Ihope

Tedaviye Dayanıklı Şizofreni

FAZACLO, standart antipsikotik tedaviye yeterince yanıt vermeyen şizofreni hastalarının tedavisi için endikedir. Şiddetli nötropeni ve kullanımıyla ilişkili nöbet riskleri nedeniyle, FAZACLO sadece standart antipsikotik tedaviye yeterince cevap vermeyen hastalarda kullanılmalıdır.

Klozapinin tedaviye dirençli şizofrenideki etkinliği, diğer antipsikotikleri başarısız olan hastalarda klozapin ve klorpromazini karşılaştıran 6 haftalık, randomize, çift kör, aktif kontrollü bir çalışmada gösterilmiştir.

Şizofreni veya Şizoaffektif Bozuklukta Tekrarlayan İntihar Davranışı Riskinde Azaltma

FAZACLO'nun, tarihe ve yakın klinik duruma bağlı olarak intihar davranışını yeniden deneyimlemek için kronik risk altında olduğu düşünülen şizofreni veya şizoaffektif bozukluğu olan hastalarda tekrarlayan intihar davranışı riskini azalttığı belirtilmektedir. İntihar davranışı, hastanın kendisini ölüm riskine sokan eylemleri ifade eder.

Klozapinin tekrarlayan intihar davranışı riskini azaltmada etkinliği, InterSePT ™ çalışmasında iki yıllık bir tedavi süresi boyunca gösterilmiştir.

Tedaviye Dayanıklı Şizofreni

Ihope, standart antipsikotik tedaviye yeterince yanıt vermeyen şizofreni hastalarının tedavisi için endikedir. Şiddetli nötropeni ve kullanımıyla ilişkili nöbet riskleri nedeniyle, Ihope sadece standart antipsikotik tedaviye yeterince cevap vermeyen hastalarda kullanılmalıdır.

Klozapinin tedaviye dirençli şizofrenideki etkinliği, diğer antipsikotikleri başarısız olan hastalarda klozapin ve klorpromazini karşılaştıran 6 haftalık, randomize, çift kör, aktif kontrollü bir çalışmada gösterilmiştir.

Şizofreni veya Şizoaffektif Bozuklukta Tekrarlayan İntihar Davranışı Riskinde Azaltma

Ihope, tarihe ve yakın klinik duruma bağlı olarak intihar davranışını yeniden deneyimlemek için kronik risk altında olduğu düşünülen şizofreni veya şizoaffektif bozukluğu olan hastalarda tekrarlayan intihar davranışı riskini azalttığı belirtilmektedir. İntihar davranışı, hastanın kendisini ölüm riskine sokan eylemleri ifade eder.

Klozapinin tekrarlayan intihar davranışı riskini azaltmada etkinliği, InterSePT ™ çalışmasında iki yıllık bir tedavi süresi boyunca gösterilmiştir.

Başlamadan Önce ve Terapi Sırasında Gerekli Laboratuvar Testi

FAZACLO ile tedaviye başlamadan önce bir temel ANC elde edilmelidir. Başlangıç ANC'si genel popülasyon için en az 1500 / μL ve belgelenmiş Benign Etnik Nötropeni (BEN) olan hastalar için en az 1000 / μL olmalıdır. Tedaviye devam etmek için ANC düzenli olarak izlenmelidir.

Önemli Yönetim Talimatları

FAZACLO oral olarak parçalayan tabletler, tableti blister ambalajdan veya şişeden çıkardıktan hemen sonra ağzına yerleştirilmelidir. Tablet ağız içine yerleştirildikten sonra hızla parçalanır. Tabletlerin parçalanmasına izin verilebilir veya çiğnenebilir. Tükürük ile yutulabilirler. Uygulama için su gerekmez.

Bir blister ambalajdaki oral olarak parçalanan tabletler, kullanım zamanına kadar açılmamış blisterde bırakılmalıdır. Kullanmadan hemen önce, folyoyu blisterden soyun ve oral olarak parçalanan tableti yavaşça çıkarın. Tabletleri folyodan itmeyin, çünkü bu tablete zarar verebilir.

Dozlama Bilgileri

Başlangıç dozu günde bir kez veya günde iki kez 12.5 mg'dır. Toplam günlük doz, iyi tolere edilirse, 2 hafta sonuna kadar günde 300 mg ila 450 mg (bölünmüş dozlarda uygulanır) hedef dozuna ulaşmak için günde 25 mg ila 50 mg'lık artışlarla arttırılabilir. Daha sonra, doz haftada bir veya haftada iki kez 100 mg'a kadar artışlarla arttırılabilir. Maksimum doz günde 900 mg'dır. Ortostatik hipotansiyon, bradikardi ve senkop riskini en aza indirmek için, bu düşük başlangıç dozunu, kademeli titrasyon programını ve bölünmüş dozajları kullanmak gerekir.

FAZACLO yiyecekle birlikte veya yiyeceksiz alınabilir.

Bakım Tedavisi

Genel olarak, FAZACLO'ya yanıt veren hastalar, akut atak ötesinde etkili dozlarında idame tedavisine devam etmelidir.

Tedavinin Sonlandırılması

Tedaviyi bırakma yöntemi hastanın son ANC'sine bağlı olarak değişecektir:

• Orta ila şiddetli nötropeni nedeniyle ani tedavinin kesilmesi gerekiyorsa, nötropeni seviyesine göre uygun ANC izleme için Tablo 2 veya 3'e bakınız.
• FAZACLO tedavisinin sonlandırılması planlanıyorsa ve orta ila şiddetli nötropeni kanıtı yoksa, dozu 1 ila 2 haftalık bir süre içinde kademeli olarak azaltın.
• Nötropeni ile ilgisi olmayan bir nedenden dolayı ani klozapinin kesilmesi için, ANC'leri ≥ 1500 / μL olana kadar genel popülasyon hastaları ve ANC'leri ≥ 1000 / μL olana kadar veya taban çizgilerinin üzerinde olana kadar BEN hastaları için mevcut ANC izlemesinin sürdürülmesi önerilir.
• Kesildikten sonraki 2 hafta boyunca ateş başlangıcını (38.5 ° C veya 101.3 ° F veya daha yüksek sıcaklık) bildiren herhangi bir hasta için ek ANC izleme gereklidir.
• Bol terleme, baş ağrısı, bulantı, kusma ve ishal gibi kolinerjik ribaund ile ilgili psikotik semptom ve semptomların tekrarlaması için tüm hastaları dikkatle izleyin.

Tedavinin Yeniden Başlatılması

FAZACLO'yu bırakan hastalarda FAZACLO'yu yeniden başlatırken (ör., son dozdan bu yana 2 gün veya daha fazla), günde bir kez veya günde iki kez 12.5 mg ile yeniden başlatın. Bu hipotansiyon, bradikardi ve senkop riskini en aza indirmek için gereklidir. Bu doz iyi tolere edilirse, doz, ilk tedavi için önerilenden daha hızlı bir şekilde daha önce terapötik doza yükseltilebilir.

CYP1A2, CYP2D6, CYP3A4 İnhibitörlerinin veya CYP1A2, CYP3A4 İndükleyicilerinin Birlikte Kullanımına İlişkin Dozaj Ayarlamaları

Eşzamanlı kullanımı olan hastalarda doz ayarlamaları gerekebilir: güçlü CYP1A2 inhibitörleri (ör., fluvoksamin, siprofloksasin veya enoksasin); orta veya zayıf CYP1A2 inhibitörleri (ör.oral kontraseptifler veya kafein); CYP2D6 veya CYP3A4 inhibitörleri (ör.simetidin, esitalopram, eritromisin, paroksetin, bupropion, fluoksetin, kinidin, duloksetin, terbinafin veya sertralin); CYP3A4 indükleyicileri (ör., fenitoin, karbamazepin, St. John's wort ve rifampin); veya CYP1A2 indükleyicileri (ör., tütün içimi) (Tablo 1).

Tablo 1: Eşzamanlı İlaç Alan Hastalarda Doz Ayarı

Böbrek veya Karaciğer Bozukluğu veya CYP2D6 Kötü Metabolizatörler

Önemli böbrek veya karaciğer yetmezliği olan hastalarda veya CYP2D6 zayıf metabolizörlerinde FAZACLO dozunun azaltılması gerekebilir.

Başlamadan Önce ve Terapi Sırasında Gerekli Laboratuvar Testi

Ihope ile tedaviye başlamadan önce bir temel ANC elde edilmelidir. Başlangıç ANC'si genel popülasyon için en az 1500 / μL ve belgelenmiş Benign Etnik Nötropeni (BEN) olan hastalar için en az 1000 / μL olmalıdır. Tedaviye devam etmek için ANC düzenli olarak izlenmelidir.

Önemli Yönetim Talimatları

İhope oral olarak parçalanan tabletler, tableti blister ambalajdan veya şişeden çıkardıktan hemen sonra ağzına yerleştirilmelidir. Tablet ağız içine yerleştirildikten sonra hızla parçalanır. Tabletlerin parçalanmasına izin verilebilir veya çiğnenebilir. Tükürük ile yutulabilirler. Uygulama için su gerekmez.

Bir blister ambalajdaki oral olarak parçalanan tabletler, kullanım zamanına kadar açılmamış blisterde bırakılmalıdır. Kullanmadan hemen önce, folyoyu blisterden soyun ve oral olarak parçalanan tableti yavaşça çıkarın. Tabletleri folyodan itmeyin, çünkü bu tablete zarar verebilir.

Dozlama Bilgileri

Başlangıç dozu günde bir kez veya günde iki kez 12.5 mg'dır. Toplam günlük doz, iyi tolere edilirse, 2 hafta sonuna kadar günde 300 mg ila 450 mg (bölünmüş dozlarda uygulanır) hedef dozuna ulaşmak için günde 25 mg ila 50 mg'lık artışlarla arttırılabilir. Daha sonra, doz haftada bir veya haftada iki kez 100 mg'a kadar artışlarla arttırılabilir. Maksimum doz günde 900 mg'dır. Ortostatik hipotansiyon, bradikardi ve senkop riskini en aza indirmek için, bu düşük başlangıç dozunu, kademeli titrasyon programını ve bölünmüş dozajları kullanmak gerekir.

Ihope yiyecekle birlikte veya yemeksiz alınabilir.

Bakım Tedavisi

Genel olarak, Ihope'a yanıt veren hastalar, akut atakların ötesinde etkili dozlarında idame tedavisine devam etmelidir.

Tedavinin Sonlandırılması

Tedaviyi bırakma yöntemi hastanın son ANC'sine bağlı olarak değişecektir:

• Orta ila şiddetli nötropeni nedeniyle ani tedavinin kesilmesi gerekiyorsa, nötropeni seviyesine göre uygun ANC izleme için Tablo 2 veya 3'e bakınız.
• Ihope tedavisinin sonlandırılması planlanıyorsa ve orta ila şiddetli nötropeni kanıtı yoksa, dozu 1 ila 2 haftalık bir süre içinde kademeli olarak azaltın.
• Nötropeni ile ilgisi olmayan bir nedenden dolayı ani klozapinin kesilmesi için, ANC'leri ≥ 1500 / μL olana kadar genel popülasyon hastaları ve ANC'leri ≥ 1000 / μL olana kadar veya taban çizgilerinin üzerinde olana kadar BEN hastaları için mevcut ANC izlemesinin sürdürülmesi önerilir.
• Kesildikten sonraki 2 hafta boyunca ateş başlangıcını (38.5 ° C veya 101.3 ° F veya daha yüksek sıcaklık) bildiren herhangi bir hasta için ek ANC izleme gereklidir.
• Bol terleme, baş ağrısı, bulantı, kusma ve ishal gibi kolinerjik ribaund ile ilgili psikotik semptom ve semptomların tekrarlaması için tüm hastaları dikkatle izleyin.

Tedavinin Yeniden Başlatılması

İhope'yi bırakan hastalarda Ihope'u yeniden başlatırken (ör., son dozdan bu yana 2 gün veya daha fazla), günde bir kez veya günde iki kez 12.5 mg ile yeniden başlatın. Bu hipotansiyon, bradikardi ve senkop riskini en aza indirmek için gereklidir. Bu doz iyi tolere edilirse, doz, ilk tedavi için önerilenden daha hızlı bir şekilde daha önce terapötik doza yükseltilebilir.

CYP1A2, CYP2D6, CYP3A4 İnhibitörlerinin veya CYP1A2, CYP3A4 İndükleyicilerinin Birlikte Kullanımına İlişkin Dozaj Ayarlamaları

Eşzamanlı kullanımı olan hastalarda doz ayarlamaları gerekebilir: güçlü CYP1A2 inhibitörleri (ör., fluvoksamin, siprofloksasin veya enoksasin); orta veya zayıf CYP1A2 inhibitörleri (ör.oral kontraseptifler veya kafein); CYP2D6 veya CYP3A4 inhibitörleri (ör.simetidin, esitalopram, eritromisin, paroksetin, bupropion, fluoksetin, kinidin, duloksetin, terbinafin veya sertralin); CYP3A4 indükleyicileri (ör., fenitoin, karbamazepin, St. John's wort ve rifampin); veya CYP1A2 indükleyicileri (ör., tütün içimi) (Tablo 1).

Tablo 1: Eşzamanlı İlaç Alan Hastalarda Doz Ayarı

Böbrek veya Karaciğer Bozukluğu veya CYP2D6 Kötü Metabolizatörler

Önemli böbrek veya karaciğer yetmezliği olan hastalarda veya CYP2D6 zayıf metabolizörlerinde Ihope dozunu azaltmak gerekebilir.

Aşırı duyarlılık

FAZACLO, klozapine karşı ciddi aşırı duyarlılık öyküsü olan hastalarda kontrendikedir (ör.ışığa duyarlılık, vaskülit, eritema multiforme veya Stevens-Johnson Sendromu) veya FAZACLO'nun başka herhangi bir bileşeni .

Aşırı duyarlılık

Klozapine karşı ciddi aşırı duyarlılık öyküsü olan hastalarda (örn.ışığa duyarlılık, vaskülit, eritema multiforme veya Stevens-Johnson Sendromu) veya Ihope'un herhangi bir bileşeni.

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

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

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

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

Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia

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

Table 8 summarizes pooled data from 11 studies in

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Severe Neutropenia

Background

Ihope 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 Ihope 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 Ihope 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.

Ihope Treatment and Monitoring in the General Patient Population (see Table 2)

Obtain a CBC, including the ANC value, prior to initiating treatment with Ihope 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: Ihope Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring for the General Patient Population

Ihope 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 Ihope-induced neutropenia. Additional evaluation may be needed to determine if baseline neutropenia is due to BEN. Consider hematology consultation before initiating or during Ihope treatment as necessary.

Patients with BEN require a different ANC algorithm for Ihope management due to their lower baseline ANC levels. Table 3 provides guidelines for managing Ihope treatment and ANC monitoring in patients with BEN.

Table 3: Patients with Benign Ethnic Neutropenia (BEN); Ihope Treatment Recommendations Based on Absolute Neutrophil Count (ANC) Monitoring

General Guidelines for Management of All Patients with Fever or with Neutropenia

• Fever: Interrupt Ihope 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 Ihope-related neutropenia, the risk of serious psychiatric illness from discontinuing Ihope treatment may be greater than the risk of rechallenge (e.g., patients with severe schizophrenic illness who have no treatment options other than Ihope). A hematology consultation may be useful in deciding to rechallenge a patient. In general, however, do not rechallenge patients who develop severe neutropenia with Ihope 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 Ihope rechallenge, and the severity and characteristics of the neutropenic episode.

Using Ihope 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 Ihope-induced neutropenia. There is no strong scientific rationale to avoid Ihope treatment in patients concurrently treated with these drugs. If Ihope 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

Ihope 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 Ihope must be certified with the program by enrolling and completing training.
• Patients who receive Ihope must be enrolled in the program and comply with the ANC testing and monitoring requirements.
• Pharmacies dispensing Ihope must be certified with the program by enrolling and completing training and must only dispense to patients who are eligible to receive Ihope.

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 Ihope (i.e., 2 days or more since the last dose), re-initiate treatment at 12.5 mg once daily or twice daily.

Use Ihope 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 Ihope 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 Ihope 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 Ihope 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 Ihope. However, if the benefit of Ihope treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with Ihope in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring.

Consider the possibility of myocarditis or cardiomyopathy in patients receiving Ihope 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 Ihope. 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 Ihope 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 Ihope 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 Ihope.

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 Ihope under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt Ihope 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 Ihope, 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 Ihope, and electrolyte abnormalities.

Prior to initiating treatment with Ihope, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities. Discontinue Ihope 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 Ihope.

Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of Ihope. 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). Ihope is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. Concomitant treatment with inhibitors of these enzymes can increase the concentration of Ihope.

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 Ihope.

Metabolic Changes

Atypical antipsychotic drugs, including Ihope, 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 Ihope. 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 Ihope 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

Dyslipidemia

Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including Ihope. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using Ihope, 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

Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia

Weight Gain

Weight gain has occurred with the use of antipsychotics, including Ihope. Monitor weight during treatment with Ihope. 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

Table 8 summarizes pooled data from 11 studies in

Doz aşımı Deneyimi

Klozapin doz aşımı ile ilişkili en sık bildirilen belirti ve semptomlar şunlardır: sedasyon, deliryum, koma, taşikardi, hipotansiyon, solunum depresyonu veya başarısızlık; ve hipersalivasyon. Aspirasyon pnömonisi, kardiyak aritmiler ve nöbet raporları vardır. Klozapin ile, genellikle 2500 mg'ın üzerindeki dozlarda ölümcül doz aşımı bildirilmiştir. Ayrıca aşırı dozdan 4 g'ı aşan iyileşen hastaların raporları da vardır.

Doz aşımı yönetimi

FAZACLO doz aşımının yönetimi hakkında en güncel bilgiler için sertifikalı bir Bölgesel Zehir Kontrol Merkezi (1-800-222-1222) ile iletişime geçin. Sertifikalı Bölgesel Zehir Kontrol Merkezlerinin telefon numaraları, PDR Network'ün tescilli ticari markası olan Doktorlar Masası Referans®'da listelenmiştir. Bir hava yolu kurmak ve sürdürmek; yeterli oksijenasyon ve havalandırma sağlamak. Kardiyak durumu ve hayati belirtileri izleyin. Genel semptomatik ve destekleyici önlemler kullanın. FAZACLO için spesifik bir antidot yoktur

Doz aşımı tedavisinde çoklu ilaç katılımı olasılığını göz önünde bulundurun.

Doz aşımı Deneyimi

Klozapin doz aşımı ile ilişkili en sık bildirilen belirti ve semptomlar şunlardır: sedasyon, deliryum, koma, taşikardi, hipotansiyon, solunum depresyonu veya başarısızlık; ve hipersalivasyon. Aspirasyon pnömonisi, kardiyak aritmiler ve nöbet raporları vardır. Klozapin ile, genellikle 2500 mg'ın üzerindeki dozlarda ölümcül doz aşımı bildirilmiştir. Ayrıca aşırı dozdan 4 g'ı aşan iyileşen hastaların raporları da vardır.

Doz aşımı yönetimi

Ihope doz aşımının yönetimi hakkında en güncel bilgiler için sertifikalı bir Bölgesel Zehir Kontrol Merkezi (1-800-222-1222) ile iletişime geçin. Sertifikalı Bölgesel Zehir Kontrol Merkezlerinin telefon numaraları, PDR Network'ün tescilli ticari markası olan Doktorlar Masası Referans®'da listelenmiştir. Bir hava yolu kurmak ve sürdürmek; yeterli oksijenasyon ve havalandırma sağlamak. Kardiyak durumu ve hayati belirtileri izleyin. Genel semptomatik ve destekleyici önlemler kullanın. Ihope için belirli bir antidot yoktur.

Doz aşımı tedavisinde çoklu ilaç katılımı olasılığını göz önünde bulundurun.

Emilim

İnsanda, klozapin tabletleri (25 mg ve 100 mg) bir klozapin çözeltisine göre eşit derecede biyoyararlanabilir. FAZACLO® (klozapin) oral olarak parçalanan tabletler, Novartis Pharmaceuticals Corporation'ın tescilli ticari markası olan Clozaril® (klozapin) tabletlerine biyoeşdeğerdir. 100 mg b.i.d.'lik bir dozajın ardından., ortalama kararlı durum pik plazma konsantrasyonu, dozlamadan sonra ortalama 2.3 saatte (aralık: 1-6 saat) meydana gelen 413 ng / mL (aralık: 132-854 ng / mL) idi. Kararlı durumdaki ortalama minimum konsantrasyon, 100 mg b.i.d.'den sonra 168 ng / mL (aralık: 45-574 ng / mL) idi. dozlama.

Açlık koşulları altında FAZACLO 200 mg tabletleri 2 Ã - FAZACLO 100 mg tabletleri (onaylanmış referans ürün) ile karşılaştıran 32 hastada (şizofreni veya şizoaffektif bozukluk ile) karşılaştırmalı bir biyoeşdeğerlik / biyoyararlanım çalışması yapılmıştır. Çalışma ayrıca gıda ve çiğnemenin 200 mg tabletin farmakokinetiği üzerindeki etkisini de değerlendirdi. Açlık koşulları altında, 200 mg tabletler için ortalama AUCss ve Cmin, ss klozapin, 2 x 100 mg tabletlerinkine eşdeğerdi. FAZACLO 200 mg tabletler için ortalama Cmax, ss klozapin, 2 x 100 mg FAZACLO tabletleri için% 85 idi. FAZACLO 200 mg tabletler için Cmax, ss'deki bu azalma klinik olarak anlamlı değildir.

FAZACLO 200 mg tabletler için gıda, klozapinin Cmin, ss'sini% 21 oranında önemli ölçüde arttırdı. Bununla birlikte, bu artış klinik olarak anlamlı değildir. Beslenen koşullar altında ortalama AUCss ve Cmax, ss klozapin, açlık koşulları altındakilere eşdeğerdi. Gıda, klozapin emilimini, açlık koşulları altında 2.5 saatlik medyan Tmax'tan beslenen koşullar altında 4 saate kadar 1.5 saat geciktirdi.

FAZACLO 200 mg tabletler için çiğnenmiş koşullar altında ortalama Cmax, ss klozapin, çiğnenmemiş koşullar altında 2 x 100 mg FAZACLO tabletleri için yaklaşık% 86 iken, AUCss ve Cmin, ss değerleri çiğnenmiş ve çiğnenmiş koşullar.

Gıda etkisi çalışmasında, açlık koşulları altında ve yüksek yağlı bir yemekten sonra sağlıklı gönüllülere tek bir doz FAZACLO (klozapin) oral olarak parçalanan tablet 12.5 mg uygulandı. FAZACLO yüksek yağlı bir yemekten sonra uygulandığında, hem klozapinin hem de aktif metaboliti desmetilklozapinin Cmax'ı, açlık koşulları altında uygulamaya kıyasla yaklaşık% 20 oranında azalırken, AUC değerleri değişmemiştir. Cmax'taki bu azalma klinik olarak anlamlı değildir. Bu nedenle, FAZACLO (klozapin) oral olarak parçalanan tabletler yemeklere bakılmaksızın alınabilir.

Dağıtım

Klozapin serum proteinlerine yaklaşık% 97 oranında bağlanır. Klozapin ve diğer yüksek oranda proteine bağlı ilaçlar arasındaki etkileşim tam olarak değerlendirilmemiştir, ancak önemli olabilir.

Metabolizma ve Boşaltım

Klozapin, atılımdan önce neredeyse tamamen metabolize edilir ve idrar ve dışkıda sadece eser miktarda değişmemiş ilaç tespit edilir. Klozapin, birçok sitokrom P450 izozimi, özellikle CYP1A2, CYP2D6 ve CYP3A4 için bir substrattır. Uygulanan dozun yaklaşık% 50'si idrarla ve% 30'u dışkıyla atılır. Demetillenmiş, hidroksillenmiş ve N-oksit türevleri hem idrar hem de dışkıdaki bileşenlerdir. Farmakolojik testler, desmetil metabolitinin (norklozapin) sadece sınırlı aktiviteye sahip olduğunu gösterirken, hidroksillenmiş ve N-oksit türevleri aktif değildir. Tek bir 75 mg dozdan sonra klozapinin ortalama eliminasyon yarılanma ömrü, kararlı hale geldikten sonra 12 saatlik ortalama eliminasyon yarılanma ömrüne (aralık: 4-66 saat) kıyasla 8 saat (aralık: 4-12 saat) idi. günde iki kez 100 mg doz ile durum.

Tek doz ve çok dozlu klozapin uygulamasının karşılaştırılması, eliminasyon yarılanma ömrünün, tek doz uygulamasından sonra olana göre çoklu dozlamadan sonra önemli ölçüde arttığını gösterdi ve bu da konsantrasyona bağlı farmakokinetik olasılığını düşündürdü. Bununla birlikte, kararlı durumda, günde iki kez 37.5, 75 ve 150 mg uygulandıktan sonra AUC (eğrinin altındaki alan), pik ve minimum klozapin plazma konsantrasyonlarına göre yaklaşık doz orantılı değişiklikler gözlenmiştir.

Emilim

İnsanda, klozapin tabletleri (25 mg ve 100 mg) bir klozapin çözeltisine göre eşit derecede biyoyararlanabilir. Ihope® (klozapin) oral olarak parçalanan tabletler, Novartis Pharmaceuticals Corporation'ın tescilli ticari markası olan Clozaril® (klozapin) tabletlerine biyoeşdeğerdir. 100 mg b.i.d.'lik bir dozajın ardından., ortalama kararlı durum pik plazma konsantrasyonu, dozlamadan sonra ortalama 2.3 saatte (aralık: 1-6 saat) meydana gelen 413 ng / mL (aralık: 132-854 ng / mL) idi. Kararlı durumdaki ortalama minimum konsantrasyon, 100 mg b.i.d.'den sonra 168 ng / mL (aralık: 45-574 ng / mL) idi. dozlama.

Açlık koşulları altında Ihope 200 mg tabletleri 2 Ã-Ihope 100 mg tabletleri (onaylanmış referans ürün) ile karşılaştıran 32 hastada (şizofreni veya şizoaffektif bozukluk ile) karşılaştırmalı bir biyoeşdeğerlik / biyoyararlanım çalışması yapılmıştır. Çalışma ayrıca gıda ve çiğnemenin 200 mg tabletin farmakokinetiği üzerindeki etkisini de değerlendirdi. Açlık koşulları altında, 200 mg tabletler için ortalama AUCss ve Cmin, ss klozapin, 2 x 100 mg tabletlerinkine eşdeğerdi. Ihope 200 mg tabletler için ortalama Cmax, ss klozapin, 2 x 100 mg Ihope tabletleri için% 85 idi. Ihope 200 mg tabletler için Cmax, ss'deki bu azalma klinik olarak anlamlı değildir.

Ihope 200 mg tabletler için, gıda klozapinin Cmin, ss'sini% 21 oranında önemli ölçüde arttırdı. Bununla birlikte, bu artış klinik olarak anlamlı değildir. Beslenen koşullar altında ortalama AUCss ve Cmax, ss klozapin, açlık koşulları altındakilere eşdeğerdi. Gıda, klozapin emilimini, açlık koşulları altında 2.5 saatlik medyan Tmax'tan beslenen koşullar altında 4 saate kadar 1.5 saat geciktirdi.

Ihope 200 mg tabletler için çiğnenmiş koşullar altında ortalama Cmax, ss klozapin, çiğnenmemiş koşullar altında 2 x 100 mg Ihope tabletleri için yaklaşık% 86 iken, AUCss ve Cmin, ss değerleri çiğnenmiş ve çiğnenmiş koşullar.

Gıda etkisi çalışmasında, açlık koşulları altında ve yüksek yağlı bir yemekten sonra sağlıklı gönüllülere 12.5 mg'lık tek bir doz Ihope (klozapin) oral olarak parçalanan tabletler uygulandı. Ihope yüksek yağlı bir yemekten sonra uygulandığında, hem klozapinin hem de aktif metaboliti desmetilklozapinin Cmax'ı, açlık koşulları altında uygulamaya kıyasla yaklaşık% 20 azalırken, AUC değerleri değişmedi. Cmax'taki bu azalma klinik olarak anlamlı değildir. Bu nedenle, Ihope (klozapin) oral olarak parçalayan tabletler yemeklere bakılmaksızın alınabilir.

Dağıtım

Klozapin serum proteinlerine yaklaşık% 97 oranında bağlanır. Klozapin ve diğer yüksek oranda proteine bağlı ilaçlar arasındaki etkileşim tam olarak değerlendirilmemiştir, ancak önemli olabilir.

Metabolizma ve Boşaltım

Klozapin, atılımdan önce neredeyse tamamen metabolize edilir ve idrar ve dışkıda sadece eser miktarda değişmemiş ilaç tespit edilir. Klozapin, birçok sitokrom P450 izozimi, özellikle CYP1A2, CYP2D6 ve CYP3A4 için bir substrattır. Uygulanan dozun yaklaşık% 50'si idrarla ve% 30'u dışkıyla atılır. Demetillenmiş, hidroksillenmiş ve N-oksit türevleri hem idrar hem de dışkıdaki bileşenlerdir. Farmakolojik testler, desmetil metabolitinin (norklozapin) sadece sınırlı aktiviteye sahip olduğunu gösterirken, hidroksillenmiş ve N-oksit türevleri aktif değildir. Tek bir 75 mg dozdan sonra klozapinin ortalama eliminasyon yarılanma ömrü, kararlı hale geldikten sonra 12 saatlik ortalama eliminasyon yarılanma ömrüne (aralık: 4-66 saat) kıyasla 8 saat (aralık: 4-12 saat) idi. günde iki kez 100 mg doz ile durum.

Tek doz ve çok dozlu klozapin uygulamasının karşılaştırılması, eliminasyon yarılanma ömrünün, tek doz uygulamasından sonra olana göre çoklu dozlamadan sonra önemli ölçüde arttığını gösterdi ve bu da konsantrasyona bağlı farmakokinetik olasılığını düşündürdü. Bununla birlikte, kararlı durumda, günde iki kez 37.5, 75 ve 150 mg uygulandıktan sonra AUC (eğrinin altındaki alan), pik ve minimum klozapin plazma konsantrasyonlarına göre yaklaşık doz orantılı değişiklikler gözlenmiştir.