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Oliinyk Elizabeth Ivanovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 27.03.2022
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Ziprasidon - 1 A Pharma, şizofreni tedavisi için, bipolar manik veya karışık atakların akut tedavisi için monoterapi olarak ve bipolar bozukluğun idame tedavisi için lityum veya valproata ek olarak endikedir. Ziprasidon - 1 A Şizofrenik hastalarda akut ajitasyon için kas içi ilaç endikedir. Tedaviye ihtiyaç duyan durum için mevcut alternatif tedaviler arasında karar verirken, reçete yazan kişi, diğer bazı antipsikotik ilaçlara kıyasla ziprasidonun QT / QTc aralığını uzatma kapasitesinin daha yüksek olduğunu bulmalıdır. QTc aralığının uzaması, torsade de pointes tipi aritmi, potansiyel olarak ölümcül bir polimorfik ventriküler taşikardi ve ani ölüme neden olma yeteneği olan diğer bazı ilaçlarda ilişkilidir. Birçok durumda bu, önce diğer ilaçların denenmesi gerektiği sonucuna yol açacaktır. Ziprasidonun torsade de pointes'e neden olup olmayacağı veya ani ölüm oranını artıracağı henüz bilinmemektedir
Şizofreni
Ziprasidon - 1 A Pharma, şizofreni tedavisi için endikedir. Oral ziprasidonun etkinliği, yetişkin şizofrenik yatarak tedavi gören dört kısa süreli (4- ve 6 haftalık) kontrollü çalışmada ve stabil yetişkin şizofrenik yatan hastaların bir bakım çalışmasında belirlenmiştir.
Bipolar I Bozukluk (Akut Karışık veya Manik Bölümler ve Lityum veya Valproata Yardımcı Olarak Bakım Tedavisi)
Ziprasidon - 1 A Pharma, bipolar I bozukluğu ile ilişkili manik veya karışık atakların akut tedavisi için monoterapi olarak endikedir. Yetişkin hastalarda yapılan 3 haftalık iki monoterapi çalışmasında etkinlik belirlenmiştir.
Ziprasidon - 1 A Pharma, bipolar I bozukluğunun idame tedavisi için lityum veya valproata ek olarak endikedir. Yetişkin hastalarda yapılan bir bakım çalışmasında etkinlik belirlenmiştir. Bipolar I bozukluğunun idame tedavisi için monoterapi olarak Ziprasidon - 1 A Pharma'nın etkinliği kontrollü klinik çalışmalarda sistematik olarak değerlendirilmemiştir.
Şizofrenide Ajitasyonun Akut Tedavisi
Ziprasidon - 1 A Farmak kas içi, ziprasidon tedavisinin uygun olduğu ve ajitasyonun hızlı kontrolü için kas içi antipsikotik ilaca ihtiyaç duyan şizofrenik hastalarda akut ajitasyon tedavisi için endikedir. Kas içi ziprasidonun şizofrenide akut ajitasyon için etkinliği, ajite şizofrenik yatan hastaların tek günlük kontrollü çalışmalarında belirlenmiştir
“Psikomotor ajitasyon” DSM-IV'te “iç gerilim hissi ile ilişkili aşırı motor aktivitesi” olarak tanımlanır. Ajitasyon yaşayan şizofrenik hastalar genellikle tanı ve bakımlarına müdahale eden davranışlar gösterirler, örn.tehdit edici davranışlar, artan veya acilen üzücü davranışlar veya kendi kendine tükenme davranışı, klinisyenleri ajitasyonun derhal kontrolünü sağlamak için kas içi antipsikotik ilaçların kullanımına yönlendirir.
Zaten oral ziprasidon alan şizofrenik hastalara ziprasidon kas içi uygulama güvenliği konusunda deneyim olmadığından, birlikte uygulama uygulaması önerilmez.
Kas içi ziprasidon sadece kas içi kullanım için tasarlanmıştır ve intravenöz olarak uygulanmamalıdır.
Şizofreni
Doz Seçimi
Ziprasidon - 1 A İlaç Kapsülleri, günde iki kez 20 mg'lık bir başlangıç dozunda gıda ile uygulanmalıdır. Bazı hastalarda, günlük dozaj daha sonra günde iki kez 80 mg'a kadar bireysel klinik duruma göre ayarlanabilir. Doz ayarlamaları, belirtilirse, 1 ila 3 gün içinde kararlı duruma ulaşıldığı için genellikle 2 günden az olmayan aralıklarla yapılmalıdır. En düşük etkili dozun kullanılmasını sağlamak için, hastalar yukarı doğru doz ayarlamasından önce birkaç hafta boyunca iyileşme açısından gözlemlenmelidir.
Şizofrenideki etkinlik, kısa süreli, plasebo kontrollü klinik çalışmalarda günde iki kez 20 mg ila 100 mg'lık bir doz aralığında gösterilmiştir. Günde iki kez 20 mg ila 80 mg aralığında doz tepkisine yönelik eğilimler vardı, ancak sonuçlar tutarlı değildi. Günde iki kez 80 mg'dan daha yüksek bir doza artış genellikle önerilmez. Klinik çalışmalarda günde iki kez 100 mg'ın üzerindeki dozların güvenliği sistematik olarak değerlendirilmemiştir.
Bakım Tedavisi
Ziprasidon ile tedavi edilen bir hastanın ne kadar süre kalması gerektiği sorusunu cevaplayacak hiçbir kanıt bulunmamakla birlikte, semptomatik olarak stabil olan ve daha sonra ziprasidon devam etmek veya plaseboya geçmek için randomize edilen hastalarda yapılan bir bakım çalışması, Ziprasidon - 1 A Pharma alan hastalar için nüksetme zamanında bir gecikme olduğunu göstermiştir. Günde iki kez 20 mg'ın üzerindeki dozlar için ek bir fayda gösterilmemiştir. Bakım tedavisi ihtiyacını belirlemek için hastalar periyodik olarak yeniden değerlendirilmelidir.
Bipolar I Bozukluk (Lityum veya Valproata Yardımcı Olarak Akut Karışık veya Manik Bölümler ve Bakım Tedavisi)
Manik veya Karışık Bölümlerin Akut Tedavisi
Doz Seçimi-Oral ziprasidon, günde iki kez 40 mg'lık bir başlangıç günlük dozunda gıda ile uygulanmalıdır. Doz daha sonra tedavinin ikinci gününde günde iki kez 60 mg veya 80 mg'a yükseltilebilir ve daha sonra günde iki kez 40 mg € 80 mg aralığında tolerans ve etkinlik temelinde ayarlanabilir. Esnek doz klinik çalışmalarda, uygulanan ortalama günlük doz yaklaşık 120 mg idi.
Bakım Tedavisi (lityum veya valproata ek olarak)
Günde iki kez 40 mg â € â € 80 € aralığında hastanın başlangıçta stabilize edildiği dozda tedaviye devam edin. Bakım tedavisi ihtiyacını belirlemek için hastalar periyodik olarak yeniden değerlendirilmelidir.
Şizofrenide Ajitasyonun Akut Tedavisi
Kas içi Dozlama
Önerilen doz, günde maksimum 40 mg doza kadar gerektiği şekilde 10 mg ila 20 mg'dır. 10 mg'lık dozlar iki saatte bir uygulanabilir; 20 mg'lık dozlar dört saatte bir maksimum 40 mg / güne kadar uygulanabilir. Art arda üç günden fazla ziprasidonun kas içi uygulaması araştırılmamıştır.
Uzun süreli tedavi endike ise, oral ziprasidon hidroklorür kapsülleri kas içi uygulamayı mümkün olan en kısa sürede değiştirmelidir.
Zaten oral ziprasidon alan şizofrenik hastalara ziprasidon kas içi uygulama güvenliği konusunda deneyim olmadığından, birlikte uygulama uygulaması önerilmez.
Kas içi ziprasidon sadece kas içi kullanım için tasarlanmıştır ve intravenöz olarak uygulanmamalıdır.
Uygulama İçin Kas İçi Hazırlık
Ziprasidon - 1 A Enjeksiyon için İlaç (ziprasidon mesilat) sadece kas içi enjeksiyonla uygulanmalı ve intravenöz olarak uygulanmamalıdır. Tek doz şişeler uygulamadan önce sulandırmayı gerektirir.
Şişeye 1.2 mL Enjeksiyonluk Steril Su ekleyin ve tüm ilaç çözülene kadar kuvvetlice çalkalayın. Sulandırılmış çözeltinin her mL'si 20 mg ziprasidon içerir. 10 mg'lık bir doz uygulamak için, sulandırılmış çözeltinin 0.5 mL'sini hazırlayın. 20 mg'lık bir doz uygulamak için, 1.0 mL sulandırılmış çözelti hazırlayın. Kullanılmayan kısımlar atılmalıdır. Bu üründe koruyucu veya bakteriyostatik ajan bulunmadığından, nihai çözeltinin hazırlanmasında aseptik teknik kullanılmalıdır. Bu tıbbi ürün, Enjeksiyonluk Steril Su dışındaki diğer tıbbi ürünler veya çözücülerle karıştırılmamalıdır. Parenteral ilaç ürünleri, çözelti ve kap izin verdiğinde uygulamadan önce partikül madde ve renk değişikliği açısından görsel olarak incelenmelidir.
Özel Nüfuslarda Dozlama
Oral
Doz ayarlaması genellikle yaş, cinsiyet, ırk veya böbrek veya karaciğer yetmezliği temelinde gerekli değildir. Ziprasidon - 1 A Pharma, çocuklarda veya ergenlerde kullanım için onaylanmamıştır.
Kas içi
Ziprasidon kas içi yaşlı hastalarda veya karaciğer veya böbrek yetmezliği olan hastalarda sistematik olarak değerlendirilmemiştir. Siklodekstrin eksipiyan böbrek filtrasyonu ile temizlendiğinden, ziprasidon kas içi böbrek fonksiyon bozukluğu olan hastalara dikkatle uygulanmalıdır. Cinsiyet veya ırk temelinde doz ayarlaması gerekli değildir.
QT Uzatma
Ziprasidonun QT aralığının doza bağlı uzaması ve ölümcül aritmilerin QT uzaması ile bilinen diğer bazı ilaçlar tarafından ilişkilendirilmesi nedeniyle, ziprasidon kontrendikedir:
- QT uzaması öyküsü bilinen hastalarda (konjenital uzun QT sendromu dahil)
- yakın zamanda akut miyokard enfarktüsü olan hastalarda
- telafi edilmemiş kalp yetmezliği olan hastalarda
Ziprasidon ve QT aralığını uzatan diğer ilaçlar arasında farmakokinetik / farmakodinamik çalışmalar yapılmamıştır. Ziprasidon ve QT aralığını uzatan diğer ilaçların ilave etkisi göz ardı edilemez. Bu nedenle, ziprasidon aşağıdakilerle verilmemelidir:
- dofetilid, sotalol, kinidin, diğer Sınıf Ia ve III anti-aritmikler, mezoridazin, thioridazin, klorpromazin, droperidol, pimozid, sparfloksasin, gatifloksasin, moksifloksasin, halofantrin, meflokin, pentamidin, arsenik trioksit, levometadil asetat.
- QT uzamasını farmakodinamik etkilerinden biri olarak gösteren ve bu etkiyi tam reçete bilgisinde kontrendikasyon veya kutulu veya kalın bir uyarı olarak tanımlayan diğer ilaçlar.
Aşırı duyarlılık
Ziprasidon, ürüne karşı aşırı duyarlılığı olduğu bilinen bireylerde kontrendikedir.
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. Ziprasidon - 1 A Pharma 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 Ziprasidon - 1 A Pharma 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 Ziprasidon - 1 A Pharma. Although fewer patients have been treated with Ziprasidon - 1 A Pharma, 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
Mean Random Glucose Change from Baseline mg/dL (N) | ||||||
Ziprasidone | Placebo | |||||
5 mg BID | 20 mg BID | 40 mg BID | 60 mg BID | 80 mg BID | 100 mg BID | |
-1.1 (N=45) | +2.4 (N=179) | -0.2 (N=146) | -0.5 (N=119) | -1.7 (N=104) | +4.1 (N=85) | +1.4 (N=260) |
* “Random” glucose measurements—fasting/non-fasting status unknown |
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
Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
Random Glucose | Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) | Ziprasidone | 438 | 77 (17.6%) |
Placebo | 169 | 26 (15.4%) | ||
Borderline to High ( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) | Ziprasidone | 159 | 54 (34.0%) | |
Placebo | 66 | 22 (33.3%) | ||
*“Random” glucose measurements – fasting/non-fasting status unknown |
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
Mean Fasting Glucose Change from Baseline mg/dL (N) | ||
Ziprasidone | Placebo | |
Low Dose: 20-40 mg BID | High Dose: 60-80 mg BID | |
+0.1 (N=206) | +1.6 (N=166) | +1.4 (N=287) |
*Fasting |
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
Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
Fasting Glucose | Normal to High ( < 100 mg/dL to ≥ 126 mg/dL) | Ziprasidone | 272 | 5 (1.8%) |
Placebo | 210 | 2 (1.0%) | ||
Borderline to High ( ≥ 100 mg/dL and < 126 mg/dL to ≥ 126 mg/dL) | Ziprasidone | 79 | 12 (15.2%) | |
Placebo | 71 | 7 (9.9%) | ||
*Fasting |
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
Mean Lipid Change from Baseline mg/dL (N) | |||||||
Laboratory Analyte | Ziprasidone | Placebo | |||||
5 mg BID | 20 mg BID | 40 mg BID | 60 mg BID | 80 mg BID | 100 mg BID | ||
Triglycerides | -12.9 (N=45) | -9.6 (N=181) | -17.3 (N=146) | -0.05 (N=120) | -16.0 (N=104) | +0.8 (N=85) | -18.6 (N=260) |
Total Cholesterol | -3.6 (N=45) | 1) 48 ”I | -8.2 (N=147) | -3.6 (N=120) | -10.0 (N=104) | -3.6 (N=85) | -4.7 (N=261) |
*“Random” lipid measurements, fasting/non-fasting status unknown |
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
Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
Triglycerides | Increase by ≥ 50 mg/dL | Ziprasidone | 681 | 232 (34.1%) |
Placebo | 260 | 53 (20.4%) | ||
Normal to High ( < 150 mg/dL to ≥ 200 mg/dL) | Ziprasidone | 429 | 63 (14.7%) | |
Placebo | 152 | 12 (7.9%) | ||
Borderline to High ( ≥ 150 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) | Ziprasidone | 92 | 43 (46.7%) | |
Placebo | 41 | 12 (29.3%) | ||
Total Cholesterol | Increase by ≥ 40 mg/dL | Ziprasidone | 682 | 76 (11.1%) |
Placebo | 261 | 26 (10.0%) | ||
Normal to High ( < 200 mg/dL to ≥ 240 mg/dL) | Ziprasidone | 380 | 15 (3.9%) | |
Placebo | 145 | 0 (0.0%) | ||
Borderline to High ( ≥ 200 mg/dL and < 240 mg/dL to ≥ 240 mg/dL) | Ziprasidone | 207 | 56 (27.1%) | |
Placebo | 82 | 22 (26.8%) | ||
*“Random” lipid measurements, fasting/non-fasting status unknown |
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
Laboratory Analyte | Mean Change from Baseline mg/dL (N) | ||
Ziprasidone | Placebo | ||
Low Dose: 20-40 mg BID | High Dose: 60-80 mg BID | ||
Fasting Triglycerides | +0.95 (N=206) | -3.5 (N=165) | +8.6 (N=286) |
Fasting Total Cholesterol | -2.8 (N=206) | -3.4 (N=165) | -1.6 (N=286) |
Fasting LDL Cholesterol | -3.0 (N=201) | -3.1 (N=158) | -1.97 (N=270) |
Fasting HDL cholesterol | -0.09 (N=206) | +0.3 (N=165) | -0.9 (N=286) |
*Fasting |
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
Laboratory Analyte | Category Change (at least once) from Baseline | Treatment Arm | N | n (%) |
Fasting Triglycerides | Increase by ≥ 50 mg/dL | Ziprasidone | 371 | 66 (17.8%) |
Placebo | 286 | 62 (21.7%) | ||
Normal to High ( < 150 mg/dL to ≥ 200 mg/dL) | Ziprasidone | 225 | 15 (6.7%) | |
Placebo | 179 | 13 (7.3%) | ||
Borderline to High ( ≥ 150 mg/dL and < 200 mg/dL to ≥ 200 mg/dL) | Ziprasidone | 58 | 16 (27.6%) | |
Placebo | 47 | 14 (29.8%) | ||
Fasting Total Cholesterol | Increase by ≥ 40 mg/dL | Ziprasidone | 371 | 30 (8.1%) |
Placebo | 286 | 13 (4.5%) | ||
Ziprasidone | 204 | 5 (2.5%) | ||
Placebo | 151 | 2 (1.3%) | ||
Borderline to High ( ≥ 200 mg/dL and < 240 mg/dL to ≥ 240 mg/dL) | Ziprasidone | 106 | 10 (9.4%) | |
Placebo | 87 | 15 (17.2%) | ||
Fasting LDL Cholesterol | Increase by ≥ 30 mg/dL | Ziprasidone | 359 | 39 (10.9%) |
Placebo | 270 | 17 (6.3%) | ||
Normal to High ( < 100 mg/dL to ≥ 160 mg/dL) | Ziprasidone | 115 | 0 (0%) | |
Placebo | 89 | 1 (1.1%) | ||
Borderline to High ( ≥ 100 mg/dL and < 160 mg/dL to ≥ 160 mg/dL) | Ziprasidone | 193 | 18 (9.3%) | |
Placebo | 141 | 14 (9.9%) | ||
Fasting HDL | Normal ( > =40 mg/dL) to Low ( < 40 mg/dL) | Ziprasidone | 283 | 22 (7.8%) |
Placebo | 220 | 24 (10.9%) | ||
*Fasting |
Weight Gain
Weight gain has been observed with atypical antipsychotic use. Monitoring of weight is recommended. Pooled data from short-term, placebo-controlled studies in schizophrenia and bipolar disorder are presented in Tables 9-10.
Table 9: Weight Mean Changes in Short-Term (up to 6 weeks ), Placebo-Controlled, Fixed-Dos e, Oral Zipras idone Monotherapy Trials in Adult Patients with Schizophrenia
Ziprasidone | Placebo | |||||
5 mg BID | 20 mg BID | 40 mg BID | 60 mg BID | 80 mg BID | 100 mg BID | |
Mean Weight (kg) Changes from Baseline (N) | ||||||
+0.3 (N=40) | +1.0 (N=167) | +1.0 (N=135) | +0.7 (N=109) | +1.1 (N=97) | +0.9 (N=74) | -0.4 (227) |
Proportion of Patients with ≥ 7% Increase in Weight from Baseline (N) | ||||||
0.0% (N=40) | 9.0% (N=167) | 10.4% (N=135) | 7.3% (N=109) | 15.5% (N=97) | 10.8% (N=74) | 4.0% (N=227) |
In long-term (at least 1 year), placebo-controlled, flexible-dose studies in schizophrenia, the mean change from baseline weight for ziprasidone 20-40 mg BID was -2.3 kg (N=124); for ziprasidone 60-80 mg BID was +2.5 kg (N=10); and for placebo was -2.9 kg (N=72). In the same long-term studies, the proportion of subjects with ≥ 7% increase in weight from baseline for ziprasidone 20-40 mg BID was 5.6% (N=124); for ziprasidone 60-80 mg BID was 20.0% (N=10), and for placebo was 5.6% (N=72). In a long-term (at least 1 year), placebo-controlled, fixed-dose study in schizophrenia, the mean change from baseline weight for ziprasidone 20 mg BID was -2.6 kg (N=72); for ziprasidone 40 mg BID was - 3.3 kg (N=69); for ziprasidone 80 mg BID was -2.8 kg (N=70) and for placebo was -3.8 kg (N=70). In the same long-term fixed-dose schizophrenia study, the proportion of subjects with ≥ 7% increase in weight from baseline for ziprasidone 20 mg BID was 5.6% (N=72); for ziprasidone 40 mg BID was 2.9% (N=69); for ziprasidone 80 mg BID was 5.7% (N=70) and for placebo was 2.9% (N=70).
Table 10: Summary of Weight Change in Short-Term (up to 6 weeks), Placebo-Controlled, Flexible-Dose, Oral Ziprasidone Monotherapy Trials in Adult Patients with Bipolar Disorder:
Ziprasidone | Placebo | |
Low Dose: 20-40 mg BID | High Dose*: 60-80 mg BID | |
Mean Weight (kg) Changes from Baseline (N) | ||
+0.4 (N=295) | +0.4 (N=388) | +0.1 (N=451) |
Proportion of Patients with ≥ 7% Increase in Weight from Baseline (N) | ||
2.4% (N=295) | 4.4% (N=388) | 1.8% (N=451) |
*Note that in the High Dose group, there were 2 subjects with modal 200 mg total daily dose and 1 subject with modal 100 mg total daily dose. |
Schizophrenia
The proportions of patients meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of four 4- and 6-week placebo-controlled schizophrenia clinical trials, revealing a statistically significantly greater incidence of weight gain for ziprasidone (10%) compared to placebo (4%). A median weight gain of 0.5 kg was observed in ziprasidone patients compared to no median weight change in placebo patients. In this set of clinical trials, weight gain was reported as an adverse reaction in 0.4% and 0.4% of ziprasidone and placebo patients, respectively. During long-term therapy with ziprasidone, a categorization of patients at baseline on the basis of body mass index (BMI) revealed the greatest mean weight gain and highest incidence of clinically significant weight gain ( > 7% of body weight) in patients with low BMI ( < 23) compared to normal (23–27) or overweight patients ( > 27). There was a mean weight gain of 1.4 kg for those patients with a “low” baseline BMI, no mean change for patients with a “normal” BMI, and a 1.3 kg mean weight loss for patients who entered the program with a “high” BMI.
Bipolar Disorder
During a 6-month placebo-controlled bipolar maintenance study in adults with ziprasidone as an adjunct to lithium or valproate, the incidence of clinically significant weight gain ( ≥ 7% of body weight) during the double-blind period was 5.6% for both ziprasidone and placebo treatment groups who completed the 6 months of observation for relapse. Interpretation of these findings should take into consideration that only pat
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
Body System/ Adverse Reaction | Percentage of Patients Reporting Reaction | |
Ziprasidone (N=702) | Placebo (N=273) | |
Body as a Whole | ||
Asthenia | 5 | 3 |
Accidental Injury | 4 | 2 |
Chest Pain | 3 | 2 |
Cardiovascular | ||
Tachycardia | 2 | 1 |
Digestive | ||
Nausea | 10 | 7 |
Constipation | 9 | 8 |
Dyspepsia | 8 | 7 |
Diarrhea | 5 | 4 |
Dry Mouth | 4 | 2 |
Anorexia | 2 | 1 |
Nervous | ||
Extrapyramidal Symptoms* | 14 | 8 |
Somnolence | 14 | 7 |
Akathisia | 8 | 7 |
Dizziness † | 8 | 6 |
Respiratory | ||
Respiratory Tract Infection | 8 | 3 |
Rhinitis | 4 | 2 |
Cough Increased | 3 | 1 |
Skin and Appendages | ||
Rash | 4 | 3 |
Fungal Dermatitis | 2 | 1 |
Special Senses | ||
Abnormal Vision | 3 | 2 |
*Extrapyramidal Symptoms 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 5% in schizophrenia trials. †Dizziness includes the adverse reaction terms dizziness and lightheadedness. |
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
Body System/ Adverse Reaction | Percentage of Patients Reporting Reaction | Placebo (N=136) |
Ziprasidone (N=279) | ||
Body as a Whole | ||
Headache | 18 | 17 |
Asthenia | 6 | 2 |
Accidental Injury | 4 | 1 |
Cardiovascular | ||
Hypertension | 3 | 2 |
Digestive | ||
Nausea | 10 | 7 |
Diarrhea | 5 | 4 |
Dry Mouth | 5 | 4 |
Vomiting | 5 | 2 |
Increased Salivation | 4 | 0 |
Tongue Edema | 3 | 1 |
Dysphagia | 2 | 0 |
Musculoskeletal | ||
Myalgia | 2 | 0 |
Nervous | ||
Somnolence | 31 | 12 |
Extrapyramidal Symptoms* | 31 | 12 |
Dizziness † | 16 | 7 |
Akathisia | 10 | 5 |
Anxiety | 5 | 4 |
Hypesthesia | 2 | 1 |
Speech Disorder | 2 | 0 |
Respiratory | ||
Pharyngitis | 3 | 1 |
Dyspnea | 2 | 1 |
Skin and Appendages | ||
Fungal Dermatitis | 2 | 1 |
Special Senses | ||
Abnormal Vision | 6 | 3 |
*Extrapyramidal Symptoms 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 includes the adverse reaction terms dizziness and lightheadedness. |
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
Body System/ Adverse Reaction | Percentage of Patients Reporting Reaction | ||
Ziprasidone 2 mg (N=92) | Ziprasidone 10 mg (N=63) | Ziprasidone 20 mg (N=41) | |
Body as a Whole | |||
Headache | 3 | 13 | 5 |
Injection Site Pain | 9 | 8 | 7 |
Asthenia | 2 | 0 | 0 |
Abdominal Pain | 0 | 2 | 0 |
Flu Syndrome | 1 | 0 | 0 |
Back Pain | 1 | 0 | 0 |
Cardiovascular | |||
Postural Hypotension | 0 | 0 | 5 |
Hypertension | 2 | 0 | 0 |
Bradycardia | 0 | 0 | 2 |
Vasodilation | 1 | 0 | 0 |
Digestive | |||
Nausea | 4 | 8 | 12 |
Rectal Hemorrhage | 0 | 0 | 2 |
Diarrhea | 3 | 3 | 0 |
Vomiting | 0 | 3 | 0 |
Dyspepsia | 1 | 3 | 2 |
Anorexia | 0 | 2 | 0 |
Constipation | 0 | 0 | 2 |
Tooth Disorder | 1 | 0 | 0 |
Dry Mouth | 1 | 0 | 0 |
Nervous | |||
Dizziness | 3 | 3 | 10 |
Anxiety | 2 | 0 | 0 |
Insomnia | 3 | 0 | 0 |
Somnolence | 8 | 8 | 20 |
Akathisia | 0 | 2 | 0 |
Agitation | 2 | 2 | 0 |
Extrapyramidal Syndrome | 2 | 0 | 0 |
Hypertonia | 1 | 0 | 0 |
Cogwheel Rigidity | 1 | 0 | 0 |
Paresthesia | 0 | 2 | 0 |
Personality Disorder | 0 | 2 | 0 |
Psychosis | 1 | 0 | 0 |
Speech Disorder | 0 | 2 | 0 |
Respiratory | |||
Rhinitis | 1 | 0 | 0 |
Skin and Appendages | |||
Furunculosis | 0 | 2 | 0 |
Sweating | 0 | 0 | 2 |
Urogenital | |||
Dysmenorrhea | 0 | 2 | 0 |
Priapism | 1 | 0 | 0 |
Postmarketing Experience
The following adverse reactions have been identified during post approval use of Ziprasidon - 1 A Pharma. 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.
İnsan Deneyimi
5400'den fazla hasta ve / veya normal denek içeren pazarlama öncesi çalışmalarda, 10 hastada oral ziprasidonun kazara veya kasıtlı olarak aşırı dozda alınması belgelenmiştir. Bu hastaların hepsi sekel olmadan hayatta kaldı. Doğrulanmış en büyük miktarı olan 3.240 mg alan hastada bildirilen tek semptom minimal sedasyon, konuşma bulanıklığı ve geçici hipertansiyondu (200/95). Ziprasidon doz aşımı ile bildirilen advers reaksiyonlar ekstrapiramidal semptomlar, uyku hali, titreme ve kaygıyı içerir.
Doz aşımı yönetimi
Akut doz aşımı durumunda, bir hava yolu kurun ve koruyun ve yeterli oksijenasyon ve havalandırma sağlayın. İntravenöz erişim sağlanmalı ve mide lavajı (entübasyondan sonra, hasta bilinçsizse) ve aktif kömürün müshil ile birlikte uygulanması düşünülmelidir. Doz aşımı sonrası baş ve boynun tıkanması, nöbet veya distonik reaksiyonu olasılığı, indüklenmiş kusma ile aspirasyon riski oluşturabilir.
Kardiyovasküler izleme derhal başlamalı ve olası aritmileri tespit etmek için sürekli elektrokardiyografik izleme içermelidir. Antiaritmik tedavi uygulanırsa, disopiramid, prokainamid ve kinidin, ziprasidonunkine katkıda bulunabilecek teorik bir QTprolonging etkisi tehlikesi taşır.
Hipotansiyon ve dolaşım çökmesi intravenöz sıvılar gibi uygun önlemlerle tedavi edilmelidir. Vasküler destek için sempatomimetik ajanlar kullanılırsa, epinefrin ve dopamin kullanılmamalıdır, çünkü ziprasidon ile ilişkili a antagonizması ile kombine edilmiş beta stimülasyonu hipotansiyonu kötüleştirebilir. Benzer şekilde, bretyliumun alfa-adrenerjik bloke edici özelliklerinin ziprasidonun özelliklerine katkı sağlayabileceğini ve sorunlu hipotansiyona neden olabileceğini beklemek mantıklıdır.
Şiddetli ekstrapiramidal semptomlar durumunda antikolinerjik ilaç uygulanmalıdır. Ziprasidona özgü bir antidot yoktur ve diyaliz edilemez. Çoklu ilaç katılımı olasılığı göz önünde bulundurulmalıdır. Hasta iyileşene kadar yakın tıbbi gözetim ve izleme devam etmelidir.
Ziprasidon yüksek sergilendi in vitro dopamin D2 ve D3, serotonin 5HT2A, 5HT2C, 5HT1A, 5HT1D ve a1-adrenerjik reseptörler (4.8, 7.2, 0.4, 1.3, 3.4, 2 ve 10 nM'lik Ki'ler) için bağlanma afinitesi) ve orta derecede afinite. Ziprasidon, D2, 5HT2D ve 5HT1D reseptörlerinde bir antagonist ve 5HT1A reseptöründe bir agonist olarak işlev gördü. Â Ziprasidon, serotonin ve norepinefrin sinaptik geri alımını inhibe etti. Kolinerjik muskarinik reseptör (IC> 1 μM) dahil olmak üzere test edilen diğer reseptör / bağlayıcı bölgeler için kayda değer bir afinite sergilenmemiştir. Dopamin dışındaki reseptörlerde ve benzer reseptör afinitelerine sahip 5HT2'de antagonizm, ziprasidonun diğer terapötik ve yan etkilerinden bazılarını açıklayabilir. Ziprasidonun histamin H1 reseptörleri antagonizması, bu ilaçla gözlenen uyku halini açıklayabilir. Ziprasidonun a-adrenerjik reseptörlerin antagonizması, bu ilaçla gözlenen ortostatik hipotansiyonu açıklayabilir.
Oral Farmakokinetik
Ziprasidon'un aktivitesi öncelikle ana ilaçtan kaynaklanır. Ziprasidonun çok dozlu farmakokinetiği, önerilen klinik doz aralığında dozla orantılıdır ve ziprasidon birikimi çoklu dozlama ile tahmin edilebilir. Ziprasidonun ortadan kaldırılması esas olarak, önerilen klinik doz aralığında yaklaşık 7 saatlik ortalama terminal yarılanma ömrüne sahip hepatik metabolizma yoluyla yapılır. Kararlı durum konsantrasyonları, dozlamadan bir ila üç gün sonra elde edilir. Ortalama görünür sistemik klerens 7.5 mL / dak / kg'dır. Ziprasidonun sitokrom P450 enzimleri tarafından metabolize edilen ilaçların metabolizmasına müdahale etmesi olası değildir.
Emilim
Ziprasidon oral uygulamadan sonra iyi emilir ve 6 ila 8 saat içinde pik plazma konsantrasyonlarına ulaşır. Beslenen koşullar altında 20 mg'lık bir dozun mutlak biyoyararlanımı yaklaşık% 60'tır. Ziprasidonun emilimi, yiyecek varlığında iki kata kadar arttırılır.
Dağıtım
Ziprasidon ortalama 1.5 L / kg dağılım hacmine sahiptir. Plazma proteinlerine% 99'dan daha fazla bağlanır, öncelikle albümin ve a-asit glikoproteine bağlanır. in vitro ziprasidonun plazma proteinlerine bağlanması, yüksek oranda proteine bağlı iki ilaç olan warfarin veya propranolol ile değiştirilmedi veya ziprasidon, bu ilaçların insan plazmasındaki bağlanmasını değiştirmedi. Bu nedenle, yer değiştirme nedeniyle ziprasidon ile ilaç etkileşimi potansiyeli minimaldir.
Metabolizma ve Eliminasyon
Ziprasidon, oral uygulamadan sonra, değişmemiş ilaç olarak idrarda (<% 1) veya dışkıda (<% 4) atılan az miktarda yoğun bir şekilde metabolize edilir. Ziprasidon, dört ana dolaşım metaboliti, benzizotiyazol (BITP) sülfoksit, BITP-sülfon, ziprasidon sülfoksit ve S-metildihidroziprasidon vermek için öncelikle üç metabolik yolla temizlenir. Dozun yaklaşık% 20'si idrarla atılır, yaklaşık% 66'sı dışkıda elimine edilir. Değişmemiş ziprasidon, serumdaki toplam ilaca bağlı materyalin yaklaşık% 44'ünü temsil eder. İnsan karaciğer hücre altı fraksiyonları kullanılarak yapılan in vitro çalışmalar, S-metildihidroziprasidonun iki adımda üretildiğini göstermektedir. Bu çalışmalar, indirgeme reaksiyonuna öncelikle glutatyon ile kimyasal indirgeme ve aldehit oksidaz ile enzimatik indirgeme ve müteakip metilasyona tiol metiltransferaz aracılık ettiğini göstermektedir. İn vitro insan karaciğer mikrozomları ve rekombinant enzimler kullanan çalışmalar CYP3A4'ün ziprasidonun oksidatif metabolizmasına katkıda bulunan ana CYP olduğunu göstermektedir. CYP1A2 çok daha az katkıda bulunabilir. Dayalı in vivo boşaltım metabolitlerinin bolluğu, ziprasidon metabolik klerensinin üçte birinden daha azına sitokrom P450 katalizli oksidasyon ve yaklaşık üçte ikisi indirgeme yoluyla aracılık eder. Klinik olarak anlamlı bilinen bir inhibitör veya aldehit oksidaz indükleyicisi yoktur.
Kas içi Farmakokinetik
Sistemik Biyoyararlanım: Kas içine uygulanan ziprasidonun biyoyararlanımı% 100'dür. Tek dozların kas içi uygulanmasından sonra, pik serum konsantrasyonları tipik olarak dozdan yaklaşık 60 dakika sonra veya daha erken ortaya çıkar ve ortalama yarılanma ömrü (T½) iki ila beş saat arasında değişir. Pozlama doza bağlı bir şekilde artar ve üç günlük kas içi dozlamadan sonra çok az birikim gözlenir.
Metabolizma ve Eliminasyon: IM ziprasidonun metabolizması ve eliminasyonu sistematik olarak değerlendirilmemesine rağmen, kas içi uygulama yolunun metabolik yolları değiştirmesi beklenmez.
However, we will provide data for each active ingredient