキドキする心。, または加速心拍数。; 。(2。) 発汗。; 。(3。) 震えるか揺れる。; 。(4。) 息切れや窒息の感覚。; 。(5。) 窒息感。; 。(6。) 胸の痛みや不快感。; 。(7。) 吐き気または腹部の苦痛。; 。(8。) めまいがする。, 不安定。, 立ちくらみ。, またはかすかな。; 。(9。) 脱現実。 (不道徳の気持ち。) または離人。 (自分から切り離されている。) 。(10。) コントロールを失うことへの恐怖。; 。(11。) 死ぬことへの恐怖。; 。(12。) 感覚異常。 (しびれやチクチクする感覚。) 。(13。) 悪寒またはほてり。.
有効性の長期維持は、3か月の再発防止試験で実証されました。. この試験では、パロキセチンに割り当てられたパニック障害の患者は、プラセボの患者と比較して再発率が低いことを示しました(参照)。 臨床試験。)。. それにもかかわらず、Xetanorを長期間処方する医師は、個々の患者に対する薬物の長期的な有用性を定期的に再評価する必要があります(参照)。 投与量と投与。).
社会的不安障害。
Xetanorは、DSM-IV(300.23)で定義されているように、社会恐怖症としても知られている社会不安障害の治療に適応されます。. 社会不安障害は、その人が見知らぬ人にさらされたり、他人による精査の可能性にさらされたりする1つ以上の社会的またはパフォーマンスの状況に対するマークされた持続的な恐怖によって特徴付けられます。. 恐れられている状況への暴露は、ほぼ常に不安を引き起こし、パニック発作の激しさに近づく可能性があります。. 恐れられている状況は回避されるか、激しい不安や苦痛に耐えます。. 恐れられる状況での回避、不安な期待、または苦痛は、人の通常のルーチン、職業的または学術的機能、または社会活動または関係に大きな干渉するか、恐怖症を持つことについて著しい苦痛があります。. パフォーマンスの不安や恥ずかしさの度合いが低い場合は、一般に精神薬理学的治療は必要ありません。.
Xetanorの有効性は、社会不安障害(DSM-IV)の成人患者を対象とした3つの12週間試験で確立されました。. Xetanorは、社会恐怖症のある子供や青年では研究されていません(参照)。 臨床試験。).
社会不安障害の長期治療におけるゼタノールの有効性、すなわち.、12週間以上、適切で適切に管理された試験では体系的に評価されていません。. したがって、Xetanorを長期間処方することを選択した医師は、個々の患者に対する薬物の長期的な有用性を定期的に再評価する必要があります(参照)。 投与量と投与。).
全般性不安障害。
Xetanorは、DSM-IVで定義されているように、全般性不安障害(GAD)の治療に適応されます。日常生活のストレスに関連する不安や緊張は、通常、抗不安薬による治療を必要としません。.
GADの治療におけるXetanorの有効性は、GADの成人を対象とした2つの8週間のプラセボ対照試験で確立されました。 Xetanorは、全身性不安障害の子供または青年では研究されていません(参照)。 臨床試験。).
全般性不安障害(DSM-IV)は、少なくとも6か月間持続し、人が制御するのが難しいと感じる過度の不安と心配(不安な期待)を特徴とします。. それは、次の6つの症状のうち少なくとも3つに関連付けられている必要があります。落ち着きのなさや、キーアップまたはエッジでの感覚、疲労のしやすさ、集中力の低下、または気が空白になる、イライラする、筋肉の緊張、睡眠障害。.
Xetanorを服用している間に8週間の急性治療段階で反応し、その後最大24週間の再発が観察された、全般性不安障害の患者の反応を維持する際のXetanorの有効性は、プラセボ対照で実証されました試験(参照 臨床試験。)。. それにもかかわらず、Xetanorを長期間使用することを選択した医師は、個々の患者に対する薬物の長期的な有用性を定期的に再評価する必要があります(参照)。 投与量と投与。).
外傷後ストレス障害。
Xetanorは心的外傷後ストレス障害(PTSD)の治療に使用されます。.
PTSDの治療におけるXetanorの有効性は、PTSD(DSM-IV)の成人を対象とした2つの12週間プラセボ対照試験で確立されました(参照)。 臨床試験。).
DSM-IVで定義されているPTSDは、実際のまたは脅迫された死亡または重大な傷害、または自己または他者の身体的完全性に対する脅威を伴うトラウマ的イベントへの暴露、および激しい恐怖、無力、または恐怖を伴う対応を必要とします。. 外傷性イベントへの暴露の結果として発生する症状には、侵入的思考の形でイベントを再体験することが含まれます。, フラッシュバック。, または夢。, そして、イベントへの手がかりへの暴露に対する激しい心理的苦痛と生理学的反応性。; 外傷性イベントを連想させる状況の回避。, イベントの詳細を思い出せない。, および/または重要な活動への関心の低下として現れた一般的な応答性の麻痺。, 他人からの疎遠。, 影響の範囲が制限されています。, または短縮された未来の感覚。; 興奮 ⁇ 進を含む自律性覚 ⁇ の症状。, 誇張された驚くべき反応。, 睡眠障害。, 濃度低下。, そしてイライラや怒りの爆発。. PTSD診断では、症状が少なくとも1か月間存在し、社会的、職業的、またはその他の重要な機能領域に臨床的に重大な苦痛または障害を引き起こすことが必要です。.
PTSDの長期治療におけるXetanorの有効性、つまり.、12週間以上、プラセボ対照試験で体系的に評価されていません。. したがって、Xetanorを長期間処方することを選択した医師は、個々の患者に対する薬物の長期的な有用性を定期的に再評価する必要があります(参照)。 投与量と投与。).
Major Depressive Disorder
Usual Initial Dosage
Xetanor should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of Xetanor in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.
Maintenance Therapy
There is no body of evidence available to answer the question of how long the patient treated with Xetanor should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.
Systematic evaluation of the efficacy of Xetanor has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.
Obsessive Compulsive Disorder
Usual Initial Dosage
Xetanor should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of Xetanor in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of Xetanor in the treatment of OCD. The maximum dosage should not exceed 60 mg/day.
Maintenance Therapy
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see Clinical Trials). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Panic Disorder
Usual Initial Dosage
Xetanor should be administered as a single daily dose with or without food, usually in the morning. The target dose of Xetanor in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of Xetanor. The maximum dosage should not exceed 60 mg/day.
Maintenance Therapy
Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see Clinical Trials). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Social Anxiety Disorder
Usual Initial Dosage
Xetanor should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of Xetanor was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of Xetanor has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see Clinical Trials).
Maintenance Therapy
There is no body of evidence available to answer the question of how long the patient treated with Xetanor should remain on it. Although the efficacy of Xetanor beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Generalized Anxiety Disorder
Usual Initial Dosage
Xetanor should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of Xetanor was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week.
Maintenance Therapy
Systematic evaluation of continuing Xetanor for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking Xetanor during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see Clinical Trials). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
Posttraumatic Stress Disorder
Usual Initial Dosage
Xetanor should be administered as a single daily dose with or without food, usually in the morning. The recommended starting dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of Xetanor was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at intervals of at least 1 week.
Maintenance Therapy
There is no body of evidence available to answer the question of how long the patient treated with Xetanor should remain on it. Although the efficacy of Xetanor beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Special Populations
Treatment of Pregnant Women During The Third Trimester:
Neonates exposed to Xetanor and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
Dosage For Elderly Or Debilitated Patients, And Patients With Severe Renal Or Hepatic Impairment
The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day.
Switching A Patient To Or From A Monoamine Oxidase Inhibitor (MAOI) Intended To Treat Psychiatric Disorders
At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Xetanor. Conversely, at least 14 days should be allowed after stopping Xetanor before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).
Use Of Xetanor With Other MAOIs, Such As Linezolid Or Methylene Blue
Do not start Xetanor in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).
In some cases, a patient already receiving therapy with Xetanor may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Xetanor should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Xetanor may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Xetanor is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).
Discontinuation Of Treatment With Xetanor
Symptoms associated with discontinuation of Xetanor have been reported (see PRECAUTIONS: Discontinuation of Treatment With Xetanor). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which Xetanor is being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
NOTE: SHAKE SUSPENSION WELL BEFORE USING.
セロトニン症候群のリスクが高いため、Xetanorによる精神障害の治療またはXetanorによる治療の中止から14日以内のMAOIの使用は禁 ⁇ です。. 精神障害の治療を目的としたMAOIを停止してから14日以内にXetanorを使用することも禁 ⁇ です(参照)。 警告。 と。 投与量と投与。).
セロトニン症候群のリスクが高いため、リネゾリドや静脈内メチレンブルーなどのMAOIで治療されている患者でXetanorを開始することも禁 ⁇ です(参照)。 警告。 と。 投与量と投与。).
チオリダジンとの併用は禁 ⁇ です(参照。 警告。 と。 注意。).
ピモジドを服用している患者での併用は禁 ⁇ です(参照。 注意。).
Xetanorは、パロキセチンまたはXetanorの非活性成分のいずれかに対して過敏症の患者には禁 ⁇ です。.
WARNINGS
Clinical Worsening And Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.
Table 1
Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated |
Increases Compared to Placebo | |
< 18 | 14 additional cases |
18-24 | 5 additional cases |
Decreases Compared to Placebo | |
25-64 | 1 fewer case |
≥ 65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION: Discontinuation of Treatment With Xetanor, for a description of the risks of discontinuation of Xetanor).
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Xetanor should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients For Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Xetanor is not approved for use in treating bipolar depression.
Serotonin Syndrome
The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Xetanor, alone but particularly 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 (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
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). Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of Xetanor with MAOIs intended to treat psychiatric disorders is contraindicated. Xetanor should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Xetanor. Xetanor should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).
If concomitant use of Xetanor with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John's Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Xetanor and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many antidepressant drugs including Xetanor may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
Potential Interaction With Thioridazine
Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose related.
An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).
Usage In Pregnancy
Teratogenic Effects
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. The findings from these studies are summarized below:
- 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 odds ratio was 2.5 (95% confidence interval, 1.0 to 6.0, 7 exposed infants) and in the other study the odds ratio 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 [POR] 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.
If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. 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 (see PRECAUTIONS: Discontinuation of Treatment With Xetanor). 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.
Animal Findings
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 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m² basis. These studies have revealed no evidence of teratogenic effects. 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-sixth 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.
Nonteratogenic Effects
Neonates exposed to Xetanor and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), 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 (see WARNINGS: Serotonin Syndrome).
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 - 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including Xetanor) in pregnancy and PPHN. Other studies do not show a significant statistical association.
Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with Xetanor, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS: Postmarketing Reports).
PRECAUTIONS
General
Activation Of Mania/Hypomania
During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with Xetanor compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for Xetanor and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, Xetanor should be used cautiously in patients with a history of mania.
Seizures
During premarketing testing, seizures occurred in 0.1% of patients treated with Xetanor, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Xetanor should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures.
Discontinuation Of Treatment With Xetanor
Recent clinical trials supporting the various approved indications for Xetanor employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped.
With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for Xetanor and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention.
During marketing of Xetanor and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing treatment with Xetanor. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).
See also PRECAUTIONS: Pediatric Use, for adverse events reported upon discontinuation of treatment with Xetanor in pediatric patients.
Tamoxifen
Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine's irreversible inhibition of CYP2D6 (see DRUG INTERACTIONS). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of coadministration. 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.
Akathisia
Hyponatremia
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Xetanor. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use). Discontinuation of Xetanor should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
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.
Abnormal Bleeding
SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory 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 SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation.
Bone Fracture
Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising.
Use In Patients With Concomitant Illness
Clinical experience with Xetanor in patients with certain concomitant systemic illness is limited. Caution is advisable in using Xetanor in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with Xetanor. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when Xetanor is prescribed for patients with narrow angle glaucoma.
Xetanor has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing. Evaluation of electrocardiograms of 682 patients who received Xetanor in double-blind, placebo-controlled trials, however, did not indicate that Xetanor is associated with the development of significant ECG abnormalities. Similarly, Xetanor does not cause any clinically important changes in heart rate or blood pressure.
Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance < 30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION).
Information For Patients
Xetanor should not be chewed or crushed, and should be swallowed whole.
Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Xetanor and triptans, tramadol, or other serotonergic agents.
Patients should be advised that taking Xetanor can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Xetanor and should counsel them in its appropriate use. A patient Medication Guide is available for Xetanor. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Xetanor.
Clinical Worsening And Suicide Risk
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
Interference With Cognitive And Motor Performance
Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies Xetanor has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with Xetanor does not affect their ability to engage in such activities.
Completing Course Of Therapy
While patients may notice improvement with treatment with Xetanor in 1 to 4 weeks, they should be advised to continue therapy as directed.
Concomitant Medication
Patients should be advised 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 interactions.
Alcohol
Although Xetanor has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking Xetanor.
Pregnancy
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects).
Nursing
Patients should be advised to notify their physician if they are breastfeeding an infant (see PRECAUTIONS: Nursing Mothers).
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
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 2.4 (mouse) and 3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD on a mg/m² basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. 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.
Mutagenesis
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 2.9 times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a 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 (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m² basis).
Pregnancy
Pregnancy Category D. See WARNINGS: Usage in P
Associated With Discontinuation Of Treatment
Twenty percent (1,199/6,145) of patients treated with Xetanor in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with Xetanor in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD, and PTSD, respectively, discontinued treatment due to an adverse event. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for Xetanor compared to placebo) included the following:
Major Depressive Disorder | OCD | Panic Disorder | Social Anxiety Disorder | Generalized Anxiety Disorder | PTSD | |||||||
Xetanor | Placebo | Xetanor | Placebo | Xetanor | Placebo | Xetanor | Placebo | Xetanor | Placebo | Xetanor | Placebo | |
CNS | ||||||||||||
Somnolence | 2.3% | 0.7% | — | 1.9% | 0.3% | 3.4% | 0.3% | 2.0% | 0.2% | 2.8% | 0.6% | |
Insomnia | — | — | 1.7% | 0% | 1.3% | 0.3% | 3.1% | 0% | — | — | ||
Agitation | 1.1% | 0.5% | — | — | — | |||||||
Tremor | 1.1% | 0.3% | — | 1.7% | 0% | 1.0% | 0.2% | |||||
Anxiety | — | — | — | 1.1% | 0% | — | — | |||||
Dizziness | — | — | 1.5% | 0% | 1.9% | 0% | 1.0% | 0.2% | — | — | ||
Gastrointestinal | ||||||||||||
Constipation | — | 1.1% | 0% | — | — | |||||||
Nausea | 3.2% | 1.1% | 1.9% | 0% | 3.2% | 1.2% | 4.0% | 0.3% | 2.0% | 0.2% | 2.2% | 0.6% |
Diarrhea | 1.0% | 0.3% | — | |||||||||
Dry mouth | 1.0% | 0.3% | — | — | — | |||||||
Vomiting | 1.0% | 0.3% | — | 1.0% | 0% | — | — | |||||
Flatulence | 1.0% | 0.3% | — | — | ||||||||
Other | ||||||||||||
Asthenia | 1.6% | 0.4% | 1.9% | 0.4% | 2.5% | 0.6% | 1.8% | 0.2% | 1.6% | 0.2% | ||
Abnormal Ejaculationa | 1.6% | 0% | 2.1% | 0% | 4.9% | 0.6% | 2.5% | 0.5% | — | — | ||
Sweating | 1.0% | 0.3% | — | 1.1% | 0% | 1.1% | 0.2% | — | — | |||
Impotencea | — | 1.5% | 0% | — | — | |||||||
Libido | ||||||||||||
Decreased | 1.0% | 0% | — | — | ||||||||
Where numbers are not provided the incidence of the adverse events in patients treated with Xetanor was not > 1% or was not greater than or equal to 2 times the incidence of placebo. a Incidence corrected for gender. |
Commonly Observed Adverse Events
Major Depressive Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Xetanor at least twice that for placebo, derived from Table 2) were: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders.
Obsessive Compulsive Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Xetanor at least twice that of placebo, derived from Table 3) were: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation.
Panic Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Xetanor at least twice that for placebo, derived from Table 3) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence.
Social Anxiety Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Xetanor at least twice that for placebo, derived from Table 3) were: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence.
Generalized Anxiety Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Xetanor at least twice that for placebo, derived from Table 4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.
Posttraumatic Stress Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for Xetanor at least twice that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied.
Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology.
Table 2: Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disordera
Body System | Preferred Term | Xetanor (n = 421) | Placebo (n = 421) |
Body as a Whole | Headache | 18% | 17% |
Asthenia | 15% | 6% | |
Cardiovascular | Palpitation | 3% | 1% |
Vasodilation | 3% | 1% | |
Dermatologic | Sweating | 11% | 2% |
Rash | 2% | 1% | |
Gastrointestinal | Nausea | 26% | 9% |
Dry Mouth | 18% | 12% | |
Constipation | 14% | 9% | |
Diarrhea | 12% | 8% | |
Decreased Appetite | 6% | 2% | |
Flatulence | 4% | 2% | |
Oropharynx Disorderb | 2% | 0% | |
Dyspepsia | 2% | 1% | |
Musculoskeletal | Myopathy | 2% | 1% |
Myalgia | 2% | 1% | |
Myasthenia | 1% | 0% | |
Nervous System | Somnolence | 23% | 9% |
Dizziness | 13% | 6% | |
Insomnia | 13% | 6% | |
Tremor | 8% | 2% | |
Nervousness | 5% | 3% | |
Anxiety | 5% | 3% | |
Paresthesia | 4% | 2% | |
Libido Decreased | 3% | 0% | |
Drugged Feeling | 2% | 1% | |
Confusion | 1% | 0% | |
Respiration | Yawn | 4% | 0% |
Special Senses | Blurred Vision | 4% | 1% |
Taste Perversion | 2% | 0% | |
Urogenital System | Ejaculatory Disturbancec,d | 13% | 0% |
Other Male Genital Disordersc,e | 10% | 0% | |
Urinary Frequency | 3% | 1% | |
Urination Disorderf | 3% | 0% | |
Female Genital Disordersc,g | 2% | 0% | |
a Events reported by at least 1% of patients treated with Xetanor are included, except the following events which had an incidence on placebo ≥ Xetanor: Abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly “cold symptoms” or “URI”), trauma, and vomiting. b Includes mostly “lump in throat” and “tightness in throat.” c Percentage corrected for gender. d Mostly “ejaculatory delay.” e Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.” f Includes mostly “difficulty with micturition” and “urinary hesitancy.” g Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” |
Obsessive Compulsive Disorder, Panic Disorder, And Social Anxiety Disorder
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on Xetanor who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on Xetanor who participated in placebo-controlled trials of 10-to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on Xetanor who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day.
Table 3: Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disordera
Body System | Preferred Term | Obsessive Compulsive Disorder | Panic Disorder | Social Anxiety Disorder | |||
Xetanor (n = 542) | Placebo (n = 265) | Xetanor (n = 469) | Placebo (n = 324) | Xetanor (n = 425) | Placebo (n = 339) | ||
Body as a Whole | Asthenia | 22% | 14% | 14% | 5% | 22% | 14% |
Abdominal Pain | — | — | 4% | 3% | — | — | |
Chest Pain | 3% | 2% | — | — | — | — | |
Back Pain | — | — | 3% | 2% | — | — | |
Chills | 2% | 1% | 2% | 1% | — | — | |
Trauma | — | — | — | — | 3% | 1% | |
Cardiovascular | Vasodilation | 4% | 1% | — | — | — | — |
Palpitation | 2% | 0% | — | — | — | — | |
Dermatologic | Sweating | 9% | 3% | 14% | 6% | 9% | 2% |
Rash | 3% | 2% | — | — | — | — | |
Gastrointestinal | Nausea | 23% | 10% | 23% | 17% | 25% | 7% |
Dry Mouth | 18% | 9% | 18% | 11% | 9% | 3% | |
Constipation | 16% | 6% | 8% | 5% | 5% | 2% | |
Diarrhea | 10% | 10% | 12% | 7% | 9% | 6% | |
Decreased Appetite | 9% | 3% | 7% | 3% | 8% | 2% | |
Dyspepsia | — | — | — | — | 4% | 2% | |
Flatulence | — | — | — | — | 4% | 2% | |
Increased Appetite | 4% | 3% | 2% | 1% | — | — | |
Vomiting | — | — | — | — | 2% | 1% | |
Musculoskeletal | Myalgia | _ | — | — | — | 4% | 3% |
Nervous System | Insomnia | 24% | 13% | 18% | 10% | 21% | 16% |
Somnolence | 24% | 7% | 19% | 11% | 22% | 5% | |
Dizziness | 12% | 6% | 14% | 10% | 11% | 7% | |
Tremor | 11% | 1% | 9% | 1% | 9% | 1% | |
Nervousness | 9% | 8% | — | — | 8% | 7% | |
Libido Decreased | 7% | 4% | 9% | 1% | 12% | 1% | |
Agitation | — | — | 5% | 4% | 3% | 1% | |
Anxiety | — | — | 5% | 4% | 5% | 4% | |
Abnormal Dreams | 4% | 1% | — | — | — | — | |
Concentration Impaired | 3% | 2% | — | — | 4% | 1% | |
Depersonalization | 3% | 0% | — | — | — | — | |
Myoclonus | 3% | 0% | 3% | 2% | 2% | 1% | |
Amnesia | 2% | 1% | — | — | — | — | |
Respiratory System | Rhinitis | — | — | 3% | 0% | — | — |
Pharyngitis | — | — | — | — | 4% | 2% | |
Yawn | — | — | — | — | 5% | 1% | |
Special Senses | Abnormal Vision | 4% | 2% | — | — | 4% | 1% |
Taste Perversion | 2% | 0% | — | — | — | — | |
Urogenital System | Abnormal | ||||||
Ejaculationb | 23% | 1% | 21% | 1% | 28% | 1% | |
Dysmenorrhea | — | — | — | — | 5% | 4% | |
Female Genital Disorderb | 3% | 0% | 9% | 1% | 9% | 1% | |
Impotenceb | 8% | 1% | 5% | 0% | 5% | 1% | |
Urinary Frequency | 3% | 1% | 2% | 0% | — | — | |
Urination Impaired | 3% | 0% | — | — | — | — | |
Urinary Tract Infection | 2% | 1% | 2% | 1% | — | — | |
a Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with Xetanor are included, except the following events which had an incidence on placebo ≥ Xetanor: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and sinusitis. b Percentage corrected for gender. |
Generalized Anxiety Disorder And Posttraumatic Stress Disorder
Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on Xetanor who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on Xetanor who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg/day to 50 mg/day.
Table 4: Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disordera
Body System | Preferred Term | Generalized Anxiety Disorder | Posttraumatic Stress Disorder | ||
Xetanor (n = 735) | Placebo (n = 529) | Xetanor (n = 676) | Placebo (n = 504) | ||
Body as a Whole | Asthenia | 14% | 6% | 12% | 4% |
Headache | 17% | 14% | — | — | |
Infection | 6% | 3% | 5% | 4% | |
Abdominal Pain | 4% | 3% | |||
Trauma | 6% | 5% | |||
Cardiovascular | Vasodilation | 3% | 1% | 2% | 1% |
Dermatologic | Sweating | 6% | 2% | 5% | 1% |
Gastrointestinal | Nausea | 20% | 5% | 19% | 8% |
Dry Mouth | 11% | 5% | 10% | 5% | |
Constipation | 10% | 2% | 5% | 3% | |
Diarrhea | 9% | 7% | 11% | 5% | |
Decreased Appetite | 5% | 1% | 6% | 3% | |
Vomiting | 3% | 2% | 3% | 2% | |
Dyspepsia | — | — | 5% | 3% | |
Nervous System | Insomnia | 11% | 8% | 12% | 11% |
Somnolence | 15% | 5% | 16% | 5% | |
Dizziness | 6% | 5% | 6% | 5% | |
Tremor | 5% | 1% | 4% | 1% | |
Nervousness | 4% | 3% | — | — | |
Libido Decreased | 9% | 2% | 5% | 2% | |
Abnormal Dreams | 3% | 2% | |||
Respiratory System | Respiratory Disorder | 7% | 5% | — | — |
Sinusitis | 4% | 3% | — | — | |
Yawn | 4% | — | 2% | < 1% | |
Special Senses | Abnormal Vision | 2% | 1% | 3% | 1% |
Urogenital System | Abnormal Ejaculationb | 25% | 2% | 13% | 2% |
Female Genital | 4% | 1% | 5% | 1% | |
Disorderb | |||||
Impotenceb | 4% | 3% | 9% | 1% | |
a Events reported by at least 2% of GAD and PTSD in patients treated with Xetanor are included, except the following events which had an incidence on placebo ≥ Xetanor [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain, headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis. b Percentage corrected for gender. |
Dose Dependency Of Adverse Events
A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of Xetanor with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of Xetanor, as shown in Table 5:
Table 5: Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disordera
Body System/ Preferred Term | Placebo n = 51 | Xetanor | |||
10 mg n = 102 | 20 mg n = 104 | 30 mg n = 101 | 40 mg n = 102 | ||
Body as a Whole | |||||
Asthenia | 0.0% | 2.9% | 10.6% | 13.9% | 12.7% |
Dermatology Sweating | 2.0% | 1.0% | 6.7% | 8.9% | 11.8% |
Gastrointestinal | |||||
Constipation | 5.9% | 4.9% | 7.7% | 9.9% | 12.7% |
Decreased Appetite | 2.0% | 2.0% | 5.8% | 4.0% | 4.9% |
Diarrhea | 7.8% | 9.8% | 19.2% | 7.9% | 14.7% |
Dry Mouth | 2.0% | 10.8% | 18.3% | 15.8% | 20.6% |
Nausea | 13.7% | 14.7% | 26.9% | 34.7% | 36.3% |
Nervous System | |||||
Anxiety | 0.0% | 2.0% | 5.8% | 5.9% | 5.9% |
Dizziness | 3.9% | 6.9% |
人間の経験。
米国でのXetanorの導入以来、パロキセチン治療中の故意または偶発的な過剰摂取の342件の自発的症例が世界中で報告されています(1999年頃)。. これらには、パロキセチン単独および他の物質との併用による過剰摂取が含まれます。. これらのうち、48例が致命的であり、死亡者数17例がパロキセチンのみを含むようでした。. 摂取されたパロキセチンの量を記録した8つの致命的な症例は、一般的に他の薬物またはアルコールの摂取または重大な併存疾患の存在によって混乱しました。. 既知の結果を伴う145の非致命的な症例のうち、ほとんどが後遺症なしで回復した。. 最大の既知の摂取は、回復した患者の2,000 mgのパロキセチン(最大推奨日用量の33倍)を含みました。.
パロキセチンの過剰摂取に関連して一般的に報告されている有害事象には、傾眠、 ⁇ 睡、吐き気、振戦、頻脈、 ⁇ 乱、 ⁇ 吐、めまいなどがあります。. パロキセチンを含む過剰摂取で観察された他の注目すべき兆候と症状。 (単独で、または他の物質と一緒に。) mydriasisを含めます。, けいれん。 (てんかんを含む。) 心室性不整脈。 (トルサードドポワントを含む。) 高血圧。, 攻撃的な反応。, 失神。, 低血圧。, ⁇ 迷。, 徐脈。, ジストニア。, 横紋筋融解症。, 肝機能障害の症状。 (肝不全を含む。, 肝壊死。, 黄 ⁇ 。, 肝炎。, 肝脂肪症。) セロトニン症候群。, ⁇ 反応。, ミオクローヌス。, 急性腎不全。, そして尿閉。.
過剰摂取管理。
パロキセチンの特定の解毒剤は知られていない。. 治療は、大うつ病性障害の治療に有効な薬物の過剰摂取の管理に使用される一般的な対策で構成する必要があります。.
適切な気道、酸素化、換気を確保します。. 心臓のリズムとバイタルサインを監視します。. 一般的な支援的および対症療法も推奨されます。. ⁇ 吐の誘発は推奨されません。. この薬物の大量の分布のため、強制利尿、透析、 ⁇ 流、または交換輸血は、利益になりそうにありません。.
特定の注意には、過剰な量の三環系抗うつ薬を摂取する可能性のあるパロキセチンを服用している、または最近服用した患者が含まれます。. そのような場合、親三環系および/または活性代謝物の蓄積は、臨床的に重要な後遺症の可能性を高め、綿密な医学的観察に必要な時間を延長する可能性があります(参照)。 注意。: チトクロームCYP2D6によって代謝される薬物。).
過剰摂取の管理では、複数の薬物関与の可能性を検討してください。. 医師は、過剰摂取の治療に関する追加情報について、毒物管理センターに連絡することを検討する必要があります。. 認定毒物管理センターの電話番号は、医師のデスクリファレンス(PDR)に記載されています。.
大うつ病性障害の治療におけるパロキセチンの有効性。, 社会不安障害。, 強迫性障害。 (OCD。) パニック障害。 (PD。) 全般性不安障害。 (GAD。) 外傷後ストレス障害。 (PTSD。) セロトニンの神経再取り込みの阻害に起因する中枢神経系のセロトニン作動性の増強に関連していると推定されます。 (5-ヒドロキシ-トリプタミン。, 5-HT。). ヒトの臨床的に関連する用量での研究は、パロキセチンがセロトニンのヒト血小板への取り込みをブロックすることを示しています。. In vitro。 動物での研究はまた、パロキセチンが神経セロトニン再取り込みの強力で選択性の高い阻害剤であり、ノルエピネフリンとドーパミン神経再取り込みに非常に弱い影響しか及ぼさないことを示唆しています。. In vitro。 放射性リガンド結合研究は、パロキセチンがムスカリン、α1-、α2-、ベータ-アドレナリン作動性、ドーパミン(D2)-、5-HT1-、5-HT2-、およびヒスタミン(H1)受容体にほとんど親和性がないことを示しています。ムスカリン、ヒスタミン作動性、およびα1アドレナリン作動性抗体の ⁇ 抗作用は、.
パロキセチンの主要な代謝産物の相対効力は親化合物の最大1/50であるため、それらは本質的に不活性です。.
塩酸パロキセチンは、塩酸塩塩の溶液を経口投与した後に完全に吸収されます。. 平均排 ⁇ 半減期は、30 mgの錠剤のXetanorを30日間毎日経口投与した後、約21時間(CV 32%)です。. パロキセチンは広範囲に代謝され、代謝物は不活性であると考えられています。. 薬物動態の非線形性は、用量の増加とともに観察されます。. パロキセチン代謝は、一部はCYP2D6によって媒介され、代謝産物は主に尿中に排 ⁇ され、ある程度 ⁇ 便中に排 ⁇ されます。. パロキセチンの薬物動態学的挙動は、CYP2D6が不足している被験者(代謝不良者)では評価されていません。.
20 mg /日から40 mg /日の複数回投与後に健康なボランティアで行われた4つの研究からのパロキセチンのメタ分析では、男性は女性よりも有意に低いCmaxまたはAUCを示しませんでした。.
吸収と分布。
パロキセチンは、経口懸 ⁇ 液と錠剤から同様に生物学的に利用可能です。.
塩酸パロキセチンは、塩酸塩塩の溶液を経口投与した後に完全に吸収されます。. 通常の男性被験者(n = 15)が30日間毎日30 mgの錠剤を投与された研究では、定常状態のパロキセチン濃度はほとんどの被験者で約10日間達成されましたが、不定期の患者ではかなり長くかかる場合があります。. 定常状態では、Cmax、Tmax、Cmin、およびT½の平均値は61.7 ng / mL(CV 45%)、5.2時間でした。. (CV 10%)、30.7 ng / mL(CV 67%)、および21.0時間(CV 32%)。. 定常状態のCmaxとCminの値は、単回投与試験から予測される値の約6倍と14倍でした。. AUC0-24に基づく定常状態の薬物曝露は、これらの被験者の単回投与データから予測されたよりも約8倍高かった。. 過剰な蓄積は、パロキセチンを代謝する酵素の1つが容易に飽和可能であるという事実の結果です。.
パロキセチンのバイオアベイラビリティに対する食物の影響は、食物の有無にかかわらず単回投与された被験者で研究されました。. 薬物が食物とともに投与された場合、AUCはわずかに増加(6%)しましたが、Cmaxは29%増加しましたが、ピーク血漿濃度に達するまでの時間は、投与後6.4時間から4.9時間に減少しました。.
パロキセチンは、CNSを含む体全体に分布し、血漿中に残っているのはわずか1%です。.
パロキセチンの約95%と93%は、それぞれ100 ng / mLと400 ng / mLの血漿タンパク質に結合しています。. 臨床条件下では、パロキセチン濃度は通常400 ng / mL未満です。パロキセチンは変化しません。 in vitro。 フェニトインまたはワルファリンのタンパク質結合。.
代謝と排 ⁇ 。
Xetanorの30日間、毎日30 mgの錠剤を経口投与した後、平均排出半減期は約21時間(CV 32%)です。. 高齢者と非高齢者を対象とした定常状態の用量比例研究では、高齢者は毎日20 mg〜40 mg、非高齢者は毎日20 mg〜50 mgの用量で、両方の集団でいくつかの非線形性が観察され、再び飽和代謝経路が反映されました。. 1日20 mg以降のCmin値と比較すると、1日40 mg以降の値は、2倍の約2〜3倍でした。.
パロキセチンは経口投与後に広範囲に代謝されます。. 主要な代謝産物は、酸化とメチル化の極性で共役した生成物であり、容易に除去されます。. グルクロン酸と硫酸塩との共役が優勢であり、主要な代謝産物が分離され、同定されています。. データは、代謝物がセロトニンの取り込みを阻害する際に親化合物の効力を1/50以下であることを示しています。. パロキセチンの代謝は、CYP2D6によって部分的に達成されます。. 臨床用量でのこの酵素の飽和は、用量の増加と治療期間の増加に伴うパロキセチン動態の非線形性を説明しているようです。. パロキセチン代謝におけるこの酵素の役割は、潜在的な薬物間相互作用も示唆しています(参照)。 注意。: CYP2D6によって代謝される薬物。).
30 mgのパロキセチンの経口溶液投与量の約64%が尿中に排 ⁇ され、2%が親化合物、62%が代謝物として10日間の投与後に排 ⁇ されました。. 約36%が ⁇ 便中に(おそらく胆 ⁇ を介して)排 ⁇ され、主に代謝物として、10日間の投与後の期間に親化合物として1%未満でした。.
However, we will provide data for each active ingredient