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治療オプション：
Militian Inessa Mesropovna 、薬局による医学的評価、 最終更新日：26.06.2023
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治療耐性統合失調症。
FAZACLOは、標準的な抗精神病薬治療に適切に対応できない統合失調症の重症患者の治療に適応されます。. 重度の好中球減少症とその使用に関連する発作のリスクがあるため、FAZACLOは、標準的な抗精神病治療に適切に対応できなかった患者にのみ使用する必要があります。.
治療抵抗性統合失調症におけるクロザピンの有効性は、他の抗精神病薬に失敗した患者のクロザピンとクロルプロマジンを比較した6週間の無作為化二重盲検アクティブ対照試験で実証されました。.
統合失調症または統合失調感情障害における再発性の自殺行動のリスクの低減。
FAZACLOは、病歴と最近の臨床状態に基づいて、自殺行動を再経験する慢性リスクがあると判断された統合失調症または統合失調感情障害の患者の再発性自殺行動のリスクを軽減することが示されています。. 自殺行動とは、患者が死亡の危険にさらされる行動を指します。.
InterSePT™試験では、2年間の治療期間にわたって、再発する自殺行動のリスクを軽減する上でのクロザピンの有効性が実証されました。.
治療耐性統合失調症。
Uspenは、標準的な抗精神病治療に適切に対応できない統合失調症の重症患者の治療に適応されます。. 重度の好中球減少症とその使用に関連する発作のリスクがあるため、Uspenは標準的な抗精神病治療に適切に対応できなかった患者にのみ使用する必要があります。.
治療抵抗性統合失調症におけるクロザピンの有効性は、他の抗精神病薬に失敗した患者のクロザピンとクロルプロマジンを比較した6週間の無作為化二重盲検アクティブ対照試験で実証されました。.
統合失調症または統合失調感情障害における再発性の自殺行動のリスクの低減。
Uspenは、病歴と最近の臨床状態に基づいて、自殺行動を再体験する慢性リスクがあると判断された統合失調症または統合失調感情障害の患者の再発性自殺行動のリスクを軽減することが示されています。. 自殺行動とは、患者が死亡の危険にさらされる行動を指します。.
InterSePT™試験では、2年間の治療期間にわたって、再発する自殺行動のリスクを軽減する上でのクロザピンの有効性が実証されました。.
開始前および治療中に必要な臨床検査。
FAZACLOによる治療を開始する前に、ベースラインANCを取得する必要があります。. ベースラインANCは、一般集団では少なくとも1500 /μL、文書化された良性好中球減少症(BEN)の患者では少なくとも1000 /μLでなければなりません。. 治療を継続するには、ANCを定期的に監視する必要があります。.
重要な管理手順。
FAZACLOの経口分解錠剤は、ブリスターパックまたはボトルから錠剤を取り出した後、すぐに口に入れてください。. 錠剤は口に入れると急速に崩壊します。. 錠剤は分解することが許されるか、または噛まれる可能性があります。. ⁇ 液を飲み込むことがあります。. 投与に水は必要ありません。.
ブリスターパック内の経口崩壊錠は、使用時まで開封されていないブリスターに残しておく必要があります。. 使用直前に、ブリスターからホイルをはがし、経口崩壊錠を静かに取り除きます。. これは錠剤を損傷する可能性があるため、錠剤をホイルに押し込まないでください。.
投薬情報。
開始用量は1日1回または1日2回12.5 mgです。. 1日の総用量は、忍容性が良好であれば、1日あたり25 mg〜50 mgずつ増やして、2週間の終わりまでに1日あたり300 mg〜450 mgの目標用量(分割用量で投与)を達成できます。. その後、1週間に1回または週に2回、最大100 mgずつ増量できます。. 最大用量は1日あたり900 mgです。. 起立性低血圧、徐脈、失神のリスクを最小限に抑えるには、この低い開始用量、段階的な滴定スケジュール、および分割された用量を使用する必要があります。.
FAZACLOは、食事の有無にかかわらず服用できます。.
メンテナンス処理。
一般に、FAZACLOに反応する患者は、急性エピソードを超えて、実効線量の維持療法を継続する必要があります。.
治療の中止。
治療中止の方法は、患者の最後のANCによって異なります。
- 中等度から重度の好中球減少症のために突然の治療中止が必要な場合は、好中球減少症のレベルに基づく適切なANCモニタリングについては、表2または3を参照してください。.
- FAZACLO療法の終了が計画されており、中等度から重度の好中球減少症の証拠がない場合は、1〜2週間にわたって用量を徐々に減らします。.
- 好中球減少症とは無関係の理由でクロザピンを突然中止する場合は、ANCが1500 /μL以上になるまで一般集団患者に、ANCが1000 /μL以上またはベースラインを超えるまでBEN患者に、既存のANCモニタリングの継続が推奨されます。.
- 中止後2週間の発熱(38.5°Cまたは101.3°F以上の温度)の発症を報告する患者には、追加のANCモニタリングが必要です。.
- 大量の発汗、頭痛、吐き気、 ⁇ 吐、下 ⁇ などのコリン作動性リバウンドに関連する精神症状と症状の再発がないか、すべての患者を注意深く監視します。.
治療の再開始。
FAZACLOを中止した患者(すなわち、.、最終投与から2日以上)、1日1回または1日2回12.5 mgで再接種します。. これは、低血圧、徐脈、失神のリスクを最小限に抑えるために必要です。. その用量が忍容性が高い場合、用量は初期治療に推奨されるよりも早く、以前に治療した用量まで増やすことができます。.
CYP1A2、CYP2D6、CYP3A4阻害剤またはCYP1A2、CYP3A4インデューサーの併用による投与量の調整。
強力なCYP1A2阻害剤(例:.、フルボキサミン、シプロフロキサシン、またはエノキサシン);中程度または弱いCYP1A2阻害剤(例:.、経口避妊薬、またはカフェイン); CYP2D6またはCYP3A4阻害剤(例:.、シメチジン、エシタロプラム、エリスロマイシン、パロキセチン、ブプロピオン、フルオキセチン、キニジン、デュロキセチン、テルビナフィン、またはセルトラリン); CYP3A4インデューサー(例:.、フェニトイン、カルバマゼピン、セント. ジョンの麦 ⁇ 、およびリファンピン);またはCYP1A2インデューサー(例:.、喫煙)(表1)。.
表1:併用薬を服用している患者の用量調整。
| 共同薬。 | シナリオ。 | |
| 共同薬を服用しながらFAZACLOを開始します。 | FAZACLOを服用している間に共同治療を追加します。 | FAZACLOを継続しながら共同治療を中止する。 |
| 強力なCYP1A2阻害剤。 | FAZACLO用量の3分の1を使用します。. | 臨床反応に基づいてFAZACLO用量を増やします。. |
| 中程度または弱いCYP1A2阻害剤。 | 副作用を監視します。. 必要に応じて、ファザクロの用量を減らすことを検討してください。. | 有効性の欠如を監視します。. 必要に応じて、ファザクロの用量を増やすことを検討してください。. |
| CYP2D6またはCYP3A4阻害剤。 | ||
| 強力なCYP3A4インデューサー。 | 併用はお勧めしません。. ただし、インデューサーが必要な場合は、ファザクロの用量を増やす必要がある場合があります。. 効果の低下を監視します。. | 臨床反応に基づいてファザクロの用量を減らします。. |
| 中程度または弱いCYP1A2またはCYP3A4インデューサー。 | 効果の低下を監視します。. 必要に応じてFAZACLOの用量を増やすことを検討してください。. | 副作用を監視します。. 必要に応じて、ファザクロの用量を減らすことを検討してください。. |
腎または肝障害またはCYP2D6代謝不良者。
腎機能障害または肝機能障害が著しい患者、またはCYP2D6代謝不良者のFAZACLO用量を減らす必要があるかもしれません。.
開始前および治療中に必要な臨床検査。
Uspenによる治療を開始する前に、ベースラインANCを取得する必要があります。. ベースラインANCは、一般集団では少なくとも1500 /μL、文書化された良性好中球減少症(BEN)の患者では少なくとも1000 /μLでなければなりません。. 治療を継続するには、ANCを定期的に監視する必要があります。.
重要な管理手順。
ウスペンの経口分解錠剤は、ブリスターパックまたはボトルから錠剤を取り出した後、すぐに口に入れてください。. 錠剤は口に入れると急速に崩壊します。. 錠剤は分解することが許されるか、または噛まれる可能性があります。. ⁇ 液を飲み込むことがあります。. 投与に水は必要ありません。.
ブリスターパック内の経口崩壊錠は、使用時まで開封されていないブリスターに残しておく必要があります。. 使用直前に、ブリスターからホイルをはがし、経口崩壊錠を静かに取り除きます。. これは錠剤を損傷する可能性があるため、錠剤をホイルに押し込まないでください。.
投薬情報。
開始用量は1日1回または1日2回12.5 mgです。. 1日の総用量は、忍容性が良好であれば、1日あたり25 mg〜50 mgずつ増やして、2週間の終わりまでに1日あたり300 mg〜450 mgの目標用量(分割用量で投与)を達成できます。. その後、1週間に1回または週に2回、最大100 mgずつ増量できます。. 最大用量は1日あたり900 mgです。. 起立性低血圧、徐脈、失神のリスクを最小限に抑えるには、この低い開始用量、段階的な滴定スケジュール、および分割された用量を使用する必要があります。.
ウスペンは、食事の有無にかかわらず服用できます。.
メンテナンス処理。
一般に、ウスペンに反応する患者は、急性エピソードを超えて、実効線量の維持療法を継続する必要があります。.
治療の中止。
治療中止の方法は、患者の最後のANCによって異なります。
- 中等度から重度の好中球減少症のために突然の治療中止が必要な場合は、好中球減少症のレベルに基づく適切なANCモニタリングについては、表2または3を参照してください。.
- Uspen療法の終了が計画されており、中等度から重度の好中球減少症の証拠がない場合は、1〜2週間にわたって徐々に用量を減らします。.
- 好中球減少症とは無関係の理由でクロザピンを突然中止する場合は、ANCが1500 /μL以上になるまで一般集団患者に、ANCが1000 /μL以上またはベースラインを超えるまでBEN患者に、既存のANCモニタリングの継続が推奨されます。.
- 中止後2週間の発熱(38.5°Cまたは101.3°F以上の温度)の発症を報告する患者には、追加のANCモニタリングが必要です。.
- 大量の発汗、頭痛、吐き気、 ⁇ 吐、下 ⁇ などのコリン作動性リバウンドに関連する精神症状と症状の再発がないか、すべての患者を注意深く監視します。.
治療の再開始。
Uspenを中止した患者(つまり、.、最終投与から2日以上)、1日1回または1日2回12.5 mgで再接種します。. これは、低血圧、徐脈、失神のリスクを最小限に抑えるために必要です。. その用量が忍容性が高い場合、用量は初期治療に推奨されるよりも早く、以前に治療した用量まで増やすことができます。.
CYP1A2、CYP2D6、CYP3A4阻害剤またはCYP1A2、CYP3A4インデューサーの併用による投与量の調整。
強力なCYP1A2阻害剤(例:.、フルボキサミン、シプロフロキサシン、またはエノキサシン);中程度または弱いCYP1A2阻害剤(例:.、経口避妊薬、またはカフェイン); CYP2D6またはCYP3A4阻害剤(例:.、シメチジン、エシタロプラム、エリスロマイシン、パロキセチン、ブプロピオン、フルオキセチン、キニジン、デュロキセチン、テルビナフィン、またはセルトラリン); CYP3A4インデューサー(例:.、フェニトイン、カルバマゼピン、セント. ジョンの麦 ⁇ 、およびリファンピン);またはCYP1A2インデューサー(例:.、喫煙)(表1)。.
表1:併用薬を服用している患者の用量調整。
| 共同薬。 | シナリオ。 | |
| 共同薬を服用しながらUspenを開始します。 | Uspenを服用している間に共同治療を追加します。 | Uspenを継続しながら共同治療を中止する。 |
| 強力なCYP1A2阻害剤。 | Uspen用量の3分の1を使用します。. | 臨床反応に基づいてウスペンの用量を増やします。. |
| 中程度または弱いCYP1A2阻害剤。 | 副作用を監視します。. 必要に応じてUspenの用量を減らすことを検討してください。. | 有効性の欠如を監視します。. 必要に応じてUspenの用量を増やすことを検討してください。. |
| CYP2D6またはCYP3A4阻害剤。 | ||
| 強力なCYP3A4インデューサー。 | 併用はお勧めしません。. ただし、誘導剤が必要な場合は、ウスペンの用量を増やす必要があるかもしれません。. 効果の低下を監視します。. | 臨床反応に基づいてウスペンの用量を減らします。. |
| 中程度または弱いCYP1A2またはCYP3A4インデューサー。 | 効果の低下を監視します。. 必要に応じてUspenの用量を増やすことを検討してください。. | 副作用を監視します。. 必要に応じてUspenの用量を減らすことを検討してください。. |
腎または肝障害またはCYP2D6代謝不良者。
腎機能障害または肝機能障害が著しい患者、またはCYP2D6代謝不良者のUspen用量を減らす必要があるかもしれません。.
過敏症。
FAZACLOは、クロザピンに対する重度の過敏症の病歴がある患者には禁 ⁇ です(例:.、光線過敏症、血管炎、多形紅斑、またはスティーブンス・ジョンソン症候群)またはFAZACLOの他のコンポーネント.
過敏症。
ウスペンは、クロザピンに対する重度の過敏症の病歴がある患者には禁 ⁇ です(例:.、光線過敏症、血管炎、多形紅斑、またはスティーブンス・ジョンソン症候群)またはUspenの他のコンポーネント。.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Severe Neutropenia
Background
FAZACLO can cause neutropenia (a low absolute neutrophil count [ANC]), defined as a reduction below pre-treatment normal levels of blood neutrophils. The ANC is usually available as a component of the complete blood count (CBC), including differential, and is more relevant to drug-induced neutropenia than is the white blood cell (WBC) count. The ANC may also be calculated using the following formula: ANC equals the Total WBC count multiplied by the total percentage of neutrophils obtained from the differential (neutrophil “segs” plus neutrophil “bands”). Other granulocytes (basophils and eosinophils) contribute minimally to neutropenia and their measurement is not necessary. Neutropenia may be mild, moderate, or severe (see Tables 2 and 3). To improve and standardize understanding, “severe neutropenia” replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis.
Severe neutropenia, ANC less than ( < ) 500/μL, occurs in a small percentage of patients taking FAZACLO and is associated with an increase in the risk of serious and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks on treatment and then declines. The mechanism by which FAZACLO causes neutropenia is unknown and is not dose-dependent.
Two separate management algorithms are provided below, the first for patients in the general population, and the second for patients identified to have baseline neutropenia.
FAZACLO Treatment and Monitoring in the General Patient Population (see Table 2)
Obtain a CBC, including the ANC value, prior to initiating treatment with FAZACLO to ensure the presence of a normal baseline neutrophil count (equal to or greater than 1500/μL) and to permit later comparisons. Patients in the general population with an ANC equal to or greater than ( ≥ )1500/μL are considered within normal range (Table 2) and are eligible to initiate treatment. Weekly ANC monitoring is required for all patients during the first 6 months of treatment. If a patient's ANC remains equal to or greater than 1500/μL for the first 6 months of treatment, monitoring frequency may be reduced to every 2 weeks for the next 6 months. If the ANC remains equal to or greater than 1500/μL for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks thereafter.
Table 2: FAZACLO Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population
| ANC Level | FAZACLO Treatment Recommendations | ANC Monitoring |
| Normal range ( ≥ 1500/μL) |
|
|
|
| |
| Mild Neutropenia (1000 to 1499/μL)* |
|
|
| Moderate Neutropenia (500 to 999/μL)* |
|
|
| Severe Neutropenia (less than 500/μL)* |
|
|
| * Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours ** If clinically appropriate |
FAZACLO Treatment and Monitoring in Patients with Benign Ethnic Neutropenia (see Table 3)
Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose average ANC values are lower than “standard” laboratory ranges for neutrophils. It is most commonly observed in individuals of African descent (approximate prevalence of 25-50%), some Middle Eastern ethnic groups, and in other non-Caucasian ethnic groups with darker skin. BEN is more common in men. Patients with BEN have normal hematopoietic stem-cell number and myeloid maturation, are healthy, and do not suffer from repeated or severe infections. They are not at increased risk for developing FAZACLO-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider hematology consultation before initiating or during FAZACLO treatment as necessary.
Patients with BEN require a different ANC algorithm for FAZACLO management due to their lower baseline ANC levels. Table 3 provides guidelines for managing FAZACLO treatment and ANC monitoring in patients with BEN.
Table 3: Patients with Benign Ethnic Neutropenia (BEN); FAZACLO Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring
| ANC Level | Treatment Recommendations | ANC Monitoring |
| Normal BEN Range (Established ANC baseline > 1000/μL ) |
|
|
|
| |
| BEN Neutropenia (500 to 999/μL)* |
|
|
| BEN Severe Neutropenia (less than 500/μL)* |
|
|
| * Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours ** If clinically appropriate |
General Guidelines for Management of All Patients with Fever or with Neutropenia
- Fever: Interrupt FAZACLO as a precautionary measure in any patient who develops fever, defined as a temperature of 38.5°C [101.3°F] or greater, and obtain an ANC level. Fever is often the first sign of neutropenic infection.
- ANC less than 1000/μL: If fever occurs in any patient with an ANC less than 1000/μL, initiate appropriate workup and treatment for infection and refer to Tables 2 or 3 for management.
- Consider hematology consultation.
- See Neuroleptic Malignant Syndrome (NMS) and Fever under WARNINGS AND PRECAUTIONS and Instructions for Patients, under PATIENT INFORMATION).
Rechallenge after an ANC less than 500/μL (Severe Neutropenia)
For some patients who experience severe FAZACLO-related neutropenia, the risk of serious psychiatric illness from discontinuing FAZACLO treatment may be greater than the risk of rechallenge (e.g., patients with severe schizophrenic illness who have no treatment options other than FAZACLO). A hematology consultation may be useful in deciding to rechallenge a patient. In general, however, do not rechallenge patients who develop severe neutropenia with FAZACLO or a clozapine product.
If a patient will be rechallenged, the clinician should consider thresholds provided in Tables 2 and 3, the patient's medical and psychiatric history, a discussion with the patient and his/her caregiver about the benefits and risks of FAZACLO rechallenge, and the severity and characteristics of the neutropenic episode.
Using FAZACLO with Other Drugs Associated with Neutropenia
It is unclear if concurrent use of other drugs known to cause neutropenia increases the risk or severity of FAZACLO-induced neutropenia. There is no strong scientific rationale to avoid FAZACLO treatment in patients concurrently treated with these drugs. If FAZACLO is used concurrently with an agent known to cause neutropenia (e.g., some chemotherapeutic agents), consider monitoring patients more closely than the treatment guidelines provided in Tables 2 and 3. Consult with the treating oncologist in patients receiving concomitant chemotherapy.
Clozapine REMS Program
FAZACLO is only available through a restricted program under a REMS called the Clozapine REMS Program because of the risk of severe neutropenia.
Notable requirements of the Clozapine REMS Program include:
- Healthcare professionals who prescribe FAZACLO must be certified with the program by enrolling and completing training.
- Patients who receive FAZACLO must be enrolled in the program and comply with the ANC testing and monitoring requirements.
- Pharmacies dispensing FAZACLO must be certified with the program by enrolling and completing training and must only dispense to patients who are eligible to receive FAZACLO.
Further information is available at www.clozapinerems.com or 1-844-267-8678.
Orthostatic Hypotension, Bradycardia, And Syncope
Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).
Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions. Consider reducing the dose if hypotension occurs. When restarting patients who have had even a brief interval off FAZACLO (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily.
Use FAZACLO cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).
Seizures
Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing.
Use caution when administering FAZACLO to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with FAZACLO use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).
Myocarditis And Cardiomyopathy
Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue FAZACLO and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with FAZACLO. However, if the benefit of FAZACLO treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with FAZACLO in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.
Consider the possibility of myocarditis or cardiomyopathy in patients receiving FAZACLO who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period during treatment with FAZACLO. It is common for nonspecific flu-like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction.
Increased Mortality In Elderly Patients With Dementia-Related Psychosis
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. FAZACLO is not approved for the treatment of patients with dementia-related psychosis.
Eosinophilia
Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS).
If eosinophilia develops during FAZACLO treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue FAZACLO immediately.
If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue FAZACLO.
Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue FAZACLO under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt FAZACLO therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.
QT Interval Prolongation
QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing FAZACLO, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of FAZACLO, and electrolyte abnormalities.
Prior to initiating treatment with FAZACLO, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue FAZACLO if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue FAZACLO.
Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of FAZACLO. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). FAZACLO is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of FAZACLO.
Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with FAZACLO.
Metabolic Changes
Atypical antipsychotic drugs, including FAZACLO, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus
Patients with an established diagnosis of diabetes mellitus who are started on FAZACLO should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4). The clozapine doses were 100-900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine.
Table 4: Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia
| Laboratory Parameter | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
| Fasting Glucose | Normal ( < 100 mg/dL) to High ( ≥ 126 mg/dL) | Clozapine | 198 | 53 (27) |
| Chlorpromazine | 135 | 14 (10) | ||
| Borderline (100 to 125 mg/dL) to High ( ≥ 126 mg/dL) | Clozapine | 57 | 24 (42) | |
| Chlorpromazine | 43 | 12 (28) |
Dyslipidemia
Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including FAZACLO. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using FAZACLO, is recommended.
In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6. The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.
Table 5: Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia
| Treatment Arm | Baseline Total Cholesterol Concentration (mg/dL) | Change from Baseline mg/dL (%) |
| Clozapine (N=334) | 184 | +13 (7) |
| Chlorpromazine (N=185) | 182 | +15 (8) |
| Baseline Triglyceride Concentration (mg/dL) | Change from Baseline mg/dL (%) | |
| Clozapine (N=6) | 130 | +71 (54) |
| Chlorpromazine (N=7) | 110 | +39 (35) |
Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia
| Laboratory Parameter | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
| Total Cholesterol (random or fasting) | Increase by ≥ 40 mg/dL | Clozapine | 334 | 111 (33) |
| Chlorpromazine | 185 | 46 (25) | ||
| Normal ( < 200 mg/dL) to High ( ≥ 240 mg/dL) | Clozapine | 222 | 18 (8) | |
| Chlorpromazine | 132 | 3 (2) | ||
| Borderline (200 - 239 mg/dL) to High ( ≥ 240 mg/dL) | Clozapine | 79 | 30 (38) | |
| Chlorpromazine | 34 | 14 (41) | ||
| Triglycerides (fasting) | Increase by ≥ 50 mg/dL | Clozapine | 6 | 3 (50) |
| Chlorpromazine | 7 | 3 (43) | ||
| Normal ( < 150 mg/dL) to High ( ≥ 200 mg/dL) | Clozapine | 4 | 0 (0) | |
| Chlorpromazine | 6 | 2 (33) | ||
| Borderline ( ≥ 150 mg/dL and < 200 mg/dL) to High ( ≥ 200 mg/dL) | Clozapine | 1 | 1 (100) | |
| Chlorpromazine | 1 | 0 (0) |
Weight Gain
Weight gain has occurred with the use of antipsychotics, including FAZACLO. Monitor weight during treatment with FAZACLO. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.
Table 7: Mean Change in Body Weight (kg) by duration of exposure from studies in adult subjects with schizophrenia
| Metabolic Parameter | Exposure Duration | Clozapine (N=669) | Olanzapine (N=442) | Chlorpromazine N=155) | |||
| n | Mean | n | Mean | n | Mean | ||
| Weight change from baseline | 2 weeks (Day 11 - 17) | 6 | +0.9 | 3 | +0.7 | 2 | -0.5 |
| 4 weeks (Day 21 - 35) | 23 | +0.7 | 8 | +0.8 | 17 | +0.6 | |
| 8 weeks (Day 49 - 63) | 12 | + 1.9 | 13 | + 1.8 | 16 | +0.9 | |
| 12 weeks (Day 70 - 98) | 17 | +2.8 | 5 | +3.1 | 0 | 0 | |
| 24 weeks (Day 154 - 182) | 42 | -0.6 | 12 | +5.7 | 0 | 0 | |
| 48 weeks (Day 322 - 350) | 3 | +3.7 | 3 | +13.7 | 0 | 0 |
Table 8 summarizes pooled data from 11 studies in
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Severe Neutropenia
Background
Uspen can cause neutropenia (a low absolute neutrophil count [ANC]), defined as a reduction below pre-treatment normal levels of blood neutrophils. The ANC is usually available as a component of the complete blood count (CBC), including differential, and is more relevant to drug-induced neutropenia than is the white blood cell (WBC) count. The ANC may also be calculated using the following formula: ANC equals the Total WBC count multiplied by the total percentage of neutrophils obtained from the differential (neutrophil “segs” plus neutrophil “bands”). Other granulocytes (basophils and eosinophils) contribute minimally to neutropenia and their measurement is not necessary. Neutropenia may be mild, moderate, or severe (see Tables 2 and 3). To improve and standardize understanding, “severe neutropenia” replaces the previous terms severe leukopenia, severe granulocytopenia, or agranulocytosis.
Severe neutropenia, ANC less than ( < ) 500/μL, occurs in a small percentage of patients taking Uspen and is associated with an increase in the risk of serious and potentially fatal infections. Risk of neutropenia appears greatest during the first 18 weeks on treatment and then declines. The mechanism by which Uspen causes neutropenia is unknown and is not dose-dependent.
Two separate management algorithms are provided below, the first for patients in the general population, and the second for patients identified to have baseline neutropenia.
Uspen Treatment and Monitoring in the General Patient Population (see Table 2)
Obtain a CBC, including the ANC value, prior to initiating treatment with Uspen to ensure the presence of a normal baseline neutrophil count (equal to or greater than 1500/μL) and to permit later comparisons. Patients in the general population with an ANC equal to or greater than ( ≥ )1500/μL are considered within normal range (Table 2) and are eligible to initiate treatment. Weekly ANC monitoring is required for all patients during the first 6 months of treatment. If a patient's ANC remains equal to or greater than 1500/μL for the first 6 months of treatment, monitoring frequency may be reduced to every 2 weeks for the next 6 months. If the ANC remains equal to or greater than 1500/μL for the second 6 months of continuous therapy, ANC monitoring frequency may be reduced to once every 4 weeks thereafter.
Table 2: Uspen Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population
| ANC Level | Uspen Treatment Recommendations | ANC Monitoring |
| Normal range ( ≥ 1500/μL) |
|
|
|
| |
| Mild Neutropenia (1000 to 1499/μL)* |
|
|
| Moderate Neutropenia (500 to 999/μL)* |
|
|
| Severe Neutropenia (less than 500/μL)* |
|
|
| * Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours ** If clinically appropriate |
Uspen Treatment and Monitoring in Patients with Benign Ethnic Neutropenia (see Table 3)
Benign ethnic neutropenia (BEN) is a condition observed in certain ethnic groups whose average ANC values are lower than “standard” laboratory ranges for neutrophils. It is most commonly observed in individuals of African descent (approximate prevalence of 25-50%), some Middle Eastern ethnic groups, and in other non-Caucasian ethnic groups with darker skin. BEN is more common in men. Patients with BEN have normal hematopoietic stem-cell number and myeloid maturation, are healthy, and do not suffer from repeated or severe infections. They are not at increased risk for developing Uspen-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider hematology consultation before initiating or during Uspen treatment as necessary.
Patients with BEN require a different ANC algorithm for Uspen management due to their lower baseline ANC levels. Table 3 provides guidelines for managing Uspen treatment and ANC monitoring in patients with BEN.
Table 3: Patients with Benign Ethnic Neutropenia (BEN); Uspen Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring
| ANC Level | Treatment Recommendations | ANC Monitoring |
| Normal BEN Range (Established ANC baseline > 1000/μL ) |
|
|
|
| |
| BEN Neutropenia (500 to 999/μL)* |
|
|
| BEN Severe Neutropenia (less than 500/μL)* |
|
|
| * Confirm all initial reports of ANC less than 1500/μL with a repeat ANC measurement within 24 hours ** If clinically appropriate |
General Guidelines for Management of All Patients with Fever or with Neutropenia
- Fever: Interrupt Uspen as a precautionary measure in any patient who develops fever, defined as a temperature of 38.5°C [101.3°F] or greater, and obtain an ANC level. Fever is often the first sign of neutropenic infection.
- ANC less than 1000/μL: If fever occurs in any patient with an ANC less than 1000/μL, initiate appropriate workup and treatment for infection and refer to Tables 2 or 3 for management.
- Consider hematology consultation.
- See Neuroleptic Malignant Syndrome (NMS) and Fever under WARNINGS AND PRECAUTIONS and Instructions for Patients, under PATIENT INFORMATION).
Rechallenge after an ANC less than 500/μL (Severe Neutropenia)
For some patients who experience severe Uspen-related neutropenia, the risk of serious psychiatric illness from discontinuing Uspen treatment may be greater than the risk of rechallenge (e.g., patients with severe schizophrenic illness who have no treatment options other than Uspen). A hematology consultation may be useful in deciding to rechallenge a patient. In general, however, do not rechallenge patients who develop severe neutropenia with Uspen or a clozapine product.
If a patient will be rechallenged, the clinician should consider thresholds provided in Tables 2 and 3, the patient's medical and psychiatric history, a discussion with the patient and his/her caregiver about the benefits and risks of Uspen rechallenge, and the severity and characteristics of the neutropenic episode.
Using Uspen with Other Drugs Associated with Neutropenia
It is unclear if concurrent use of other drugs known to cause neutropenia increases the risk or severity of Uspen-induced neutropenia. There is no strong scientific rationale to avoid Uspen treatment in patients concurrently treated with these drugs. If Uspen is used concurrently with an agent known to cause neutropenia (e.g., some chemotherapeutic agents), consider monitoring patients more closely than the treatment guidelines provided in Tables 2 and 3. Consult with the treating oncologist in patients receiving concomitant chemotherapy.
Clozapine REMS Program
Uspen is only available through a restricted program under a REMS called the Clozapine REMS Program because of the risk of severe neutropenia.
Notable requirements of the Clozapine REMS Program include:
- Healthcare professionals who prescribe Uspen must be certified with the program by enrolling and completing training.
- Patients who receive Uspen must be enrolled in the program and comply with the ANC testing and monitoring requirements.
- Pharmacies dispensing Uspen must be certified with the program by enrolling and completing training and must only dispense to patients who are eligible to receive Uspen.
Further information is available at www.clozapinerems.com or 1-844-267-8678.
Orthostatic Hypotension, Bradycardia, And Syncope
Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation. These reactions can occur with the first dose, at doses as low as 12.5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB).
Treatment must begin at a maximum dose of 12.5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. Use cautious titration and a divided dosage schedule to minimize the risk of serious cardiovascular reactions. Consider reducing the dose if hypotension occurs. When restarting patients who have had even a brief interval off Uspen (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily.
Use Uspen cautiously in patients with cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (e.g., concomitant use of antihypertensives, dehydration and hypovolemia).
Seizures
Seizure has been estimated to occur in association with clozapine use at a cumulative incidence at one year of approximately 5%, based on the occurrence of one or more seizures in 61 of 1743 patients exposed to clozapine during its clinical testing prior to domestic marketing (i.e., a crude rate of 3.5%). The risk of seizure is dose-related. Initiate treatment with a low dose (12.5 mg), titrate slowly, and use divided dosing.
Use caution when administering Uspen to patients with a history of seizures or other predisposing risk factors for seizure (e.g., head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). Because of the substantial risk of seizure associated with Uspen use, caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others (e.g., driving an automobile, operating complex machinery, swimming, climbing).
Myocarditis And Cardiomyopathy
Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue Uspen and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with Uspen. However, if the benefit of Uspen treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with Uspen in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.
Consider the possibility of myocarditis or cardiomyopathy in patients receiving Uspen who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period during treatment with Uspen. It is common for nonspecific flu-like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase-MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction.
Increased Mortality In Elderly Patients With Dementia-Related Psychosis
Eosinophilia
Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia. Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS).
If eosinophilia develops during Uspen treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia. If clozapine-related systemic disease is suspected, discontinue Uspen immediately.
If a cause of eosinophilia unrelated to clozapine is identified (e.g., asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue Uspen.
Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of clozapine, without recurrence of eosinophilia. In the absence of organ involvement, continue Uspen under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt Uspen therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.
QT Interval Prolongation
QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing Uspen, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions. Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of Uspen, and electrolyte abnormalities.
Prior to initiating treatment with Uspen, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue Uspen if the QTc interval exceeds 500 msec. If patients experience symptoms consistent with Torsades de Pointes or other arrhythmias (e.g., syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue Uspen.
Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of Uspen. Drugs that cause QT prolongation include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, thioridazine, mesoridazine, droperidol, pimozide), specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin), Class 1A antiarrhythmic medications (e.g., quinidine, procainamide) or Class III antiarrhythmics (e.g., amiodarone, sotalol), and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Uspen is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of Uspen.
Hypokalemia and hypomagnesemia increase the risk of QT prolongation. Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes. Correct electrolyte abnormalities before initiating treatment with Uspen.
Metabolic Changes
Atypical antipsychotic drugs, including Uspen, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus
Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including Uspen. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on Uspen should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4). The clozapine doses were 100-900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine.
Table 4: Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia
| Laboratory Parameter | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
| Fasting Glucose | Normal ( < 100 mg/dL) to High ( ≥ 126 mg/dL) | Clozapine | 198 | 53 (27) |
| Chlorpromazine | 135 | 14 (10) | ||
| Borderline (100 to 125 mg/dL) to High ( ≥ 126 mg/dL) | Clozapine | 57 | 24 (42) | |
| Chlorpromazine | 43 | 12 (28) |
Dyslipidemia
Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including Uspen. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using Uspen, is recommended.
In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol. No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride. The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6. The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively. The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.
Table 5: Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia
| Treatment Arm | Baseline Total Cholesterol Concentration (mg/dL) | Change from Baseline mg/dL (%) |
| Clozapine (N=334) | 184 | +13 (7) |
| Chlorpromazine (N=185) | 182 | +15 (8) |
| Baseline Triglyceride Concentration (mg/dL) | Change from Baseline mg/dL (%) | |
| Clozapine (N=6) | 130 | +71 (54) |
| Chlorpromazine (N=7) | 110 | +39 (35) |
Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia
| Laboratory Parameter | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
| Total Cholesterol (random or fasting) | Increase by ≥ 40 mg/dL | Clozapine | 334 | 111 (33) |
| Chlorpromazine | 185 | 46 (25) | ||
| Normal ( < 200 mg/dL) to High ( ≥ 240 mg/dL) | Clozapine | 222 | 18 (8) | |
| Chlorpromazine | 132 | 3 (2) | ||
| Borderline (200 - 239 mg/dL) to High ( ≥ 240 mg/dL) | Clozapine | 79 | 30 (38) | |
| Chlorpromazine | 34 | 14 (41) | ||
| Triglycerides (fasting) | Increase by ≥ 50 mg/dL | Clozapine | 6 | 3 (50) |
| Chlorpromazine | 7 | 3 (43) | ||
| Normal ( < 150 mg/dL) to High ( ≥ 200 mg/dL) | Clozapine | 4 | 0 (0) | |
| Chlorpromazine | 6 | 2 (33) | ||
| Borderline ( ≥ 150 mg/dL and < 200 mg/dL) to High ( ≥ 200 mg/dL) | Clozapine | 1 | 1 (100) | |
| Chlorpromazine | 1 | 0 (0) |
Weight Gain
Weight gain has occurred with the use of antipsychotics, including Uspen. Monitor weight during treatment with Uspen. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.
Table 7: Mean Change in Body Weight (kg) by duration of exposure from studies in adult subjects with schizophrenia
| Metabolic Parameter | Exposure Duration | Clozapine (N=669) | Olanzapine (N=442) | Chlorpromazine N=155) | |||
| n | Mean | n | Mean | n | Mean | ||
| Weight change from baseline | 2 weeks (Day 11 - 17) | 6 | +0.9 | 3 | +0.7 | 2 | -0.5 |
| 4 weeks (Day 21 - 35) | 23 | +0.7 | 8 | +0.8 | 17 | +0.6 | |
| 8 weeks (Day 49 - 63) | 12 | + 1.9 | 13 | + 1.8 | 16 | +0.9 | |
| 12 weeks (Day 70 - 98) | 17 | +2.8 | 5 | +3.1 | 0 | 0 | |
| 24 weeks (Day 154 - 182) | 42 | -0.6 | 12 | +5.7 | 0 | 0 | |
| 48 weeks (Day 322 - 350) | 3 | +3.7 | 3 | +13.7 | 0 | 0 |
Table 8 summarizes pooled data from 11 studies in
以下の副作用については、ラベル表示の他のセクションで詳しく説明します。
- 重度の好中球減少症。.
- 起立性低血圧、徐脈、失神。.
- 発作。.
- 心筋炎と心筋症。.
- 認知症関連精神病の高齢患者の死亡率の増加。.
- 好酸球増加症。.
- QT間隔延長。.
- 代謝の変化(高血糖と糖尿病、脂質異常症、体重増加)。.
- 神経遮断薬悪性症候群。.
- 発熱。.
- 肺塞栓症。.
- 抗コリン作用毒性。.
- 認知および運動パフォーマンスとの干渉。.
- 遅発性ジスキネジア。.
- フェニルケトン尿症の患者。.
- 脳血管副作用。.
- 突然の中止後の精神病とコリン作動性リバウンドの再発。.
臨床試験の経験。
臨床試験はさまざまな条件下で行われるため、薬物の臨床試験で観察された副作用率は、他の薬物の臨床試験の率と直接比較することはできず、臨床診療で観察された率を反映しない場合があります。.
クロザピンの臨床試験で最も一般的に報告された副作用(≥5%)は次のとおりです。鎮静、めまい/めまい、頭痛、振戦を含むCNS反応。頻脈、低血圧、失神などの心血管反応;過食、発汗、口渇、視覚障害などの自律神経系反応;便秘や吐き気を含む胃腸反応;そして発熱。. 表9は、治療抵抗性統合失調症の重要な6週間の対照試験におけるクロザピン治療患者(クロルプロマジン治療患者と比較)で最も一般的に報告されている副作用(≥5%)をまとめたものです。.
表9:治療耐性統合失調症における6週間無作為化クロルプロマジン対照試験における一般的な副作用(≥5%)。
| 副作用。 | クロザピン。 (N = 126)(%)。 | クロルプロマジン。 (N = 142)(%)。 |
| 鎮静。 | 21 | 13 |
| 頻脈。 | 17 | 11 |
| 便秘。 | 16 | 12 |
| めまい。 | 14 | 16 |
| 低血圧。 | 13 | 38 |
| 発熱(高体温)。 | 13 | 4 |
| ハイパーサリベーション。 | 13 | 1 |
| 高血圧。 | 12 | 5 |
| 頭痛。 | 10 | 10 |
| 吐き気/ ⁇ 吐。 | 10 | 12 |
| 口渇。 | 5 | 20 |
表10は、すべてのクロザピン研究(2年間のInterSePT™研究を除く)で、クロザピン治療患者で2%以上の頻度で報告された副作用をまとめたものです。. これらの率は、曝露期間中は調整されません。.
表10:すべてのクロザピン研究(2年間のInterSePT™研究を除く)にわたってクロザピン治療患者(N = 842)で報告される副作用(≥2%)。
| ボディシステム。 副作用。 | クロザピン。 N = 842。 患者の割合。 |
| 中央神経系。 | |
| 眠気/鎮静。 | 39 |
| めまい/めまい。 | 19 |
| 頭痛。 | 7 |
| 振戦。 | 6 |
| 失神。 | 6 |
| 睡眠障害/悪夢。 | 4 |
| 落ち着きのなさ。 | 4 |
| 低運動症/運動失調。 | 4 |
| 興奮。 | 4 |
| 発作(けいれん)。 | 3† |
| ⁇ 性。 | 3 |
| アカティシア。 | 3 |
| 混乱。 | 3 |
| 疲労。 | 2 |
| 不眠症。 | 2 |
| 心血管。 | |
| 頻脈。 | 25 ⁇ 。 |
| 低血圧。 | 9 |
| 高血圧。 | 4 |
| 消化器。 | |
| 便秘。 | 14 |
| 吐き気。 | 5 |
| 腹部不快感/ハートバーン。 | 4 |
| 吐き気/ ⁇ 吐。 | 3 |
| ⁇ 吐。 | 3 |
| 下 ⁇ 。 | 2 |
| ⁇ 尿生殖器。 | |
| 尿異常。 | 2 |
| 自律神経系。 | |
| ⁇ 液分 ⁇ 。 | 31 |
| 発汗。 | 6 |
| 口渇。 | 6 |
| 視覚障害。 | 5 |
| 皮膚。 | |
| 発疹。 | 2 |
| 貧血/リンパ。 | |
| 白血球減少症/減少WBC /好中球減少症。 | 3 |
| その他。 | |
| 発熱。 | 5 |
| ウェイトゲイン。 | 4 |
| ⁇ クロザピンの市販前の臨床評価中に暴露された約1700人の人口に基づく率。. | |
表11は、InterSePT™研究で最も一般的に報告された副作用(クロザピンまたはオランザピン群の10%以上)をまとめたものです。. これは、統合失調症または統合失調感情障害の患者の自殺行動のリスクを軽減するオランザピンと比較したクロザピンの有効性を評価する、適切で適切に管理された2年間の研究でした。. 率は暴露期間中は調整されません。.
表11:InterSePT™研究におけるクロザピンまたはオランザピンで治療された患者の有害反応の発生率(クロザピンまたはオランザピングループで≥10%)。
| 副作用。 | クロザピン。 N = 479%レポート。 | オランザピン。 N = 477%レポート。 |
| ⁇ 液分 ⁇ 過多。 | 48%。 | 6% |
| 傾眠。 | 46%。 | 25%。 |
| 体重が増加した。 | 31%。 | 56%。 |
| めまい(めまいを除く)。 | 27%。 | 12%。 |
| 便秘。 | 25%。 | 10%。 |
| 不眠症。 | 20%。 | 33%。 |
| 吐き気。 | 17%。 | 10%。 |
| ⁇ 吐。 | 17%。 | 9% |
| 消化不良。 | 14%。 | 8% |
ダイストニア。
クラスの影響:ジストニアの症状、筋肉群の長期にわたる異常な収縮は、治療の最初の数日間、感受性の高い個人で発生する可能性があります。. 失神症状には、首の筋肉のけいれん、喉の圧迫感、 ⁇ 下困難、呼吸困難、舌の突出などがあります。. これらの症状は低用量で発生する可能性がありますが、より頻繁に発生し、高効力および高用量の第一世代抗精神病薬により重症度が高くなります。. 急性ジストニアのリスクの上昇は、男性および若い年齢層で観察されます。.
市販後の経験。
クロザピンの承認後の使用中に、以下の副作用が確認されています。. これらの反応は不確実なサイズの集団から自発的に報告されるため、その頻度を確実に推定したり、薬物曝露との因果関係を確立したりすることは常に可能ではありません。.
中央神経系。
せん妄、脳波異常、ミオクローヌス、感覚異常、脱 ⁇ の可能性、てんかんの状態、強迫性症状、および中止後のコリン作動性リバウンド副作用。.
心血管系。
心房または心室細動、心室頻拍、QT間隔延長、トルサードドポワント、心筋 ⁇ 塞、心停止、および眼 ⁇ 周囲浮腫。.
内分 ⁇ 系。
偽血小板腫。.
消化器系。
急性 ⁇ 炎、 ⁇ 下障害、 ⁇ 液腺の腫れ。.
肝胆道系。
胆 ⁇ うっ滞、肝炎、黄 ⁇ 、肝毒性、肝脂肪症、肝壊死、肝線維症、肝硬変、肝障害(肝、胆 ⁇ うっ滞、混合)、および肝不全。.
免疫系障害。
血管浮腫、白血球破砕性血管炎。.
⁇ 尿生殖器系。
急性間質性腎炎、夜尿症、持続勃起症、腎不全。.
皮膚および皮下組織障害。
過敏症反応:光線過敏症、血管炎、多形紅斑、皮膚の色素沈着障害、スティーブンス・ジョンソン症候群。.
筋骨格系および結合組織障害。
筋無力症候群、横紋筋融解症、全身性エリテマトーデス。.
呼吸器系。
誤 ⁇ 、胸水、肺炎、下気道感染症。.
貧血およびリンパ系。
軽度、中等度、または重度の白血球減少症、無 ⁇ 粒球減少症、WBCの減少、深部静脈血栓症、ヘモグロビン/ヘマトクリットの上昇、赤血球沈降速度(ESR)の増加、敗血症、血小板増加症、および血小板減少症。.
視力障害。
狭角緑内障。.
その他。
クレアチンホスホキナーゼの上昇、高尿酸血症、低ナトリウム血症、体重減少。.
過剰摂取の経験。
クロザピンの過剰摂取に関連する最も一般的に報告されている兆候と症状は次のとおりです。鎮静、せん妄、 ⁇ 睡、頻脈、低血圧、呼吸抑制または失敗。そして過食。. 誤 ⁇ 性肺炎、不整脈、発作の報告があります。. 致命的な過剰摂取は、クロザピンで、一般的に2500 mgを超える用量で報告されています。. 4 gをはるかに超える過剰摂取から回復した患者の報告もあります。.
過剰摂取の管理。
FAZACLOの過剰摂取の管理に関する最新情報については、認定された地域毒物管理センター(1-800-222-1222)にお問い合わせください。. 認定された地域毒物管理センターの電話番号は、PDRネットワークの登録商標であるPhysicians DeskReference®に記載されています。. 気道を確立して維持します。適切な酸素化と換気を確保します。. 心臓の状態とバイタルサインを監視します。. 一般的な症状と支援策を使用します。. FAZACLOの特定の解毒剤はありません。
過剰摂取の管理では、多剤関与の可能性を検討してください。.
過剰摂取の経験。
クロザピンの過剰摂取に関連する最も一般的に報告されている兆候と症状は次のとおりです。鎮静、せん妄、 ⁇ 睡、頻脈、低血圧、呼吸抑制または失敗。そして過食。. 誤 ⁇ 性肺炎、不整脈、発作の報告があります。. 致命的な過剰摂取は、クロザピンで、一般的に2500 mgを超える用量で報告されています。. 4 gをはるかに超える過剰摂取から回復した患者の報告もあります。.
過剰摂取の管理。
Uspenの過剰摂取の管理に関する最新情報については、認定された地域毒物管理センター(1-800-222-1222)にお問い合わせください。. 認定された地域毒物管理センターの電話番号は、PDRネットワークの登録商標であるPhysicians DeskReference®に記載されています。. 気道を確立して維持します。適切な酸素化と換気を確保します。. 心臓の状態とバイタルサインを監視します。. 一般的な症状と支援策を使用します。. Uspenの特定の解毒剤はありません。.
過剰摂取の管理では、多剤関与の可能性を検討してください。.
クロザピンは、ヒスタミンH1の受容体に対する結合親和性を示しました。 (Ki 1.1 nM。) 副腎α1A。 (Ki 1.6 nM。) セロトニン5-HT6。 (Ki 4 nM。) セロトニン5-HT2A。 (Ki 5.4 nM。) ムスカリンM1。 (Ki 6.2 nM。) セロトニン5-HT7。 (Ki 6.3 nM。) セロトニン5-HT2C。 (Ki 9.4 nM。) ドーパミンD4。 (Ki 24 nM。) 副腎α2A。 (Ki 90 nM。) セロトニン5-HT3。 (Ki 95 nM。) セロトニン5HT1A。 (Ki 120 nM。) ドーパミンD2。 (Ki 160 nM。) ドーパミンD1。 (Ki 270 nM。) ドーパミンD5。 (Ki 454 nM。) ドーパミンD3。 (Ki 555 nM。).
クロザピンはプロラクチンの上昇をほとんどまたはまったく引き起こしません。.
臨床脳波(EEG)の研究では、クロザピンがデルタおよびシータの活性を増加させ、主要なアルファ周波数を遅くすることが示されました。. 強化された同期が発生します。. 鋭い波の活動とスパイクと波の複合体も発達する可能性があります。. 患者はクロザピン療法中の夢の活動の強化を報告しました。. REM睡眠は、総睡眠時間の85%に増加することがわかりました。. これらの患者では、REM睡眠の開始は、眠りについた直後に発生しました。.
吸収。
男性では、クロザピン錠(25 mgおよび100 mg)は、クロザピン溶液と比較して同様に生物学的に利用可能です。. FAZACLO®(クロザピン)経口分解錠剤は、Novartis Pharmaceuticals Corporationの登録商標であるClozaril®(クロザピン)錠剤と生物学的に同等です。. 100 mg b.i.d.の投与後.、平均定常ピーク血漿濃度は413 ng / mL(範囲:132-854 ng / mL)で、投与後平均2.3時間(範囲:1〜6時間)で発生しました。. 定常状態での平均最小濃度は、100 mg b.i.d.後、168 ng / mL(範囲:45-574 ng / mL)でした。. 投薬。.
空腹時の状態で、FAZACLO 200 mg錠剤を2 ⁇ — FAZACLO 100 mg錠剤(承認された参照製品)と比較して、32人の患者(統合失調症または統合失調感情障害)で比較生物学的同等性/バイオアベイラビリティ研究が行われました。. この研究では、200 mg錠剤の薬物動態に対する食品と噛みの影響も評価しました。. 空腹時の状態では、200 mg錠剤のクロザピンの平均AUCssおよびCmin、ssは、2 x 100 mg錠剤のものと同等でした。. FAZACLO 200 mg錠剤のクロザピンの平均Cmax、ssは、2 x 100 mg FAZACLO錠剤の85%でした。. FAZACLO 200 mg錠剤のCmax、ssのこの減少は、臨床的に有意ではありません。.
FAZACLO 200 mg錠剤の場合、食品はクロザピンのCmin、ssを21%大幅に増加させました。. ただし、この増加は臨床的に重要ではありません。. 摂食条件下でのクロザピンの平均AUCssおよびCmax、ssは、絶食条件下でのものと同等でした。. 食品はクロザピンの吸収を1.5時間遅らせ、空腹時のTmaxの中央値2.5時間から摂食時の4時間まで遅らせました。.
FAZACLO 200 mg錠剤の噛んだ状態でのクロザピンの平均Cmax、ssは、噛んでいない状態での2 x 100 mg FAZACLO錠剤の約86%でしたが、AUCssとCmin、ssの値は、噛んだ状態と非噛んだ状態。.
食物効果研究では、空腹時および高脂肪食後に、FAZACLO(クロザピン)経口崩壊錠12.5 mgを1回投与して健康なボランティアに投与しました。. 高脂肪食後にFAZACLOを投与した場合、クロザピンとその活性代謝物であるデスメチルクロザピンの両方のCmaxは、空腹時の投与と比較して約20%減少しましたが、AUC値は変化していません。. このCmaxの減少は臨床的に重要ではありません。. したがって、FAZACLO(クロザピン)経口崩壊錠は、食事に関係なく服用できます。.
分布。
クロザピンは約97%が血清タンパク質に結合しています。. クロザピンと他の高タンパク質結合薬との相互作用は完全には評価されていませんが、重要かもしれません。.
代謝と排 ⁇ 。
クロザピンは排 ⁇ 前にほぼ完全に代謝され、尿と ⁇ 便中に検出された薬物の量はごくわずかです。. クロザピンは、多くのチトクロームP450アイソザイム、特にCYP1A2、CYP2D6、およびCYP3A4の基質です。. 投与量の約50%が尿中に排 ⁇ され、30%が ⁇ 便中に排 ⁇ されます。. デメチル化、ヒドロキシル化、およびN-オキシド誘導体は、尿と ⁇ の両方の成分です。. 薬理学的検査では、デスメチル代謝物(ノルクロザピン)の活性は限定的であるのに対し、ヒドロキシル化およびN-オキシド誘導体は不活性であることが示されています。. 75 mg単回投与後のクロザピンの平均排出半減期は8時間(範囲:4〜12時間)でしたが、定常を達成した後の平均排出半減期は12時間(範囲:4〜66時間)でした。 100 mgを1日2回投与する状態。.
クロザピンの単回投与と複数回投与の比較では、単回投与後のそれと比較して、複数回投与後の消失半減期が大幅に増加し、濃度依存の薬物動態の可能性を示唆しています。. ただし、定常状態では、AUC(曲線下面積)、ピーク、および最小クロザピン血漿濃度に関するおおよその用量比例的変化が、37.5、75、および150 mgを1日2回投与した後に観察されました。.
吸収。
男性では、クロザピン錠(25 mgおよび100 mg)は、クロザピン溶液と比較して同様に生物学的に利用可能です。. Uspen®(クロザピン)経口分解錠剤は、Novartis Pharmaceuticals Corporationの登録商標であるClozaril®(クロザピン)錠剤と生物学的に同等です。. 100 mg b.i.d.の投与後.、平均定常ピーク血漿濃度は413 ng / mL(範囲:132-854 ng / mL)で、投与後平均2.3時間(範囲:1〜6時間)で発生しました。. 定常状態での平均最小濃度は、100 mg b.i.d.後、168 ng / mL(範囲:45-574 ng / mL)でした。. 投薬。.
空腹時の条件下で、Uspen 200 mg錠剤を2 ⁇ — Uspen 100 mg錠剤(承認された参照製品)と比較した32人の患者(統合失調症または統合失調感情障害)で、生物学的同等性/バイオアベイラビリティの比較研究が行われました。. この研究では、200 mg錠剤の薬物動態に対する食品と噛みの影響も評価しました。. 空腹時の状態では、200 mg錠剤のクロザピンの平均AUCssおよびCmin、ssは、2 x 100 mg錠剤のものと同等でした。. Uspen 200 mg錠剤のクロザピンの平均Cmax、ssは、2 x 100 mg Uspen錠剤の85%でした。. Uspen 200 mg錠剤のCmax、ssのこの減少は、臨床的に有意ではありません。.
Uspen 200 mg錠剤の場合、食品はクロザピンのCmin、ssを21%大幅に増加させました。. ただし、この増加は臨床的に重要ではありません。. 摂食条件下でのクロザピンの平均AUCssおよびCmax、ssは、絶食条件下でのものと同等でした。. 食品はクロザピンの吸収を1.5時間遅らせ、空腹時のTmaxの中央値2.5時間から摂食時の4時間まで遅らせました。.
Uspen 200 mg錠剤の噛んだ状態でのクロザピンの平均Cmax、ssは、噛んでいない状態での2 x 100 mg Uspen錠剤の約86%でしたが、AUCssとCmin、ssの値は、噛んだ状態と非噛んだ状態の間で類似していました条件。.
食物効果研究では、空腹時および高脂肪食後に、Uspen(クロザピン)経口崩壊錠12.5 mgを健康なボランティアに単回投与しました。. 高脂肪食後にウスペンを投与した場合、クロザピンとその活性代謝物であるデスメチルクロザピンの両方のCmaxは、空腹時の投与と比較して約20%減少しましたが、AUC値は変化していません。. このCmaxの減少は臨床的に重要ではありません。. したがって、食事に関係なく、ウスペン(クロザピン)経口崩壊錠を服用できます。.
分布。
クロザピンは約97%が血清タンパク質に結合しています。. クロザピンと他の高タンパク質結合薬との相互作用は完全には評価されていませんが、重要かもしれません。.
代謝と排 ⁇ 。
クロザピンは排 ⁇ 前にほぼ完全に代謝され、尿と ⁇ 便中に検出された薬物の量はごくわずかです。. クロザピンは、多くのチトクロームP450アイソザイム、特にCYP1A2、CYP2D6、およびCYP3A4の基質です。. 投与量の約50%が尿中に排 ⁇ され、30%が ⁇ 便中に排 ⁇ されます。. デメチル化、ヒドロキシル化、およびN-オキシド誘導体は、尿と ⁇ の両方の成分です。. 薬理学的検査では、デスメチル代謝物(ノルクロザピン)の活性は限定的であるのに対し、ヒドロキシル化およびN-オキシド誘導体は不活性であることが示されています。. 75 mg単回投与後のクロザピンの平均排出半減期は8時間(範囲:4〜12時間)でしたが、定常を達成した後の平均排出半減期は12時間(範囲:4〜66時間)でした。 100 mgを1日2回投与する状態。.
クロザピンの単回投与と複数回投与の比較では、単回投与後のそれと比較して、複数回投与後の消失半減期が大幅に増加し、濃度依存の薬物動態の可能性を示唆しています。. ただし、定常状態では、AUC(曲線下面積)、ピーク、および最小クロザピン血漿濃度に関するおおよその用量比例的変化が、37.5、75、および150 mgを1日2回投与した後に観察されました。.
