Zixadox

ジキサドックスは、統合失調症の治療、双極性 ⁇ 病または混合エピソードの急性治療の単剤療法、および双極性障害の維持治療のためのリチウムまたはバルプロ酸の補助として適応されます。. Zixadox筋肉内は、統合失調症患者の急性興奮に適応されます。. 治療が必要な状態で利用可能な代替治療を決定するとき、処方者は、他のいくつかの抗精神病薬と比較して、QT / QTc間隔を延長するジプラシドンのより大きな能力の発見を検討する必要があります。. QTc間隔の延長は、トルサードドポワント型不整脈、致命的な可能性のある多型心室頻脈、および突然死を引き起こす能力を持つ他のいくつかの薬物に関連しています。. 多くの場合、これは他の薬が最初に試されるべきであるという結論につながります。. ジプラシドンがトルサードドポワントを引き起こすのか、突然死の割合を上げるのかはまだわかっていません。

統合失調症。

ジキサドックスは統合失調症の治療に使用されます。. 経口ジプラシドンの有効性は、成人の統合失調症入院患者の4つの短期(4週間および6週間)対照試験と、安定した成人の統合失調症入院患者の1つの維持試験で確立されました。.

双極性I障害(リチウムまたはバルプロ酸の補助としての急性混合または ⁇ 病エピソードおよび維持療法)。

ジキサドックスは、双極性I障害に関連する ⁇ 病または混合エピソードの急性治療の単剤療法として示されています。. 有効性は、成人患者を対象とした2つの3週間の単剤療法研究で確立されました。.

ジキサドックスは、双極性I障害の維持治療のためのリチウムまたはバルプロ酸の補助として示されています。. 有効性は成人患者の維持試験で確立されました。. 双極性I障害の維持治療のための単剤療法としてのジキサドックスの有効性は、対照臨床試験で体系的に評価されていません。.

統合失調症の興奮の急性治療。

ジキサドックス筋肉内は、ジプラシドンによる治療が適切であり、興奮を迅速に制御するために筋肉内抗精神病薬を必要とする統合失調症患者の急性興奮の治療に適応されます。. 統合失調症の急性興奮に対する筋肉内ジプラシドンの有効性は、興奮した統合失調症入院患者の1日対照試験で確立されました。

「精神運動興奮」は、DSM-IVで「内面の緊張感に関連する過度の運動活動」として定義されています。. 興奮を経験している統合失調症の患者は、診断やケアを妨げる行動をしばしば示します。.、脅迫的な行動、エスカレートまたは緊急の苦痛な行動、または自己嫌悪行動により、臨床医は筋肉内抗精神病薬を使用して興奮を即座に制御します。.

すでにジプラシドンを経口投与している統合失調症患者に筋肉内ジプラシドンを投与する安全性に関する経験がないため、同時投与の実践は推奨されません。.

筋肉内ジプラシドンは筋肉内使用のみを目的としており、静脈内投与しないでください。.

統合失調症。

線量選択。

ジキサドックスカプセルは、1日2回20 mgの初回投与量で食物とともに投与する必要があります。. 一部の患者では、その後、1日2回80 mgまでの個々の臨床状態に基づいて1日の投与量を調整できます。. 定常状態は1〜3日以内に達成されるため、必要に応じて、投与量の調整は通常2日以上の間隔で行われる必要があります。. 最低有効用量の使用を確実にするために、患者は通常、上向きの用量調整の前に数週間改善を観察されるべきです。.

統合失調症の有効性は、短期間のプラセボ対照臨床試験で、1日2回20 mg〜100 mgの用量範囲で実証されました。. 1日2回20 mg〜80 mgの範囲で用量反応に向かう傾向がありましたが、結果は一貫していませんでした。. 1日2回80 mgを超える用量への増加は、一般的に推奨されません。. 1日2回100 mgを超える用量の安全性は、臨床試験で体系的に評価されていません。.

メンテナンス処理。

ジプラシドンで治療された患者がどれくらいの期間その上に留まるべきかという質問に答えることができる証拠の本体はありませんが。, 症状が安定し、その後無作為化されてジプラシドンを継続するかプラセボに切り替えた患者を対象とした維持研究では、ジキサドックスを投与された患者の再発までの時間の遅れが示されました。. 1日2回20 mgを超える用量では、追加の利益は示されませんでした。. 患者は、維持療法の必要性を判断するために定期的に再評価されるべきです。.

双極性I障害(リチウムまたはバルプロ酸の補助としての急性混合または ⁇ 病エピソードおよび維持療法)。

⁇ 病または混合エピソードの急性治療。

用量選択-オーラルジプラシドンは、食物と一緒に1日2回40 mgの初期1日用量で投与する必要があります。. その後、治療2日目に1日2回60 mgまたは80 mgに用量を増やし、その後、1日2回40 mg ⁇ ¢¬80 mgの範囲内の耐性と有効性に基づいて調整します。. 柔軟な用量の臨床試験では、投与された1日の平均用量は約120 mgでした。.

メンテナンス処理(リチウムまたはバルプロ酸の補助として)。

患者が最初に安定したのと同じ用量で、1日2回40 mg ⁇ ¢ ⁇ 80 mgの範囲内で治療を続けます。. 患者は、維持療法の必要性を判断するために定期的に再評価されるべきです。.

統合失調症の興奮の急性治療。

筋肉内投与。

推奨用量は、必要に応じて1日あたり最大40 mgまで10 mg〜20 mgを投与します。. 10 mgの用量は2時間ごとに投与できます。 20 mgの用量は、4時間ごとに最大40 mg /日まで投与できます。. 3日以上連続してジプラシドンを筋肉内投与することは研究されていません。.

長期療法が適応となる場合、経口塩酸ジプラシドンカプセルはできるだけ早く筋肉内投与を置き換える必要があります。.

すでにジプラシドンを経口投与している統合失調症患者に筋肉内ジプラシドンを投与する安全性に関する経験がないため、同時投与の実践は推奨されません。.

筋肉内ジプラシドンは筋肉内使用のみを目的としており、静脈内投与しないでください。.

投与のための筋肉内準備。

注射用ジキサドックス(メシル酸ジプラシドン)は筋肉内注射によってのみ投与し、静脈内投与しないでください。. 単回投与バイアルは、投与前に再構成する必要があります。.

注射用の滅菌水1.2 mLをバイアルに加え、すべての薬剤が溶解するまで激しく振ります。. 再構成した溶液の各mLには、20 mgのジプラシドンが含まれています。. 10 mgの用量を投与するには、0.5 mLの再構成溶液を作成します。. 20 mgの用量を投与するには、1.0 mLの再構成溶液を作成します。. 未使用の部分は破棄してください。. この製品には防腐剤や静菌剤が存在しないため、最終溶液の準備には無菌技術を使用する必要があります。. この医薬品は、注射用の滅菌水以外の医薬品や溶剤と混合してはなりません。. 非経口医薬品は、溶液と容器が許す限り、投与前に粒子状物質と変色がないか目視検査する必要があります。.

特別な集団での投薬。

経口。

投与量の調整は、通常、年齢、性別、人種、または腎障害または肝障害に基づいて必要ありません。. Zixadoxは、子供または青年での使用は承認されていません。.

筋肉内。

筋肉内ジプラシドンは、高齢患者や肝機能障害または腎機能障害のある患者では体系的に評価されていません。. シクロデキストリン ⁇ 形剤は腎 ⁇ 過により除去されるため、腎機能障害のある患者には注意してジプラシドン筋肉内投与する必要があります。. 性別や人種に基づく投与量の調整は必要ありません。.

QT延長。

ジプラシドンの用量に関連したQT間隔の延長と、他の薬物によるQT延長と致命的な不整脈の既知の関連のため、ジプラシドンは禁 ⁇ です。

• QT延長の既知の歴史を持つ患者(先天性QT症候群を含む)。
• 最近の急性心筋 ⁇ 塞の患者。
• 補償のない心不全の患者。

QT間隔を延長するジプラシドンと他の薬物との間の薬物動態/薬力学的研究は行われていません。. QT間隔を延長するジプラシドンおよび他の薬物の相加効果は除外できません。. したがって、ジプラシドンには以下を与えるべきではありません。

• ドフェチリド、ソタロール、キニジン、その他のクラスIaおよびIII抗不整脈薬、メソリダジン、チオリダジン、クロルプロマジン、ドロペリドール、ピモジド、スパルフロキサシン、ガチフロキサシン、モキシフロキサシン、ハロファントリン、メフロキン、ペンタミジン、三酸化ヒ素、酢酸レボメタジリル.
• QT延長を薬力学的効果の1つとして実証し、この効果を完全な処方情報に禁 ⁇ または箱入りのまたは大胆な警告として記載している他の薬物。.

過敏症。

ジプラシドンは、製品に対する過敏症が知られている個人には禁 ⁇ です。.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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. Zixadox is not approved for the treatment of dementia-related psychosis.

QT Prolongation And Risk Of Sudden Death

Ziprasidone use should be avoided in combination with other drugs that are known to prolong the QTc interval. Additionally, clinicians should be alert to the identification of other drugs that have been consistently observed to prolong the QTc interval. Such drugs should not be prescribed with ziprasidone. Ziprasidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

A study directly comparing the QT/QTc prolonging effect of oral ziprasidone with several other drugs effective in the treatment of schizophrenia was conducted in patient volunteers. In the first phase of the trial, ECGs were obtained at the time of maximum plasma concentration when the drug was administered alone. In the second phase of the trial, ECGs were obtained at the time of maximum plasma concentration while the drug was co-administered with an inhibitor of the CYP4503A4 metabolism of the drug.

In the first phase of the study, the mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (risperidone, olanzapine, quetiapine, and haloperidol), but was approximately 14 msec less than the prolongation observed for thioridazine.

In the second phase of the study, the effect of ziprasidone on QTc length was not augmented by the presence of a metabolic inhibitor (ketoconazole 200 mg twice daily).

In placebo-controlled trials, oral ziprasidone increased the QTc interval compared to placebo by approximately 10 msec at the highest recommended daily dose of 160 mg. In clinical trials with oral ziprasidone, the electrocardiograms of 2/2988 (0.06%) patients who received Zixadox and 1/440 (0.23%) patients who received placebo revealed QTc intervals exceeding the potentially clinically relevant threshold of 500 msec. In the ziprasidone-treated patients, neither case suggested a role of ziprasidone. One patient had a history of prolonged QTc and a screening measurement of 489 msec; QTc was 503 msec during ziprasidone treatment. The other patient had a QTc of 391 msec at the end of treatment with ziprasidone and upon switching to thioridazine experienced QTc measurements of 518 and 593 msec.

Some drugs that prolong the QT/QTc interval have been associated with the occurrence of torsade de pointes and with sudden unexplained death. The relationship of QT prolongation to torsade de pointes is clearest for larger increases (20 msec and greater) but it is possible that smaller QT/QTc prolongations may also increase risk, or increase it in susceptible individuals. Although torsade de pointes has not been observed in association with the use of ziprasidone in premarketing studies and experience is too limited to rule out an increased risk, there have been rare post-marketing reports (in the presence of multiple confounding factors).

A study evaluating the QT/QTc prolonging effect of intramuscular ziprasidone, with intramuscular haloperidol as a control, was conducted in patient volunteers. In the trial, ECGs were obtained at the time of maximum plasma concentration following two injections of ziprasidone (20 mg then 30 mg) or haloperidol (7.5 mg then 10 mg) given four hours apart. Note that a 30 mg dose of intramuscular ziprasidone is 50% higher than the recommended therapeutic dose. The mean change in QTc from baseline was calculated for each drug, using a sample-based correction that removes the effect of heart rate on the QT interval. The mean increase in QTc from baseline for ziprasidone was 4.6 msec following the first injection and 12.8 msec following the second injection. The mean increase in QTc from baseline for haloperidol was 6.0 msec following the first injection and 14.7 msec following the second injection. In this study, no patients had a QTc interval exceeding 500 msec.

As with other antipsychotic drugs and placebo, sudden unexplained deaths have been reported in patients taking ziprasidone at recommended doses. The premarketing experience for ziprasidone did not reveal an excess risk of mortality for ziprasidone compared to other antipsychotic drugs or placebo, but the extent of exposure was limited, especially for the drugs used as active controls and placebo. Nevertheless, ziprasidone's larger prolongation of QTc length compared to several other antipsychotic drugs raises the possibility that the risk of sudden death may be greater for ziprasidone than for other available drugs for treating schizophrenia. This possibility needs to be considered in deciding among alternative drug products.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

It is recommended that patients being considered for ziprasidone treatment who are at risk for significant electrolyte disturbances, hypokalemia in particular, have baseline serum potassium and magnesium measurements. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia. Hypokalemia may result from diuretic therapy, diarrhea, and other causes. Patients with low serum potassium and/or magnesium should be repleted with those electrolytes before proceeding with treatment. It is essential to periodically monitor serum electrolytes in patients for whom diuretic therapy is introduced during ziprasidone treatment. Persistently prolonged QTc intervals may also increase the risk of further prolongation and arrhythmia, but it is not clear that routine screening ECG measures are effective in detecting such patients. Rather, ziprasidone should be avoided in patients with histories of significant cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. Ziprasidone should be discontinued in patients who are found to have persistent QTc measurements > 500 msec.

For patients taking ziprasidone who experience symptoms that could indicate the occurrence of torsade de pointes, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, e.g., Holter monitoring may be useful.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system (CNS) pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

Severe Cutaneous Adverse Reactions

Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with Ziprasidone exposure. DRESS consists of a combination of three or more of the following: cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, lymphadenopathy and one or more systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and pericarditis. DRESS is sometimes fatal. Discontinue ziprasidone if DRESS is suspected.

Other Severe Cutaneous Adverse Reactions

Other severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported with ziprasidone exposure. Severe cutaneous adverse reactions are sometimes fatal. Discontinue ziprasidone if severe cutaneous adverse reactions are suspected.

Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients undergoing treatment with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, ziprasidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on ziprasidone, drug discontinuation should be considered. However, some patients may require treatment with ziprasidone despite the presence of the syndrome.

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia And Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with Zixadox. Although fewer patients have been treated with Zixadox, it is not known if this more limited experience is the sole reason for the paucity of such reports. 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. 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 atypical antipsychotics 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 antidiabetic treatment despite discontinuation of the suspect drug.

Pooled data from short-term, placebo-controlled studies in schizophrenia and bipolar disorder are presented in Tables 1-4. Note that for the flexible dose studies in both schizophrenia and bipolar disorder, each subject is categorized as having received either low (20-40 mg BID) or high (60–80 mg BID) dose based on the subject's modal daily dose. In the tables showing categorical changes, the percentages (% column) are calculated as 100×(n/N).

Table 1: Glucose* Mean Change from Baseline in Short-Term (up to 6 weeks ), Placebo- Controlled, Fixed-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Schizophrenia

Table 2: Glucose Categorical Changes in Short-Term (up to 6 weeks ), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Schizophrenia

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline in random glucose for ziprasidone 20-40 mg BID was -3.4 mg/dL (N=122); for ziprasidone 60-80 mg BID was +1.3 mg/dL (N=10); and for placebo was +0.3 mg/dL (N=71).

Table 3: Glucose* Mean Change from Baseline in Short-Term (up to 6 weeks ), Placebo- Controlled, Flexible-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Bipolar Disorder

Table 4: Glucose* Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled, Flexible-Dose, Oral Ziprasidone, Monotherapy Trials in Adult Patients with Bipolar Disorder

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo-controlled studies in schizophrenia and bipolar disorder are presented in Tables 5-8.

Table 5: Lipid* Mean Change from Baseline in Short-Term (up to 6 weeks ), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

Table 6: Lipid Categorical Changes in Short-Term (up to 6 weeks), Placebo-Controlled, Fixed-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Schizophrenia

In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline in random triglycerides for ziprasidone 20-40 mg BID was +26.3 mg/dL (N=15); for ziprasidone 60-80 mg BID was -39.3 mg/dL (N=10); and for placebo was +12.9 mg/dL (N=9). In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline in random total cholesterol for ziprasidone 20-40 mg BID was +2.5 mg/dL (N=14); for ziprasidone 60-80 mg BID was -19.7 mg/dL (N=10); and for placebo was -28.0 mg/dL (N=9).

Table 7: Lipid* Mean Change from Baseline in Short-Term (up to 6 weeks ), Placebo-Controlled, Flexible-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Bipolar Disorder

Table 8: Lipid* Categorical Changes in Short-Term (up to 6 weeks ), Placebo-Controlled, Flexible-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Bipolar Disorder

ウェイトゲイン。

非定型の抗精神病薬の使用で体重増加が観察されています。. 体重のモニタリングが推奨されます。. 統合失調症と双極性障害の短期プラセボ対照試験のプールされたデータを表9-10に示します。.

表9:短期(最大6週間)の体重平均変化、プラセボ対照、固定用量e、統合失調症の成人患者における経口ジプラのイドン単剤療法試験。

統合失調症の長期(少なくとも1年)のプラセボ対照フレキシブル用量研究では、ジプラシドン20-40 mg BIDのベースライン重量からの平均変化は-2.3 kg(N = 124)でした。ジプラシドン60-80 mg BIDは+2.5 kg(N = 10)でした。プラセボの場合-2でした。. 同じ長期研究では、ジプラシドン20-40 mg BIDのベースラインから体重が7%以上増加した被験者の割合は5.6%(N = 124)でした。ジプラシドン60-80 mg BIDは20.0%(N = 10)、プラセボは5.6%(N = 72)でした。. 長期的には。 (少なくとも1年。) プラセボ対照。, 統合失調症の固定用量研究。, ジプラシドン20 mg BIDのベースライン重量からの平均変化は-2.6 kgでした。 (N = 72。) ジプラシドン40 mg BIDは-3.3 kgでした。 (N = 69。) ジプラシドン80 mg BIDは-2.8 kgでした。 (N = 70。) プラセボは-3.8 kgでした。 (N = 70。). 同じ長期固定用量統合失調症の研究で。, ジプラシドン20 mg BIDのベースラインから体重が7%以上増加した被験者の割合は5.6%でした。 (N = 72。) ジプラシドン40 mg BIDは2.9%でした。 (N = 69。) ジプラシドン80 mg BIDは5.7%でした。 (N = 70。) プラセボは2.9%でした。 (N = 70。).

表10:双極性障害の成人患者における短期(最大6週間)の体重変化の概要、プラセボ対照、柔軟な用量、経口ジプラシドン単剤療法試験:。

統合失調症。

体重の7%以上の体重増加基準を満たす患者の割合は、4週間および6週間のプラセボ対照統合失調症の臨床試験のプールで比較され、ジプラシドン(10 %)プラセボと比較して(4%)。. プラセボ患者では体重の中央値の変化がないのに対し、ジプラシドン患者では0.5 kgの中央値体重増加が観察されました。. この一連の臨床試験では、ジプラシドン患者とプラセボ患者のそれぞれ0.4%と0.4%で、体重増加が副作用として報告されました。. ジプラシドンによる長期治療中。, ボディマスインデックスに基づくベースライン時の患者の分類。 (BMI。) 最大の平均体重増加と臨床的に有意な体重増加の最高の発生率を明らかにしました。 ( 体重の7%以上。) BMIが低い患者。 ( <23。) 通常と比較して。 (23 ⁇ ¢â¬“ 27。) または太りすぎの患者。 ( > 27。). 「低」ベースラインBMIの患者の平均体重増加は1.4 kg、「正常な」BMIの患者の平均変化はなく、「高」でプログラムに参加した患者の平均体重減少は1.3 kgでした。 BMI .

双極性障害。

リチウムまたはバルプロ酸の補助としてジプラシドンを使用した成人の6か月間のプラセボ対照双極性維持試験中。, 臨床的に有意な体重増加の発生率。 ( 体重の7%以上。) 再発の6か月の観察を完了したジプラシドンとプラセボ治療グループの両方で、二重盲検期間中は5.6%でした。. これらの調査結果の解釈では、パットのみを考慮に入れる必要があります。

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical trials for oral ziprasidone included approximately 5700 patients and/or normal subjects exposed to one or more doses of ziprasidone. Of these 5700, over 4800 were patients who participated in multiple-dose effectiveness trials, and their experience corresponded to approximately 1831 patientyears. These patients include: (1) 4331 patients who participated in multiple-dose trials, predominantly in schizophrenia, representing approximately 1698 patient-years of exposure as of February 5, 2000; and (2) 472 patients who participated in bipolar mania trials representing approximately 133 patient-years of exposure. An additional 127 patients with bipolar disorder participated in a long-term maintenance treatment study representing approximately 74.7 patient-years of exposure to ziprasidone. The conditions and duration of treatment with ziprasidone included open-label and double-blind studies, inpatient and outpatient studies, and short-term and longer-term exposure.

Clinical trials for intramuscular ziprasidone included 570 patients and/or normal subjects who received one or more injections of ziprasidone. Over 325 of these subjects participated in trials involving the administration of multiple doses.

Adverse reactions during exposure were obtained by collecting voluntarily reported adverse experiences, as well as results of physical examinations, vital signs, weights, laboratory analyses, ECGs, and results of ophthalmologic examinations.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Findings Observed In Short-Term, Placebo-Controlled Trials With Oral Ziprasidone

The following findings are based on the short-term placebo-controlled premarketing trials for schizophrenia (a pool of two 6-week, and two 4-week fixed-dose trials) and bipolar mania (a pool of two 3-week flexible-dose trials) in which ziprasidone was administered in doses ranging from 10 to 200 mg/day.

Commonly Observed Adverse Reactions In Short Term-Placebo-Controlled Trials

The following adverse reactions were the most commonly observed adverse reactions associated with the use of ziprasidone (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (ziprasidone incidence at least twice that for placebo):

Schizophrenia Trials (see Table 11)

• Somnolence
• Respiratory Tract Infection

Bipolar Trials (see Table 12)

• Somnolence
• Extrapyramidal Symptoms which includes the following adverse reaction terms: extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching. None of these adverse reactions occurred individually at an incidence greater than 10% in bipolar mania trials.
• Dizziness which includes the adverse reaction terms dizziness and lightheadedness.
• Akathisia
• Abnormal Vision
• Asthenia
• Vomiting

Schizophrenia

Adverse Reactions Associated With Discontinuation Of Treatment In Short-Term, Placebo- Controlled Trials Of Oral Ziprasidone

Approximately 4.1% (29/702) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 2.2% (6/273) on placebo. The most common reaction associated with dropout was rash, including 7 dropouts for rash among ziprasidone patients (1%) compared to no placebo patients.

Adverse Reactions Occurring At An Incidence Of 2% or More Among Ziprasidone-Treated Patients In Short-Term, Oral, Placebo-Controlled Trials

Table 11 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 6 weeks) in predominantly patients with schizophrenia, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.

Table 11: Treatment-Emergent Adverse Reaction Incidence In Short-Term Oral Placebo-Controlled Trials – Schizophrenia

Dose Dependency Of Adverse Reactions In Short-Term, Fixed-Dose, Placebo-Controlled Trials

An analysis for dose response in the schizophrenia 4-study pool revealed an apparent relation of adverse reaction to dose for the following reactions: asthenia, postural hypotension, anorexia, dry mouth, increased salivation, arthralgia, anxiety, dizziness, dystonia, hypertonia, somnolence, tremor, rhinitis, rash, and abnormal vision.

Extrapyramidal Symptoms (EPS) - The incidence of reported EPS (which included the adverse reaction terms extrapyramidal syndrome, hypertonia, dystonia, dyskinesia, hypokinesia, tremor, paralysis and twitching) for ziprasidone-treated patients in the short-term, placebo-controlled schizophrenia trials was 14% vs. 8% for placebo. Objectively collected data from those trials on the Simpson-Angus Rating Scale (for EPS) and the Barnes Akathisia Scale (for akathisia) did not generally show a difference between ziprasidone and placebo.

Dystonia - Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Vital Sign Changes - Ziprasidone is associated with orthostatic hypotension

ECG Changes - Ziprasidone is associated with an increase in the QTc interval. In the schizophrenia trials, ziprasidone was associated with a mean increase in heart rate of 1.4 beats per minute compared to a 0.2 beats per minute decrease among placebo patients.

Other Adverse Reactions Observed During The Premarketing Evaluation Of Oral Ziprasidone

Following is a list of COSTART terms that reflect treatment-emergent adverse reactions as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with ziprasidone in schizophrenia trials at multiple doses > 4 mg/day within the database of 3834 patients. All reported reactions are included except those already listed in Table 11 or elsewhere in labeling, those reaction terms that were so general as to be uninformative, reactions reported only once and that did not have a substantial probability of being acutely life-threatening, reactions that are part of the illness being treated or are otherwise common as background reactions, and reactions considered unlikely to be drugrelated. It is important to emphasize that, although the reactions reported occurred during treatment with ziprasidone, they were not necessarily caused by it.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions:

Frequent - adverse reactions occurring in at least 1/100 patients ( ≥ 1.0% of patients) (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing);

Infrequent - adverse reactions occurring in 1/100 to 1/1000 patients (in 0.1-1.0% of patients)

Rare - adverse reactions occurring in fewer than 1/1000 patients ( < 0.1% of patients).

Body as a Whole

abdominal pain, flu syndrome, fever, accidental fall, face edema,

Frequent chills, photosensitivity reaction, flank pain, hypothermia, motor vehicle accident

Cardiovascular System

Frequent tachycardia, hypertension, postural hypotension

Infrequent bradycardia, angina pectoris, atrial fibrillation first degree AV block, bundle branch block, phlebitis, pulmonary

Rare embolus, cardiomegaly, cerebral infarct, cerebrovascular accident, deep thrombophlebitis, myocarditis, thrombophlebitis

Digestive System

Frequent anorexia, vomiting

Infrequent rectal hemorrhage, dysphagia, tongue edema

Rare gum hemorrhage, jaundice, fecal impaction, gamma glutamyl transpeptidase increased, hematemesis, cholestatic jaundice, hepatitis, hepatomegaly, leukoplakia of mouth, fatty liver deposit, melena

Endocrine

Rare hypothyroidism, hyperthyroidism, thyroiditis

Hemic and Lymphatic System

Infrequent anemia, ecchymosis, leukocytosis, leukopenia, eosinophilia, lymphadenopathy

Rare thrombocytopenia, hypochromic anemia, lymphocytosis, monocytosis, basophilia, lymphedema, polycythemia, thrombocythemia

Metabolic and Nutritional Disorders

Infrequent thirst, transaminase increased, peripheral edema, hyperglycemia, creatine phosphokinase increased, alkaline phosphatase increased, hypercholesteremia, dehydration, lactic dehydrogenase increased, albuminuria, hypokalemia

Rare BUN increased, creatinine increased, hyperlipemia, hypocholesteremia, hyperkalemia, hypochloremia, hypoglycemia, hyponatremia, hypoproteinemia, glucose tolerance decreased, gout, hyperchloremia, hyperuricemia, hypocalcemia, hypoglycemicreaction, hypomagnesemia, ketosis, respiratory alkalosis

Musculoskeletal System

Frequent myalgia

Infrequent tenosynovitis

Rare myopathy

Nervous System

Frequent agitation, extrapyramidal syndrome, tremor, dystonia, hypertonia, dyskinesia, hostility, twitching, paresthesia, confusion, vertigo, hypokinesia, hyperkinesia, abnormal gait, oculogyric crisis, hypesthesia, ataxia, amnesia, cogwheel rigidity, delirium, hypotonia, akinesia, dysarthria, withdrawal syndrome, buccoglossal syndrome, choreoathetosis, diplopia, incoordination, neuropathy

Infrequent paralysis

Rare myoclonus, nystagmus, torticollis, circumoral paresthesia, opisthotonos, reflexes increased, trismus

Respiratory System

Frequent dyspnea

Infrequent pneumonia, epistaxis

Rare hemoptysis, laryngismus

Skin and Appendages

Infrequent maculopapular rash, urticaria, alopecia, eczema, exfoliative dermatitis, contact dermatitis, vesiculobullous rash

Special Senses

Frequent fungal dermatitis

Infrequent conjunctivitis, dry eyes, tinnitus, blepharitis, cataract, photophobia

Rare eye hemorrhage, visual field defect, keratitis, keratoconjunctivitis

Urogenital System

Infrequent impotence, abnormal ejaculation, amenorrhea, hematuria, menorrhagia, female lactation, polyuria, urinary retention metrorrhagia, male sexual dysfunction, anorgasmia, glycosuria

Rare gynecomastia, vaginal hemorrhage, nocturia, oliguria, female sexual dysfunction, uterine hemorrhage

Bipolar Disorder

Acute Treatment of Manic or Mixed Episodes

Adverse Reactions Associated With Discontinuation Of Treatment In Short Term, Placebo-Controlled Trials

Approximately 6.5% (18/279) of ziprasidone-treated patients in short-term, placebo-controlled studies discontinued treatment due to an adverse reaction, compared with about 3.7% (5/136) on placebo. The most common reactions associated with dropout in the ziprasidone-treated patients were akathisia, anxiety, depression, dizziness, dystonia, rash and vomiting, with 2 dropouts for each of these reactions among ziprasidone patients (1%) compared to one placebo patient each for dystonia and rash (1%) and no placebo patients for the remaining adverse reactions.

Adverse Reactions Occurring At An Incidence Of 2% Or More Among Ziprasidone-Treated Patients In Short-Term, Oral, Placebo-Controlled Trials

Table 12 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy (up to 3 weeks) in patients with bipolar mania, including only those reactions that occurred in 2% or more of patients treated with ziprasidone and for which the incidence in patients treated with ziprasidone was greater than the incidence in placebo-treated patients.

Table 12: Treatment-Emergent Adverse Reactions Incidence In Short-Term Oral Placebo-Controlled Trials - Manic and Mixed Episodes Associated with Bipolar Disorder

Explorations for interactions on the basis of gender did not reveal any clinically meaningful differences in the adverse reaction occurrence on the basis of this demographic factor.

Intramuscular Ziprasidone

Adverse Reactions Occurring At An Incidence Of 1% Or More Among Ziprasidone-Treated Patients In Short-Term Trials Of Intramuscular Ziprasidone

Table 13 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse reactions that occurred during acute therapy with intramuscular ziprasidone in 1% or more of patients.

In these studies, the most commonly observed adverse reactions associated with the use of intramuscular ziprasidone (incidence of 5% or greater) and observed at a rate on intramuscular ziprasidone (in the higher dose groups) at least twice that of the lowest intramuscular ziprasidone group were headache (13%), nausea (12%), and somnolence (20%).

Table 13: Treatment-Emergent Adverse Reaction Incidence In Short-Term Fixed-Dose Intramuscular Trials

Postmarketing Experience

The following adverse reactions have been identified during post approval use of Zixadox. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reaction reports not listed above that have been received since market introduction include rare occurrences of the following : Cardiac Disorders: Tachycardia, torsade de pointes (in the presence of multiple confounding factors), ; Digestive System Disorders: Swollen Tongue; Reproductive System and Breast Disorders: Galactorrhea, priapism; Nervous System Disorders: Facial Droop, neuroleptic malignant syndrome, serotonin syndrome (alone or in combination with serotonergic medicinal products), tardive dyskinesia; Psychiatric Disorders: Insomnia, mania/hypomania; Skin and subcutaneous Tissue Disorders: Allergic reaction (such as allergic dermatitis, angioedema, orofacial edema, urticaria), rash, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS); Urogenital System Disorders: Enuresis, urinary incontinence; Vascular Disorders: Postural hypotension, syncope.

人間の経験。

5400人以上の患者および/または正常な被験者を対象とした市販前試験では、経口ジプラシドンの偶発的または意図的な過剰摂取が10人の患者で記録されました。. これらの患者はすべて後遺症なしで生き残った。. 確認された最大の量である3,240 mgを服用している患者では、報告された症状は、鎮静の最小化、発話のぼやけ、および一時的な高血圧(200/95)だけでした。. ジプラシドンの過剰摂取で報告された副作用には、 ⁇ 体外路症状、傾眠、振戦、不安が含まれていました。.

過剰摂取の管理。

急性の過剰摂取の場合は、気道を確立して維持し、適切な酸素化と換気を確保します。. 静脈内アクセスを確立し、胃洗浄(挿管後、患者が意識不明の場合)と活性炭の投与を下剤と一緒に考慮する必要があります。. 過剰摂取後の頭 ⁇ 部の鈍化、発作、またはジストニック反応の可能性は、誘発された ⁇ 吐を伴う誤 ⁇ のリスクを引き起こす可能性があります。.

心血管モニタリングは直ちに開始する必要があり、不整脈の可能性を検出するための継続的な心電図モニタリングを含める必要があります。. 抗不整脈療法が投与される場合、ジソピラミド、プロカインアミド、およびキニジンは、ジプラシドンのそれらに追加されるかもしれない添加剤QTプロロンギング効果の理論的危険を伴います。.

低血圧と循環虚脱は、静脈内輸液などの適切な手段で治療する必要があります。. 交感神経刺激剤が血管サポートに使用される場合、ジプラシドンに関連するα ⁇ 抗作用と組み合わせたベータ刺激が低血圧を悪化させる可能性があるため、エピネフリンとドーパミンは使用しないでください。. 同様に、ブレチリウムのアルファアドレナリン遮断特性がジプラシドンの特性に相加的であり、問題のある低血圧をもたらす可能性があると期待することは合理的です。.

重度の ⁇ 体外路症状の場合は、抗コリン薬を投与する必要があります。. ジプラシドンに対する特定の解毒剤はなく、透析可能ではありません。. 複数の薬物関与の可能性を検討する必要があります。. 患者が回復するまで、綿密な医学的監督とモニタリングを継続する必要があります。.

ジプラシドンは高い展示をしました。 in vitro。 ドーパミンD2およびD3、セロトニン5HT2A、5HT2C、5HT1A、5HT1D、およびα1アドレナリン受容体の結合親和性(Ki s of 4.8、7.2、0.4、1.3、3.4、2、および10 nM)それぞれ)、および中程度の親和性. ジプラシドンは、D2、5HT2D、および5HT1D受容体で ⁇ 抗薬として、および5HT1A受容体でアゴニストとして機能しました。. ジプラシドンはセロトニンとノルエピネフリンのシナプス再取り込みを阻害しました。. コリン作動性ムスカリン受容体(IC> 1μM)を含む、テストされた他の受容体/結合部位には、有意な親和性は示されませんでした。. ドーパミンおよび5HT2以外の受容体での同様の受容体親和性による ⁇ 抗作用は、ジプラシドンの他の治療効果および副作用の一部を説明する可能性があります。. ジプラシドンのヒスタミンH1受容体の ⁇ 抗作用は、この薬で観察された傾眠を説明している可能性があります。. ジプラシドンのα-アドレナリン受容体の ⁇ 抗作用は、この薬で観察された起立性低血圧を説明している可能性があります。.

経口薬物動態。

ジプラシドンの活動は主に親薬物によるものです。. ジプラシドンの複数回投与の薬物動態は、提案された臨床投与範囲内で用量に比例し、ジプラシドンの蓄積は複数回投与で予測可能です。. ジプラシドンの除去は主に肝代謝を介して行われ、提案された臨床用量範囲内の平均終末半減期は約7時間です。. 定常状態の濃度は、投与後1〜3日以内に達成されます。. 見かけの全身クリアランスの平均は7.5 mL / min / kgです。. ジプラシドンは、チトクロームP450酵素によって代謝される薬物の代謝を妨げる可能性は低いです。.

吸収。

ジプラシドンは経口投与後によく吸収され、6〜8時間でピーク血漿濃度に達します。. 摂食条件下での20 mg用量の絶対バイオアベイラビリティは約60%です。. ジプラシドンの吸収は、食物の存在下で最大2倍に増加します。.

分布。

ジプラシドンの平均見かけの分布量は1.5 L / kgです。. それは血漿タンパク質に結合している99%を超え、主にアルブミンとα-酸糖タンパク質に結合しています。. 。 in vitro。 ジプラシドンの血漿タンパク質結合は、2つの高タンパク質結合薬物であるワルファリンまたはプロプラノロールによって変化せず、ジプラシドンはこれらの薬物のヒト血漿への結合を変化させませんでした。. したがって、変位によるジプラシドンとの薬物相互作用の可能性は最小限です。.

代謝と排除。

ジプラシドンは経口投与後に広範囲に代謝され、少量の尿(<1%)または ⁇ 便(<4%)が未変化の薬物として排 ⁇ されます。. ジプラシドンは主に3つの代謝経路を介して除去され、4つの主要な循環代謝物、ベンジソチアゾール(BITP)スルホキシド、BITP-スルホン、ジプラシドンスルホキシド、およびS-メチルジヒドロジプラシドンを生成します。. 用量の約20%が尿中に排 ⁇ され、約66%が ⁇ 便から排出されます。. 変化のないジプラシドンは、血清中の薬物関連物質全体の約44%を占めます。. ヒト肝細胞内画分を使用したin vitro試験では、S-メチルジヒドロジプラシドンが2つのステップで生成されることが示されています。. これらの研究は、還元反応が主にグルタチオンによる化学的還元とアルデヒドオキシダーゼによる酵素的還元によって媒介され、その後のメチル化がチオールメチルトランスフェラーゼによって媒介されることを示しています。. In vitro。 ヒト肝ミクロソームと組換え酵素を使用した研究では、CYP3A4がジプラシドンの酸化代謝に寄与する主要なCYPであることを示しています。. CYP1A2は、はるかに少ない程度で貢献する可能性があります。. に基づく。 in vivo。 豊富な排 ⁇ 代謝物、ジプラシドン代謝クリアランスの3分の1未満は、チトクロームP450触媒酸化によって媒介され、還元によって約3分の2が媒介されます。. 臨床的に関連する既知の阻害剤またはアルデヒドオキシダーゼの誘導剤はありません。.

筋肉内薬物動態。

全身バイオアベイラビリティ。: 筋肉内に投与されるジプラシドンのバイオアベイラビリティは100%です。. 単回投与の筋肉内投与後、ピーク血清濃度は通常、投与後約60分またはそれ以前に発生し、平均半減期(T½)は2〜5時間の範囲です。. 曝露は用量に関連して増加し、筋肉内投与の3日後にほとんど蓄積が観察されません。.

代謝と排除。: IMジプラシドンの代謝と排 ⁇ は体系的に評価されていませんが、筋肉内投与経路が代謝経路を変えるとは予想されていません。.