PMS-Atomoxetine

Dikkat Eksikliği / Hiperaktivite Bozukluğu (DEHB)

PMS-Atomoksetin, Dikkat Eksikliği / Hiperaktivite Bozukluğu (DEHB) tedavisi için endikedir.

PMS-Atomoksetin Kapsüllerinin etkinliği DEHB olan ayaktan hastalarda yapılan yedi klinik çalışmada belirlenmiştir: pediyatrik hastalarda (6 ila 18 yaş arası) dört 6 ila 9 haftalık çalışma, yetişkinlerde iki 10 haftalık çalışma ve pediatride bir bakım çalışması (6 ila 15 yaş arası).

Teşhis Konuları

DEHB (DSM-IV) tanısı, bozulmaya neden olan ve 7 yaşından önce mevcut olan hiperaktif-dürtüsel veya dikkatsiz semptomların varlığını ima eder. Semptomlar kalıcı olmalı, karşılaştırılabilir bir gelişim seviyesindeki bireylerde tipik olarak gözlemlenenden daha şiddetli olmalı, klinik olarak anlamlı bozulmaya neden olmalıdır, örn.sosyal, akademik veya mesleki işlevlerde ve 2 veya daha fazla ortamda mevcut olmalıdır, ör., okul (veya iş) ve evde. Semptomlar başka bir zihinsel bozukluk tarafından daha iyi açıklanmamalıdır.

DEHB'nin spesifik etiyolojisi bilinmemektedir ve tek bir tanı testi yoktur. Yeterli tanı sadece tıbbi değil, aynı zamanda özel psikolojik, eğitimsel ve sosyal kaynakların da kullanılmasını gerektirir. Öğrenme bozulabilir veya bozulmaz. Tanı, sadece gerekli sayıda DSM-IV özelliğinin varlığına değil, hastanın tam geçmişine ve değerlendirmesine dayanmalıdır.

Dikkatsiz Tip için, aşağıdaki semptomlardan en az 6'sı en az 6 ay devam etmiş olmalıdır: detaylara dikkat eksikliği / dikkatsiz hatalar, sürekli dikkat eksikliği, kötü dinleyici, görevleri yerine getirememe, kötü organizasyon, sürekli zihinsel çaba gerektiren görevlerden kaçınır, bir şeyler kaybeder, kolayca dikkati dağılmış, unutkan. Hiperaktif-Dürtüsel Tip için, aşağıdaki semptomlardan en az 6'sı en az 6 ay boyunca devam etmiş olmalıdır: kıpır kıpır / kıvrılma, koltuktan ayrılma, uygunsuz koşu / tırmanma, sessiz aktivitelerle ilgili zorluk, “hareket halindeyken” aşırı konuşma, bulanık cevaplar, dönüş bekleyemez, müdahaleci. Kombine Tip tanısı için hem dikkatsiz hem de hiperaktif-dürtüsel kriterler karşılanmalıdır.

Kapsamlı Tedavi Programına İhtiyaç

PMS-Atomoksetin, bu sendromlu hastalar için diğer önlemleri (psikolojik, eğitimsel, sosyal) içerebilecek toplam DEHB tedavi programının ayrılmaz bir parçası olarak endikedir. Bu sendromlu tüm hastalar için ilaç tedavisi endike olmayabilir. İlaç tedavisi, çevresel faktörlere ikincil semptomlar ve / veya psikoz dahil diğer primer psikiyatrik bozukluklar sergileyen hastada kullanılmak üzere tasarlanmamıştır. Bu tanı ve psikososyal müdahale olan çocuklar ve ergenler için uygun eğitim yerleştirme genellikle yararlıdır. Tavuk iyileştirici önlemler tek başına yetersiz olduğunda, ilaç tedavisi ilaçlarını reçete etme kararı, doktorun hastanın semptomlarının kronikliği ve ciddiyeti hakkındaki değerlendirmesine bağlı olacaktır.

Akut Tedavi

70 kg'a Kadar Çocuk ve Ergenlerin Dozu Vücut Ağırlığı

PMS-Atomoksetin, yaklaşık 0.5 mg / kg'lık toplam günlük dozda başlatılmalı ve en az 3 gün sonra, sabahları tek bir günlük doz olarak veya eşit olarak uygulanan yaklaşık 1.2 mg / kg'lık bir hedef toplam günlük doza yükseltilmelidir. sabahları bölünmüş dozlar ve öğleden sonra / akşam başı. 1.2 mg / kg / gün'den yüksek dozlar için ek bir fayda gösterilmemiştir.

Çocuklarda ve ergenlerde toplam günlük doz, hangisi daha azsa, 1.4 mg / kg veya 100 mg'ı geçmemelidir.

70 kg'ın üzerindeki Çocukların ve Ergenlerin Dozu Vücut Ağırlığı ve Yetişkinler

PMS-Atomoksetin, toplam günlük 40 mg'lık bir dozda başlatılmalı ve en az 3 gün sonra, sabahları tek bir günlük doz olarak veya sabahları eşit olarak bölünmüş dozlar olarak uygulanan yaklaşık 80 mg'lık bir hedef toplam günlük doza yükseltilmelidir. ve geç öğleden sonra / akşam başı. 2 ila 4 hafta sonra, optimal yanıt alamayan hastalarda doz maksimum 100 mg'a çıkarılabilir. Daha yüksek dozlarda artan etkinliği destekleyen hiçbir veri yoktur.

70 kg'ın üzerindeki çocuklarda ve ergenlerde ve yetişkinlerde önerilen maksimum toplam günlük doz 100 mg'dır.

Bakım / Genişletilmiş Tedavi

DEHB'nin farmakolojik tedavisinin uzun süreler için gerekli olabileceği genel olarak kabul edilmektedir. Kontrollü bir çalışmada, 1.2 ila 1.8 mg / kg / gün doz aralığında bir yanıt elde ettikten sonra PMS-Atomoksetin üzerinde DEHB olan pediyatrik hastaların (6-15 yaş) korunmasının yararı gösterilmiştir. Bakım aşamasında PMS-Atomoksetine atanan hastalar genellikle açık etiket aşamasında yanıt almak için kullanılan dozda devam ettirildi. PMS-Atomoksetin'i uzun süre kullanmayı seçen doktor, ilacın bireysel hasta için uzun süreli yararlılığını periyodik olarak yeniden değerlendirmelidir.

Genel Dozlama Bilgileri

PMS-Atomoksetin, yiyecekle birlikte veya yiyeceksiz alınabilir.

PMS-Atomoksetin konikleştirilmeden kesilebilir.

PMS-Atomoksetin kapsüllerinin açılması amaçlanmamıştır, bütün olarak alınmalıdır.

120 mg'ın üzerindeki tek dozların ve 150 mg'ın üzerindeki toplam günlük dozların güvenliği sistematik olarak değerlendirilmemiştir.

Spesifik Popülasyonlarda Dozlama

Hepatik Bozulmuş Hastalar İçin Doz Ayarı

Karaciğer yetmezliği (HI) olan DEHB hastaları için doz ayarlaması aşağıdaki gibi önerilir: Orta HI (Child-Pugh Sınıf B) olan hastalar için, başlangıç ve hedef dozlar normal dozun% 50'sine düşürülmelidir (hastalıklı hastalar için) HI). Şiddetli HI (Child-Pugh Sınıf C) olan hastalar için başlangıç dozu ve hedef dozlar normalin% 25'ine düşürülmelidir.

Güçlü CYP2D6 İnhibitörü ile veya CYP2D6 PM olduğu bilinen hastalarda kullanım için doz ayarlaması

70 kg'a kadar vücut ağırlığına kadar olan çocuklarda ve ergenlerde güçlü CYP2D6 inhibitörleri, ör.paroksetin, fluoksetin ve kinidin veya CYP2D6 PM olduğu bilinen hastalarda, PMS-Atomoksetin 0.5 mg / kg / gün'de başlatılmalı ve semptomlar başarısız olursa sadece 1.2 mg / kg / gün normal hedef doza yükseltilmelidir. 4 hafta sonra düzelir ve başlangıç dozu iyi tolere edilir.

70 kg'ın üzerindeki çocuklarda ve ergenlerde vücut ağırlığı ve yetişkinlerde güçlü CYP2D6 inhibitörleri uygulanmıştır, örn.paroksetin, fluoksetin ve kinidin, PMS-Atomoksetin 40 mg / gün başlatılmalı ve semptomlar 4 hafta sonra düzelmezse ve başlangıç dozu iyi tolere edilirse sadece 80 mg / gün normal hedef doza yükseltilmelidir.

Aşırı duyarlılık

PMS-Atomoksetin, atomoksetine veya ürünün diğer bileşenlerine aşırı duyarlı olduğu bilinen hastalarda kontrendikedir.

Monoamin Oksidaz İnhibitörleri (MAOI)

PMS-Atomoksetin bir MAOI ile veya bir MAOI kesildikten sonraki 2 hafta içinde alınmamalıdır. MAOI ile tedavi, PMS-Atomoksetin kesildikten sonraki 2 hafta içinde başlatılmamalıdır. Beyin monoamin konsantrasyonlarını etkileyen diğer ilaçlarla, ciddi raporlar var, bazen ölümcül reaksiyonlar (hipertermi dahil, katılık, miyoklonus, hayati belirtilerin olası hızlı dalgalanmaları ile otonom istikrarsızlık, ve deliryum ve komaya doğru ilerleyen aşırı ajitasyonu içeren zihinsel durum değişiklikleri) bir MAOI ile kombinasyon halinde alındığında. Bazı vakalar nöroleptik malign sendroma benzeyen özelliklerle başvurdu. Bu reaksiyonlar, bu ilaçlar eşzamanlı olarak veya yakın bir yerde verildiğinde ortaya çıkabilir.

Dar Açılı Glaucoma

Klinik çalışmalarda, PMS-Atomoksetin kullanımı artmış midriyazis riski ile ilişkiliydi ve bu nedenle dar açılı glokomlu hastalarda kullanılması önerilmez.

Feokromositoma

Feokromositoma veya PMS-Atomoksetin alan feokromositoma öyküsü olan hastalarda yüksek kan basıncı ve taşiaritmi dahil ciddi reaksiyonlar bildirilmiştir. Bu nedenle, PMS-Atomoksetin, feokromositoma veya feokromositoma öyküsü olan hastalar tarafından alınmamalıdır.

Şiddetli Kardiyovasküler Bozukluklar

PMS-Atomoksetin, kan basıncında veya klinik olarak önemli olabilecek kalp atış hızında artış yaşarlarsa durumunun kötüleşmesi beklenen ciddi kardiyak veya vasküler bozuklukları olan hastalarda kullanılmamalıdır (Örneğin, Kan basıncında 15 ila 20 mm Hg veya kalp atış hızında dakikada 20 atım)..

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Suicidal Ideation

PMS-Atomoxetine increased the risk of suicidal ideation in short-term studies in children and adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD). Pooled analyses of short-term (6 to 18 weeks) placebo-controlled trials of PMS-Atomoxetine in children and adolescents have revealed a greater risk of suicidal ideation early during treatment in those receiving PMS-Atomoxetine. There were a total of 12 trials (11 in ADHD and 1 in enuresis) involving over 2200 patients (including 1357 patients receiving PMS-Atomoxetine and 851 receiving placebo). The average risk of suicidal ideation in patients receiving PMS-Atomoxetine was 0.4% (5/1357 patients), compared to none in placebo-treated patients. There was 1 suicide attempt among these approximately 2200 patients, occurring in a patient treated with PMS-Atomoxetine. No suicides occurred in these trials. All reactions occurred in children 12 years of age or younger. All reactions occurred during the first month of treatment. It is unknown whether the risk of suicidal ideation in pediatric patients extends to longer-term use. A similar analysis in adult patients treated with PMS-Atomoxetine for either ADHD or major depressive disorder (MDD) did not reveal an increased risk of suicidal ideation or behavior in association with the use of PMS-Atomoxetine.

All pediatric patients being treated with PMS-Atomoxetine should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms have been reported with PMS-Atomoxetine: anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania. Although a causal link between the emergence of such symptoms and the emergence of suicidal impulses has not been established, there is a concern that such symptoms may represent precursors to emerging suicidality. Thus, patients being treated with PMS-Atomoxetine should be observed for the emergence of such symptoms.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who are experiencing emergent suicidality or symptoms that might be precursors to emerging suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of pediatric patients being treated with PMS-Atomoxetine should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

Severe Liver Injury

Postmarketing reports indicate that PMS-Atomoxetine can cause severe liver injury. Although no evidence of liver injury was detected in clinical trials of about 6000 patients, there have been rare cases of clinically significant liver injury that were considered probably or possibly related to PMS-Atomoxetine use in postmarketing experience. Rare cases of liver failure have also been reported, including a case that resulted in a liver transplant. Because of probable underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Reported cases of liver injury occurred within 120 days of initiation of atomoxetine in the majority of cases and some patients presented with markedly elevated liver enzymes [>20 X upper limit of normal (ULN)], and jaundice with significantly elevated bilirubin levels (>2 X ULN), followed by recovery upon atomoxetine discontinuation. In one patient, liver injury, manifested by elevated hepatic enzymes up to 40 X ULN and jaundice with bilirubin up to 12 X ULN, recurred upon rechallenge, and was followed by recovery upon drug discontinuation, providing evidence that PMS-Atomoxetine likely caused the liver injury. Such reactions may occur several months after therapy is started, but laboratory abnormalities may continue to worsen for several weeks after drug is stopped. The patient described above recovered from his liver injury, and did not require a liver transplant.

PMS-Atomoxetine should be discontinued in patients with jaundice or laboratory evidence of liver injury, and should not be restarted. Laboratory testing to determine liver enzyme levels should be done upon the first symptom or sign of liver dysfunction (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu like” symptoms).

Serious Cardiovascular Events

Sudden Death And Pre-Existing Structural Cardiac Abnormalities Or Other Serious Heart Problems

Children and Adolescents

Sudden death has been reported in association with atomoxetine treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems. Although some serious heart problems alone carry an increased risk of sudden death, atomoxetine generally should not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that may place them at increased vulnerability to the noradrenergic effects of atomoxetine.

Adults

Sudden deaths, stroke, and myocardial infarction have been reported in adults taking atomoxetine at usual doses for ADHD. Although the role of atomoxetine in these adult cases is also unknown, adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Consideration should be given to not treating adults with clinically significant cardiac abnormalities.

Assessing Cardiovascular Status In Patients Being Treated With Atomoxetine

Children, adolescents, or adults who are being considered for treatment with atomoxetine should have a careful history (including assessment for a family history of sudden death or ventricular arrhythmia) and physical exam to assess for the presence of cardiac disease, and should receive further cardiac evaluation if findings suggest such disease (e.g., electrocardiogram and echocardiogram). Patients who develop symptoms such as exertional chest pain, unexplained syncope, or other symptoms suggestive of cardiac disease during atomoxetine treatment should undergo a prompt cardiac evaluation.

Effects On Blood Pressure And Heart Rate

PMS-Atomoxetine should be used with caution in patients whose underlying medical conditions could be worsened by increases in blood pressure or heart rate such as certain patients with hypertension, tachycardia, or cardiovascular or cerebrovascular disease. It should not be used in patients with severe cardiac or vascular disorders whose condition would be expected to deteriorate if they experienced clinically important increases in blood pressure or heart rate. Pulse and blood pressure should be measured at baseline, following PMS-Atomoxetine dose increases, and periodically while on therapy to detect possible clinically important increases.

The following table provides short-term, placebo-controlled clinical trial data for the proportions of patients having an increase in: diastolic blood pressure ≥15 mm Hg; systolic blood pressure ≥20 mm Hg; heart rate greater than or equal to 20 bpm, in both the pediatric and adult populations (see Table 1).

Table 1^a

In placebo-controlled registration studies involving pediatric patients, tachycardia was identified as an adverse event for 0.3% (5/1597) of these PMS-Atomoxetine patients compared with 0% (0/934) of placebo patients. The mean heart rate increase in extensive metabolizer (EM) patients was 5.0 beats/minute, and in poor metabolizer (PM) patients 9.4 beats/minute.

In adult clinical trials where EM/PM status was available, the mean heart rate increase in PM patients was significantly higher than in EM patients (11 beats/minute versus 7.5 beats/minute). The heart rate effects could be clinically important in some PM patients.

In placebo-controlled registration studies involving adult patients, tachycardia was identified as an adverse event for 1.5% (8/540) of PMS-Atomoxetine patients compared with 0.5% (2/402) of placebo patients.

In adult clinical trials where EM/PM status was available, the mean change from baseline in diastolic blood pressure in PM patients was higher than in EM patients (4.21 versus 2.13 mm Hg) as was the mean change from baseline in systolic blood pressure (PM: 2.75 versus EM: 2.40 mm Hg). The blood pressure effects could be clinically important in some PM patients.

Orthostatic hypotension and syncope have been reported in patients taking PMS-Atomoxetine. In child and adolescent registration studies, 0.2% (12/5596) of PMS-Atomoxetine-treated patients experienced orthostatic hypotension and 0.8% (46/5596) experienced syncope. In short-term child and adolescent registration studies, 1.8% (6/340) of PMS-Atomoxetine-treated patients experienced orthostatic hypotension compared with 0.5% (1/207) of placebo-treated patients. Syncope was not reported during short-term child and adolescent placebo-controlled ADHD registration studies. PMS-Atomoxetine should be used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes.

Emergence Of New Psychotic Or Manic Symptoms

Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered. In a pooled analysis of multiple short-term, placebo-controlled studies, such symptoms occurred in about 0.2% (4 patients with reactions out of 1939 exposed to atomoxetine for several weeks at usual doses) of atomoxetine-treated patients compared to 0 out of 1056 placebo-treated patients.

Screening Patients For Bipolar Disorder

In general, particular care should be taken in treating ADHD in patients with comorbid bipolar disorder because of concern for possible induction of a mixed/manic episode in patients at risk for bipolar disorder. W hether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with PMS-Atomoxetine, patients with comorbid depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression.

Aggressive Behavior Or Hostility

Patients beginning treatment for ADHD should be monitored for the appearance or worsening of aggressive behavior or hostility. Aggressive behavior or hostility is often observed in children and adolescents with ADHD. In pediatric short-term controlled clinical trials, 21/1308 (1.6%) of atomoxetine patients versus 9/806 (1.1%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.33 [95% C.I. 0.67-2.64 – not statistically significant]). In adult placebo-controlled clinical trials, 6/1697 (0.35%) of atomoxetine patients versus 4/1560 (0.26%) of placebo-treated patients spontaneously reported treatment emergent hostility-related adverse events (overall risk ratio of 1.38 [95% C.I. 0.39-4.88 – not statistically significant]). Although this is not conclusive evidence that PMS-Atomoxetine causes aggressive behavior or hostility, these behaviors were more frequently observed in clinical trials among children, adolescents, and adults treated with PMS-Atomoxetine compared to placebo.

Allergic Events

Although uncommon, allergic reactions, including anaphylactic reactions, angioneurotic edema, urticaria, and rash, have been reported in patients taking PMS-Atomoxetine.

Effects On Urine Outflow From The Bladder

In adult ADHD controlled trials, the rates of urinary retention (1.7%, 9/540) and urinary hesitation (5.6%, 30/540) were increased among atomoxetine subjects compared with placebo subjects (0%, 0/402 ; 0.5%, 2/402, respectively). Two adult atomoxetine subjects and no placebo subjects discontinued from controlled clinical trials because of urinary retention. A complaint of urinary retention or urinary hesitancy should be considered potentially related to atomoxetine.

Priapism

Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with PMS-Atomoxetine. The erections resolved in cases in which follow-up information was available, some following discontinuation of PMS-Atomoxetine. Prompt medical attention is required in the event of suspected priapism.

Effects On Growth

Data on the long-term effects of PMS-Atomoxetine on growth come from open-label studies, and weight and height changes are compared to normative population data. In general, the weight and height gain of pediatric patients treated with PMS-Atomoxetine lags behind that predicted by normative population data for about the first 9-12 months of treatment. Subsequently, weight gain rebounds and at about 3 years of treatment, patients treated with PMS-Atomoxetine have gained 17.9 kg on average, 0.5 kg more than predicted by their baseline data. After about 12 months, gain in height stabilizes, and at 3 years, patients treated with PMS-Atomoxetine have gained 19.4 cm on average, 0.4 cm less than predicted by their baseline data (see Figure 1 below).

Figure 1: Mean Weight and Height Percentiles Over Time for Patients With Three Years of PMS-Atomoxetine Treatment

This growth pattern was generally similar regardless of pubertal status at the time of treatment initiation. Patients who were pre-pubertal at the start of treatment (girls ≤8 years old, boys ≤9 years old) gained an average of 2.1 kg and 1.2 cm less than predicted after three years. Patients who were pubertal (girls >8 to ≤13 years old, boys >9 to ≤14 years old) or late pubertal (girls >13 years old, boys >14 years old) had average weight and height gains that were close to or exceeded those predicted after three years of treatment.

Growth followed a similar pattern in both extensive and poor metabolizers (EMs, PMs). PMs treated for at least two years gained an average of 2.4 kg and 1.1 cm less than predicted, while EMs gained an average of 0.2 kg and 0.4 cm less than predicted.

In short-term controlled studies (up to 9 weeks), PMS-Atomoxetine-treated patients lost an average of 0.4 kg and gained an average of 0.9 cm, compared to a gain of 1.5 kg and 1.1 cm in the placebo-treated patients. In a fixed-dose controlled trial, 1.3%, 7.1%, 19.3%, and 29.1% of patients lost at least 3.5% of their body weight in the placebo, 0.5, 1.2, and 1.8 mg/kg/day dose groups.

Growth should be monitored during treatment with PMS-Atomoxetine.

Laboratory Tests

Routine laboratory tests are not required.

CYP2D6 Metabolism

Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of PMS-Atomoxetine compared with extensive metabolizers (EMs). Approximately 7% of a Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of PMS-Atomoxetine.

Concomitant Use Of Potent CYP2D6 Inhibitors Or Use In patients Who Are Known To Be CYP2D6 PMs

Atomoxetine is primarily metabolized by the CYP2D6 pathway to 4-hydroxyatomoxetine. Dosage adjustment of PMS-Atomoxetine may be necessary when coadministered with potent CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, and quinidine) or when administered to CYP2D6 PMs..

Patient Counseling Information

See FDA-approved PATIENT INFORMATION.

General Information

Physicians should instruct their patients to read the Medication Guide before starting therapy with PMS-Atomoxetine and to reread it each time the prescription is renewed.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PMS-Atomoxetine and should counsel them in its appropriate use. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PMS-Atomoxetine.

Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, depression, and suicidal ideation, especially early during PMS-Atomoxetine treatment and when the dose is adjusted. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Severe Liver Injury

Patients initiating PMS-Atomoxetine should be cautioned that severe liver injury may develop. Patients should be instructed to contact their physician immediately should they develop pruritus, dark urine, jaundice, right upper quadrant tenderness, or unexplained “flu-like” symptoms.

Aggression Or Hostility

Patients should be instructed to call their doctor as soon as possible should they notice an increase in aggression or hostility.

Priapism

Rare postmarketing cases of priapism, defined as painful and nonpainful penile erection lasting more than 4 hours, have been reported for pediatric and adult patients treated with PMS-Atomoxetine. The parents or guardians of pediatric patients taking PMS-Atomoxetine and adult patients taking PMS-Atomoxetine should be instructed that priapism requires prompt medical attention.

Ocular Irritant

PMS-Atomoxetine is an ocular irritant. PMS-Atomoxetine capsules are not intended to be opened. In the event of capsule content coming in contact with the eye, the affected eye should be flushed immediately with water, and medical advice obtained. Hands and any potentially contaminated surfaces should be washed as soon as possible.

Drug-Drug Interaction

Pregnancy

Patients should be instructed to consult a physician if they are nursing, pregnant, or thinking of becoming pregnant while taking PMS-Atomoxetine.

Food

Patients may take PMS-Atomoxetine with or without food.

Missed Dose

If patients miss a dose, they should be instructed to take it as soon as possible, but should not take more than the prescribed total daily amount of PMS-Atomoxetine in any 24-hour period.

Interference With Psychomotor Performance

Patients should be instructed to use caution when driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected by atomoxetine.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Atomoxetine HCl was not carcinogenic in rats and mice when given in the diet for 2 years at time-weighted average doses up to 47 and 458 mg/kg/day, respectively. The highest dose used in rats is approximately 8 and 5 times the maximum human dose in children and adults, respectively, on a mg/m² basis. Plasma levels (AUC) of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive metabolizers) or 0.2 times (poor metabolizers) those in humans receiving the maximum human dose. The highest dose used in mice is approximately 39 and 26 times the maximum human dose in children and adults, respectively, on a mg/m² basis.

Mutagenesis

Atomoxetine HCl was negative in a battery of genotoxicity studies that included a reverse point mutation assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration test in Chinese hamster ovary cells, an unscheduled DNA synthesis test in rat hepatocytes, and an in vivo micronucleus test in mice. However, there was a slight increase in the percentage of Chinese hamster ovary cells with diplochromosomes, suggesting endoreduplication (numerical aberration).

The metabolite N-desmethylatomoxetine HCl was negative in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis test.

Impairment Of Fertility

Atomoxetine HCl did not impair fertility in rats when given in the diet at doses of up to 57 mg/kg/day, which is approximately 6 times the maximum human dose on a mg/m² basis.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Pregnant rabbits were treated with up to 100 mg/kg/day of atomoxetine by gavage throughout the period of organogenesis. At this dose, in 1 of 3 studies, a decrease in live fetuses and an increase in early resorptions was observed. Slight increases in the incidences of atypical origin of carotid artery and absent subclavian artery were observed. These findings were observed at doses that caused slight maternal toxicity. The no-effect dose for these findings was 30 mg/kg/day. The 100 mg/kg dose is approximately 23 times the maximum human dose on a mg/m² basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor metabolizers) those in humans receiving the maximum human dose.

Rats were treated with up to approximately 50 mg/kg/day of atomoxetine (approximately 6 times the maximum human dose on a mg/m² basis) in the diet from 2 weeks (females) or 10 weeks (males) prior to mating through the periods of organogenesis and lactation. In 1 of 2 studies, decreases in pup weight and pup survival were observed. The decreased pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study in which rats were treated with atomoxetine in the diet from 2 weeks (females) or 10 weeks (males) prior to mating throughout the period of organogenesis, a decrease in fetal weight (female only) and an increase in the incidence of incomplete ossification of the vertebral arch in fetuses were observed at 40 mg/kg/day (approximately 5 times the maximum human dose on a mg/m² basis) but not at 20 mg/kg/day.

No adverse fetal effects were seen when pregnant rats were treated with up to 150 mg/kg/day (approximately 17 times the maximum human dose on a mg/m² basis) by gavage throughout the period of organogenesis. No adequate and well-controlled studies have been conducted in pregnant women. PMS-Atomoxetine should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.

Labor And Delivery

Parturition in rats was not affected by atomoxetine. The effect of PMS-Atomoxetine on labor and delivery in humans is unknown.

Nursing Mothers

Atomoxetine and/or its metabolites were excreted in the milk of rats. It is not known if atomoxetine is excreted in human milk. Caution should be exercised if PMS-Atomoxetine is administered to a nursing woman.

Pediatric Use

Anyone considering the use of PMS-Atomoxetine in a child or adolescent must balance the potential risks with the clinical need. The pharmacokinetics of atomoxetine in children and adolescents are similar to those in adults. The safety, efficacy, and pharmacokinetics of PMS-Atomoxetine in pediatric patients less than 6 years of age have not been evaluated.

A study was conducted in young rats to evaluate the effects of atomoxetine on growth and neurobehavioral and sexual development. Rats were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8 times, respectively, the maximum human dose on a mg/m² basis) of atomoxetine given by gavage from the early postnatal period (Day 10 of age) through adulthood. Slight delays in onset of vaginal patency (all doses) and preputial separation (10 and 50 mg/kg), slight decreases in epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility or reproductive performance. A slight delay in onset of incisor eruption was seen at 50 mg/kg. A slight increase in motor activity was seen on Day 15 (males at 10 and 50 mg/kg and females at 50 mg/kg) and on Day 30 (females at 50 mg/kg) but not on Day 60 of age. There were no effects on learning and memory tests. The significance of these findings to humans is unknown.

Geriatric Use

The safety, efficacy and pharmacokinetics of PMS-Atomoxetine in geriatric patients have not been evaluated.

Hepatic Insufficiency

Atomoxetine exposure (AUC) is increased, compared with normal subjects, in EM subjects with moderate (Child-Pugh Class B) (2-fold increase) and severe (Child-Pugh Class C) (4-fold increase) hepatic insufficiency. Dosage adjustment is recommended for patients with moderate or severe hepatic insufficiency.

Renal Insufficiency

EM subjects with end stage renal disease had higher systemic exposure to atomoxetine than healthy subjects (about a 65% increase), but there was no difference when exposure was corrected for mg/kg dose. PMS-Atomoxetine can therefore be administered to ADHD patients with end stage renal disease or lesser degrees of renal insufficiency using the normal dosing regimen.

Gender

Gender did not influence atomoxetine disposition.

Ethnic Origin

Ethnic origin did not influence atomoxetine disposition (except that PMs are more common in Caucasians).

Patients With Concomitant Illness

Tics In Patients With ADHD And Comorbid Tourette’s Disorder

Atomoxetine administered in a flexible dose range of 0.5 to 1.5 mg/kg/day (mean dose of 1.3 mg/kg/day) and placebo were compared in 148 randomized pediatric (age 717 years) subjects with a DSM-IV diagnosis of ADHD and comorbid tic disorder in an 18 week, double-blind, placebo-controlled study in which the majority (80%) enrolled in this trial with Tourette’s Disorder (Tourette’s Disorder: 116 subjects; chronic motor tic disorder: 29 subjects). A non-inferiority analysis revealed that PMS-Atomoxetine did not worsen tics in these patients as determined by the Yale Global Tic Severity Scale Total Score (YGTSS). Out of 148 patients who entered the acute treatment phase, 103 (69.6%) patients discontinued the study. The primary reason for discontinuation in both the atomoxetine (38 of 76 patients, 50.0%) and placebo (45 of 72 patients, 62.5%) treatment groups was identified as lack of efficacy with most of the patients discontinuing at Week 12. This was the first visit where patients with a CGI-S≥4 could also meet the criteria for “clinical non-responder” (CGI-S remained the same or increased from study baseline) and be eligible to enter an open-label extension study with atomoxetine. There have been postmarketing reports of tics.

Anxiety In Patients With ADHD And Comorbid Anxiety Disorders

In two post-marketing, double-blind, placebo-controlled trials, it has been demonstrated that treating patients with ADHD and comorbid anxiety disorders with PMS-Atomoxetine does not worsen their anxiety.

In a 12-week double-blind, placebo-controlled trial, 176 patients, aged 8-17, who met DSM-IV criteria for ADHD and at least one of the anxiety disorders of separation anxiety disorder, generalized anxiety disorder or social phobia were randomized. Following a 2-week double-blind placebo lead-in, PMS-Atomoxetine was initiated at 0.8 mg/kg/day with increase to a target dose of 1.2 mg/kg/day (median dose 1.30 mg/kg/day +/-0.29 mg/kg/day). PMS-Atomoxetine did not worsen anxiety in these patients as determined by the Pediatric Anxiety Rating Scale (PARS). Of the 158 patients who completed the double-blind placebo lead-in, 26 (16%) patients discontinued the study.

In a separate 16-week, double-blind, placebo-controlled trial, 442 patients aged 18-65, who met DSM-IV criteria for adult ADHD and social anxiety disorder (23% of whom also had Generalized Anxiety Disorder) were randomized. Following a 2-week double-blind placebo lead-in, PMS-Atomoxetine was initiated at 40 mg/day to a maximum dose of 100 mg/day (mean daily dose 83 mg/day +/-19.5 mg/day). PMS-Atomoxetine did not worsen anxiety in these patients as determined by the Liebowitz Social Anxiety Scale (LSAS). Of the 413 patients who completed the double-blind placebo lead-in, 149 (36.1%) patients discontinued the study. There have been postmarketing reports of anxiety.

Clinical Trials Experience

PMS-Atomoxetine was administered to 5382 children or adolescent patients with ADHD and 1007 adults with ADHD in clinical studies. During the ADHD clinical trials, 1625 children and adolescent patients were treated for longer than 1 year and 2529 children and adolescent patients were treated for over 6 months.

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.

Child And Adolescent Clinical Trials

Reasons For Discontinuation Of Treatment Due To Adverse Reactions In Child And Adolescent Clinical Trials

In acute child and adolescent placebo-controlled trials, 3.0% (48/1613) of atomoxetine subjects and 1.4% (13/945) placebo subjects discontinued for adverse reactions. For all studies, (including open-label and long-term studies), 6.3% of extensive metabolizer (EM) patients and 11.2% of poor metabolizer (PM) patients discontinued because of an adverse reaction. Among PMS-Atomoxetine-treated patients, irritability (0.3%, N=5); somnolence (0.3%, N=5); aggression (0.2%, N=4); nausea (0.2%, N=4); vomiting (0.2%, N=4); abdominal pain (0.2%, N=4); constipation (0.1%, N=2); fatigue (0.1%, N=2); feeling abnormal (0.1%, N=2); and headache (0.1%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Seizures

PMS-Atomoxetine has not been systematically evaluated in pediatric patients with seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported in 0.2% (12/5073) of children whose average age was 10 years (range 6 to 16 years). In these clinical trials, the seizure risk among poor metabolizers was 0.3% (1/293) compared to 0.2% (11/4741) for extensive metabolizers.

Commonly Observed Adverse Reactions In Acute Child And Adolescent, Placebo-Controlled Trials

Commonly observed adverse reactions associated with the use of PMS-Atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (PMS-Atomoxetine incidence greater than placebo) are listed in Table 2. Results were similar in the BID and the QD trial except as shown in Table 3, which shows both BID and QD results for selected adverse reactions based on statistically significant Breslow-Day tests. The most commonly observed adverse reactions in patients treated with PMS-Atomoxetine (incidence of 5% or greater and at least twice the incidence in placebo patients, for either BID or QD dosing) were: nausea, vomiting, fatigue, decreased appetite, abdominal pain, and somnolence (see Tables 2 and 3).

Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of pediatric patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg).

Table 2: Common Treatment–Emergent Adverse Reactions Associated with the Use of PMS-Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials

Table 3: Common Treatment-Emergent Adverse Reactions Associated with the Use of PMS-Atomoxetine in Acute (up to 18 weeks) Child and Adolescent Trials

The following adverse reactions occurred in at least 2% of child and adolescent CYP2D6 PM patients and were statistically significantly more frequent in PM patients compared with CYP2D6 EM patients: insomnia (11% of PMs, 6% of EMs); weight decreased (7% of PMs, 4% of EMs); constipation (7% of PMs, 4% of EMs); depression1 (7% of PMs, 4% of EMs); tremor (5% of PMs, 1% of EMs); excoriation (4% of PMs, 2% of EMs); middle insomnia (3% of PMs, 1% of EMs); conjunctivitis (3% of PMs, 1% of EMs); syncope (3% of PMs, 1% of EMs); early morning awakening (2% of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs); sedation (4% of PMs, 2% of EMs).

¹Depression includes the following terms: depression, major depression, depressive symptoms, depressed mood, dysphoria.

Adult Clinical Trials

Reasons For Discontinuation Of Treatment Due To Adverse Reactions In Acute Adult Placebo-Controlled Trials

In the acute adult placebo-controlled trials, 11.3% (61/541) atomoxetine subjects and 3.0% (12/405) placebo subjects discontinued for adverse reactions. Among PMS-Atomoxetine-treated patients, insomnia (0.9%, N=5); nausea (0.9%, N=5); chest pain (0.6%, N=3); fatigue (0.6%, N=3); anxiety (0.4%, N=2); erectile dysfunction (0.4%, N=2); mood swings (0.4%, N=2); nervousness (0.4%, N=2); palpitations (0.4%, N=2); and urinary retention (0.4%, N=2) were the reasons for discontinuation reported by more than 1 patient.

Seizures

PMS-Atomoxetine has not been systematically evaluated in adult patients with a seizure disorder as these patients were excluded from clinical studies during the product’s premarket testing. In the clinical development program, seizures were reported on 0.1% (1/748) of adult patients. In these clinical trials, no poor metabolizers (0/43) reported seizures compared to 0.1% (1/705) for extensive metabolizers.

Commonly Observed Adverse Reactions In Acute Adult Placebo-Controlled Trials

Commonly observed adverse reactions associated with the use of PMS-Atomoxetine (incidence of 2% or greater) and not observed at an equivalent incidence among placebo-treated patients (PMS-Atomoxetine incidence greater than placebo) are listed in Table 4. The most commonly observed adverse reactions in patients treated with PMS-Atomoxetine (incidence of 5% or greater and at least twice the incidence in placebo patients) were: constipation, dry mouth, nausea, decreased appetite, dizziness, erectile dysfunction, and urinary hesitation (see Table 4). Additional data from ADHD clinical trials (controlled and uncontrolled) has shown that approximately 5 to 10% of adult patients experienced potentially clinically important changes in heart rate (≥20 beats per min) or blood pressure (≥15 to 20 mm Hg).

Table 4: Common Treatment-Emergent Adverse Reactions Associated with the Use of PMS-Atomoxetine in Acute (up to 25 weeks) Adult Trials

The following adverse events occurred in at least 2% of adult CYP2D6 poor metaboliser (PM) patients and were statistically significantly more frequent in PM patients compared to CYP2D6 extensive metaboliser (EM) patients: vision blurred (4% of PMs, 1% of EMs); dry mouth (35% of PMs, 17% of EMs); constipation (11% of PMs, 7% of EMs); feeling jittery (5% of PMs, 2% of EMs); decreased appetite (23% of PMs, 15% of EMs); tremor (5% of PMs, 1% of EMs); insomnia (19% of PMs, 11% of EMs); sleep disorder (7% of PMs, 3% of EMs); middle insomnia (5% of PMs, 3% of EMs); terminal insomnia (3% of PMs, 1% of EMs); urinary retention (6% of PMs, 1% of EMs); erectile dysfunction (21% of PMs, 9% of EMs); ejaculation disorder (6% of PMs, 2% of EMs); hyperhidrosis (15% of PMs, 7% of EMs); peripheral coldness (3% of PMs, 1% of EMs).

Male And Female Sexual Dysfunction

Atomoxetine appears to impair sexual function in some patients. Changes in sexual desire, sexual performance, and sexual satisfaction are not well assessed in most clinical trials because they need special attention and because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate the actual incidence. Table 4 above displays the incidence of sexual side effects reported by at least 2% of adult patients taking PMS-Atomoxetine in placebo-controlled trials.

There are no adequate and well-controlled studies examining sexual dysfunction with PMS-Atomoxetine treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of PMS-Atomoxetine, physicians should routinely inquire about such possible side effects.

Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval use of PMS-Atomoxetine. Unless otherwise specified, these adverse reactions have occurred in adults and children and adolescents. 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.

Cardiovascular system - QT prolongation, syncope.

Peripheral vascular effects - Raynaud’s phenomenon.

General disorders and administration site conditions - Lethargy.

Musculoskeletal system - Rhabdomyolysis.

Nervous system disorders - Hypoaesthesia; paraesthesia in children and adolescents; sensory disturbances; tics.

Psychiatric disorders - Depression and depressed mood; anxiety, libido changes.

Seizures - Seizures have been reported in the postmarketing period. The postmarketing seizure cases include patients with pre-existing seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between PMS-Atomoxetine and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in ADHD patients.

Skin and subcutaneous tissue disorders - Alopecia, hyperhidrosis.

Urogenital system - Male pelvic pain; urinary hesitation in children and adolescents; urinary retention in children and adolescents.

İnsan Deneyimi

PMS-Atomoksetin doz aşımı ile sınırlı klinik araştırma deneyimi vardır. Pazarlama sonrası dönemde, PMS-Atomoksetin ve en az bir başka ilacın aşırı dozda yutulmasıyla ilgili ölümler bildirilmiştir. 1400 mg'a kadar kasıtlı aşırı dozlar da dahil olmak üzere, sadece PMS-Atomoksetinin aşırı dozunu içeren ölüm raporları yoktur. PMS-Atomoksetin içeren bazı aşırı doz vakalarında, nöbetler bildirilmiştir. PMS-Atomoksetinin akut ve kronik aşırı dozlarına eşlik eden en sık bildirilen semptomlar gastrointestinal semptomlar, uyku hali, baş dönmesi, titreme ve anormal davranıştı. Hiperaktivite ve ajitasyon da bildirilmiştir. Hafif ila orta şiddette sempatik sinir sistemi aktivasyonu ile uyumlu belirti ve semptomlar (ör.taşikardi, kan basıncı arttı, midriyazis, ağız kuruluğu) da gözlendi. Çoğu olay hafif ila orta şiddettedir. Daha az yaygın olarak, QT uzaması ve yönelim bozukluğu ve halüsinasyonlar dahil zihinsel değişiklikler bildirilmiştir.

Doz aşımı yönetimi

Güncel rehberlik ve tavsiye için Sertifikalı Zehir Kontrol Merkezi'ne danışın. Atomoksetin yüksek oranda proteine bağlı olduğundan, diyalizin aşırı doz tedavisinde yararlı olması muhtemel değildir.

Atomoksetin (0.5, 1.2 veya 1.8 mg / kg / gün) veya plasebo ile gösterilen atomoksetin maruziyetini kapsayan bir maruziyet-yanıt analizi, Dikkat Eksikliği / Hiperaktivite Bozukluğu Derecelendirme Ölçeği-IV-Ebeveyn Versiyonu ile ölçülen etkinlik ile ilişkilidir: Araştırmacı uygulanır ve puanlanır. Maruz kalma-etkinlik ilişkisi, başlangıçtan maksimum maksimum değişikliklere yol açan en yüksek iki dozda medyan maruziyetlerle doz ve etkinlik arasında gözlemlenene benzerdi.

Kardiyak Elektrofizyoloji

PMS-Atomoksetinin QTc uzaması üzerindeki etkisi, sağlıklı erkek CYP2D6 zayıf metabolizörlerinde randomize, çift kör, pozitif (moksifloksasin 400 mg) ve plasebo kontrollü, çapraz çalışmada değerlendirildi. Toplam 120 sağlıklı deneğe 7 gün boyunca günde iki kez PMS-Atomoksetin (20 mg ve 60 mg) uygulandı. QTc aralığında büyük değişiklik yok (ör., taban çizgisinden> 60 msn artış, mutlak QTc> 480 msn) çalışma sırasında gözlenmiştir. Bununla birlikte, QTc aralığındaki küçük değişiklikler mevcut çalışmadan çıkarılamaz, çünkü çalışma test duyarlılığını gösteremedi. Artmış atomoksetin konsantrasyonu ile QTc aralığında hafif bir artış oldu.

Atomoksetin oral uygulamadan sonra iyi emilir ve gıdalardan minimal düzeyde etkilenir. Öncelikle sitokrom P450 2D6 (CYP2D6) enzimatik yolu ve daha sonra glukuronidasyon yoluyla oksidatif metabolizma ile elimine edilir. Atomoksetinin yarı ömrü yaklaşık 5 saattir. Nüfusun bir kısmı (Kafkasyalıların yaklaşık% 7'si ve Afrikalı Amerikalıların% 2'si) CYP2D6 metabolize ilaçların zayıf metabolizmalarıdır (PM). Bu bireyler, normal aktiviteye sahip insanlara kıyasla 10 kat daha yüksek AUC, 5 kat daha yüksek pik plazma konsantrasyonları ve daha yavaş eliminasyon (yaklaşık 24 saatlik plazma yarılanma ömrü) ile sonuçlanan bu yoldaki aktiviteyi azaltmıştır [kapsamlı metabolizörler (EM'ler) )]. Fluoksetin, paroksetin ve kinidin gibi CYP2D6'yı inhibe eden ilaçlar, maruziyette benzer artışlara neden olur.

Atomoksetinin farmakokinetiği, seçilmiş klinik çalışmalarda 400'den fazla çocuk ve ergende, öncelikle popülasyon farmakokinetik çalışmaları kullanılarak değerlendirilmiştir. Çocuklarda, ergenlerde ve yetişkinlerde tek doz ve kararlı durum bireysel farmakokinetik veriler de elde edilmiştir. Tavuk dozları mg / kg bazında normalleştirildi, çocuklarda, ergenlerde ve yetişkinlerde benzer yarılanma ömrü, Cmax ve AUC değerleri gözlendi. Vücut ağırlığı ayarlamasından sonra boşluk ve dağılım hacmi de benzerdi.

Emilim ve Dağıtım

Atomoksetin oral uygulamadan sonra hızla emilir, EM'lerde yaklaşık% 63 ve PM'lerde% 94 mutlak biyoyararlanım olur. Maksimum plazma konsantrasyonlarına (Cmax) dozlamadan yaklaşık 1 ila 2 saat sonra ulaşılır.

PMS-Atomoksetin, yiyecekle birlikte veya yiyeceksiz uygulanabilir. PMS-Atomoksetinin yetişkinlerde standart yüksek yağlı bir yemekle uygulanması, atomoksetinin (EAA) oral emilim derecesini etkilemedi, ancak emilim oranını düşürdü, bu da% 37 daha düşük Cmax ve Tmax'ı 3 saat geciktirdi . Çocuklarla ve ergenlerle yapılan klinik çalışmalarda, PMS-Atomoksetinin gıda ile uygulanması% 9 daha düşük Cmax ile sonuçlanmıştır.

İntravenöz uygulamadan sonra kararlı durum dağılım hacmi 0.85 L / kg'dır, bu da atomoksetinin öncelikle toplam vücut suyuna dağıldığını gösterir. Vücut ağırlığı için normalleştirildikten sonra dağılım hacmi hasta ağırlık aralığında benzerdir.

Terapötik konsantrasyonlarda, plazmada atomoksetinin% 98'i öncelikle albümin olmak üzere proteine bağlanır.

Metabolizma ve Eliminasyon

Atomoksetin öncelikle CYP2D6 enzimatik yolu yoluyla metabolize edilir. Bu yolda (PM) aktivitesi azalmış olan kişiler, normal aktiviteye (EM) sahip olanlara kıyasla daha yüksek plazma atomoksetin konsantrasyonlarına sahiptir. PM'ler için, atomoksetinin EAA değeri yaklaşık 10 kat ve Css, maks EM'lerden yaklaşık 5 kat daha fazladır. CYP2D6 PM'leri tanımlamak için laboratuvar testleri mevcuttur. PMS-Atomoksetinin, fluoksetin, paroksetin veya kinidin gibi güçlü CYP2D6 inhibitörleri ile birlikte uygulanması, atomoksetin plazma maruziyetinde önemli bir artışa neden olur ve doz ayarlaması gerekebilir. Atomoksetin CYP2D6 yolunu inhibe etmedi veya indüklemedi.

CYP2D6 durumuna bakılmaksızın oluşan ana oksidatif metabolit, glukuronidatlanmış 4-hidroksiatomoksetindir. 4-Hidroksiatomoksetin, norepinefrin taşıyıcısının bir inhibitörü olarak atomoksetine eşdeğerdir, ancak plazmada çok daha düşük konsantrasyonlarda (EM'lerde atomoksetin konsantrasyonunun% 1'i ve PM'lerde atomoksetin konsantrasyonunun% 0.1'i) dolaşır. 4-Hidroksiatomoksetin öncelikle CYP2D6 tarafından oluşturulur, ancak PM'lerde 4-hidroksiatomoksetin, diğer birkaç sitokrom P450 enzimi tarafından daha yavaş bir oranda oluşturulur. N-Desmetatomoksetin, CYP2C19 ve diğer sitokrom P450 enzimleri tarafından oluşturulur, ancak atomoksetine kıyasla önemli ölçüde daha az farmakolojik aktiviteye sahiptir ve daha düşük konsantrasyonlarda (EM'lerde atomoksetin konsantrasyonunun% 5'i ve PM'lerde atomoksetin konsantrasyonunun% 45'i) plazmada dolaşır.

Yetişkin EM'lerde oral uygulamadan sonra atomoksetinin ortalama plazma klerensi 0.35 L / saat / kg ve ortalama yarılanma ömrü 5.2 saattir. Atomoksetinin PM'lere oral yoldan verilmesinden sonra, ortalama görünür plazma klerensi 0.03 L / saat / kg ve ortalama yarılanma ömrü 21.6 saattir. PM'ler için, atomoksetinin EAA değeri yaklaşık 10 kat ve Css, maks EM'lerden yaklaşık 5 kat daha fazladır. 4-hidroksiatomoksetinin eliminasyon yarılanma ömrü EM deneklerinde N-desmetilatomoksetinin (6 ila 8 saat)kine benzerken, N-desmetilatomoksetinin yarılanma ömrü PM deneklerinde (34 ila 40 saat) çok daha uzundur.

Atomoksetin esas olarak idrarda (dozun% 80'inden fazla) ve daha az oranda dışkıda (dozun% 17'sinden az) 4-hidroksiatomoksetin-O-glukuronid olarak atılır. PMS-Atomoksetin dozunun sadece küçük bir kısmı değişmemiş atomoksetin (dozun% 3'ünden az) olarak atılır ve bu da kapsamlı biyotransformasyonu gösterir.

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