Kompozisyon:
Tedavide kullanılır:
Kovalenko Svetlana Olegovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 22.03.2022
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Aynı bileşenlere sahip en iyi 20 ilaç:
Aynı kullanıma sahip ilk 20 ilaç:
Dozaj Formları ve Güçlü Yönleri
Enjeksiyon: 50 mg / 10 mL (5 mg / mL)
Enjeksiyon: 200 mg / 40 mL (5 mg / mL)
Depolama ve Taşıma
YERVOY şu şekilde mevcuttur:
Karton İçeriği | NDC |
Bir 50 mg flakon (5 mg / mL), tek kullanımlık flakon | NDC 0003-2327-11 |
Bir 200 mg flakon (5 mg / mL), tek kullanımlık flakon | NDC 0003-2328-22 |
YERVOY'u 2 ° C ila 8 ° C (36 ° F ila 46 ° F) arasında soğutma altında saklayın. Dondurmayın. Şişeleri ışıktan koruyun.
Üretici: Bristol-Myers Squibb Company, Princeton, NJ 08543 ABD. Revize: Aralık 2017
İncelenemez veya Metastatik Melanom
YERVOY, yetişkinlerde ve pediatrik hastalarda (12 yaş ve üstü) rezektabl veya metastatik melanom tedavisi için endikedir.
Melanomun Adjuvan Tedavisi
YERVOY, toplam lenfadenektomi dahil olmak üzere tam rezeksiyon geçirmiş olan 1 mm'den fazla bölgesel lenf düğümlerinin patolojik tutulumu olan kutanöz melanomlu hastaların adjuvan tedavisi için endikedir.
İncelenemez veya Metastatik Melanom İçin Önerilen Dozlama
Önerilen YERVOY dozu, maksimum 4 doz için her 3 haftada bir 90 dakika boyunca intravenöz olarak uygulanan 3 mg / kg'dır. Toksisite durumunda, dozlar gecikebilir, ancak tüm tedavi ilk dozdan sonraki 16 hafta içinde uygulanmalıdır.
Melanomun Adjuvan Tedavisi İçin Önerilen Dozlama
Önerilen YERVOY dozu, 4 doz için her 3 haftada bir 90 dakika boyunca intravenöz olarak uygulanan 10 mg / kg, ardından 3 yıla kadar 12 haftada bir 10 mg / kg'dır. Toksisite durumunda, dozlar atlanır, gecikmez.
Önerilen Doz Değişiklikleri
Tablo 1: YERVOY'un Bağışıklık Aramalı Olumsuz Reaksiyonları için Önerilen Tedavi Değişiklikleri
Hedef / Organ Sistemi | Olumsuz Reaksiyon (CTCAE v4) | Tedavi Değişikliği |
Endokrin | Semptomatik endokrinopati | Olumsuz reaksiyonların tam veya kısmi çözünürlüğü (Sınıf 0 ila 1) olan ve günde 7.5 mg'dan az prednizon veya eşdeğeri alan hastalarda YERVOY'u durdurun. |
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YERVOY'u kalıcı olarak bırakın | |
Oftalmolojik | Derece 2 ila 4 reaksiyonlar
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YERVOY'u kalıcı olarak bırakın |
Diğer Tüm | Derece 2 | Olumsuz reaksiyonların tam veya kısmi çözünürlüğü (Sınıf 0 ila 1) olan ve günde 7.5 mg'dan az prednizon veya eşdeğeri alan hastalarda YERVOY'u durdurun. |
|
YERVOY'u kalıcı olarak bırakın |
Hazırlık ve Yönetim
- Ürünü sallamayın.
- Uygulamadan önce parenteral ilaç ürünlerini partikül madde ve renk değişikliği açısından görsel olarak inceleyin. Çözelti bulanıksa, belirgin renk değişikliği varsa (çözüm soluk sarı renge sahip olabilir) veya yarı saydam towhite, amorf parçacıklar dışında yabancı partikül madde varsa flakonu atın.
Çözümün Hazırlanması
- İnfüzyon hazırlanmadan önce şişelerin oda sıcaklığında yaklaşık 5 dakika bekletin.
- Gerekli miktarda YERVOY'u geri çekin ve intravenöz bir torbaya aktarın.
- 1 mg / mL ila 2 mg / mL arasında değişen nihai konsantrasyona sahip seyreltilmiş bir çözelti hazırlamak için% 0.9 Sodyum Klorür Enjeksiyonu, USP veya% 5 Dekstroz Enjeksiyonu, USP ile seyreltin. Seyreltilmiş çözeltiyi hafif ters çevirme ile karıştırın.
- Seyreltilmiş çözeltiyi 24 saatten fazla soğutma altında (2 ° C ila 8 ° C, 36 ° F ila 46 ° F) veya oda sıcaklığında (20 ° C ila 25 ° C, 68 ° F ila 77 ° F) saklayın.
- Kısmen kullanılmış şişeleri veya boş YERVOY şişelerini atın
Yönetim Talimatları
- YERVOY'u diğer tıbbi ürünlerle karıştırmayın veya infüzyon olarak uygulamayın.
- İntravenöz çizgiyi her dozdan sonra% 0.9 Sodyum Klorür Enjeksiyonu, USP veya% 5 Dekstroz Enjeksiyonu, USP ile yıkayın.
- Seyreltilmiş çözeltiyi steril, pirojenik olmayan, düşük protein bağlayıcılı bir hat içi filtre içeren intravenöz bir çizgiden 90 dakika boyunca uygulayın.
Yok.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
YERVOY can result in severe and fatal immune-mediated reactions.
Immune-Mediated Enterocolitis
Immune-mediated enterocolitis, including fatal cases, can occur with YERVOY.
Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.
Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Consider adding anti-TNF or other immunosuppressant agents for management of immune-mediated enterocolitis unresponsive to systemic corticosteroids within 3 to 5 days or recurring after symptom improvement.
Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than 1 week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent.
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3 to 5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%), and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY-treated patients (5%). Across all YERVOY-treated patients (n=511), 5 patients (1%) developed intestinal perforation, 4 patients (0.8%) died as a result of complications, and 26 patients (5%) were hospitalized for severe enterocolitis.
The median time to onset of Grade 3 to 5 enterocolitis was 1.7 months (range: 11 days to 3.1 months) and for Grade 2 enterocolitis was 1.4 months (range: 2 days to 4.3 months).
Twenty-nine patients (85%) with Grade 3 to 5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 16 days (ranging up to 3.2 months) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 1.2 months, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 (8%) of the 62 patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.
Of the 34 patients with Grade 3 to 5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.
Adjuvant Treatment Of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68 patients (14%). Seven patients (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications.
The median time to onset for Grade 3 to 4 enterocolitis was 1.1 months (range: 1 day to 33.1 months) and for Grade 2 enterocolitis was 1.1 months (range: 1 day to 20.6 months).
Seventy-one patients (95%) with Grade 3 to 4 enterocolitis were treated with systemic corticosteroids. The median duration of treatment was 4.7 months (ranging up to 52.3 months).
Of the 68 patients with moderate enterocolitis, 51 patients (75%) were treated with systemic corticosteroids with a median duration of treatment of 3.5 months (ranging up to 52.2 months). Non-corticosteroids immunosuppression, consisting almost exclusively of infliximab, was used to treat 36% of patients with Grade 3 to 4 enterocolitis and 15% of patients with a Grade 2 event.
Of the 75 patients with Grade 3 to 4 immune-mediated enterocolitis, 86% experienced complete resolution, 3% experienced improvement to Grade 1, and 11% did not improve. Among the 68 patients with Grade 2 enterocolitis, 94% experienced complete resolution, 3% experienced improvement to Grade 1, and 3% did not improve.
Immune-Mediated Hepatitis
Immune-mediated hepatitis, including fatal cases, can occur with YERVOY.
Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.
Permanently discontinue YERVOY in patients with Grade 3 to 4 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity.
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3 to 5) occurred in 8 YERVOY-treated patients (2%), with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 patients (2.5%) experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.
Adjuvant Treatment Of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3 to 4 hepatitis showed evidence of toxic or autoimmune hepatitis. The median time to onset for Grade 3 to 4 hepatitis was 2.0 months (range: 1 day to 4.2 months) and for Grade 2 hepatitis was 1.4 months (range: 13 days to 6.5 months). Of the 51 patients with Grade 3 to 4 immune-mediated hepatitis, 94% experienced complete resolution, 4% experienced improvement to Grade 1, and 2% did not improve. Of the 22 patients with Grade 2 immune-mediated hepatitis, 91% experienced complete resolution and 9% did not improve.
Forty-six patients (90%) with Grade 3 to 4 hepatitis were treated with systemic corticosteroids. The median duration of treatment was 4.4 months (ranging up to 56.1 months). Sixteen patients (73%) with moderate hepatitis were treated with systemic corticosteroids. The median duration of treatment was 2.6 months (ranging up to 41.4 months).
Concurrent Administration With Vemurafenib
In a dose-finding trial, Grade 3 increases in transaminases with or without concomitant increases in total bilirubin occurred in 6 of 10 patients who received concurrent YERVOY (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).
Immune-Mediated Dermatitis
Immune-mediated dermatitis, including fatal cases, can occur with YERVOY.
Monitor patients for signs and symptoms of dermatitis, such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.
Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms.
For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe, life-threatening, or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3 to 5) occurred in 13 YERVOY-treated patients (2.5%). One patient (0.2%) died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 patients (12%) with moderate (Grade 2) dermatitis.
The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 22 days and ranged up to 4.0 months from the initiation of YERVOY.
Seven YERVOY-treated patients (54%) with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 3.4 months followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 3.6 months.
Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 15 days, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four patients (70%) with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.
Adjuvant Treatment Of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate (Grade 2) dermatitis. The median time to onset for Grade 3 to 4 dermatitis was 14 days (range: 5 days to 11.3 months) and for Grade 2 dermatitis was 11 days (range: 1 day to 16.6 months).
Sixteen patients (84%) with Grade 3 to 4 dermatitis were treated with systemic corticosteroids for a median of 21 days (ranging up to 49.2 months) resulting in complete resolution of dermatitis within a median time of 4.3 months (range up to 44.4 months). Of the 3 patients (16%) not treated with systemic or topical corticosteroids, 2 (11%) had complete resolution and 1 had improvement to Grade 1.
Of the 99 patients with Grade 2 dermatitis, 67 (68%) were treated with systemic corticosteroids for a median of 2.6 months, 16 (16%) were treated with only topical corticosteroids and 16 (16%) did not receive systemic or topical corticosteroids. Seventy-seven patients (78%) had complete resolution, 15 (15%) improved to mild (Grade 1) severity, and 7 (7%) did not improve.
Immune-Mediated Neuropathies
Immune-mediated neuropathies, including fatal cases, can occur with YERVOY.
Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities).
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.
Adjuvant Treatment Of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain-Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%).
The time to onset across the 9 patients with Grade 2 to 5 immune-mediated neuropathy ranged from 1.4 to 27.4 months. All 8 patients with Grade 3 to 5 neuropathy were treated with systemic corticosteroids (range: 3 days to 38.3 months) and 3 also received tacrolimus. Four of the 8 patients with Grade 3 to 5 immune-mediated neuropathy experienced complete resolution, 1 improved to Grade 1, and 3 did not improve. The single patient with Grade 2 immune-mediated neuropathy experienced complete resolution without the use of corticosteroids.
Immune-Mediated Endocrinopathies
Immune-mediated endocrinopathies, including life-threatening cases, can occur with YERVOY.
Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper-or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.
Monitor clinical chemistries, adrenocorticotropic hormone (ACTH) level, and thyroid function tests at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.
Withhold YERVOY dosing in symptomatic patients and consider referral to an endocrinologist. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy.
Metastatic Melanoma
In patients receiving YERVOY 3 mg/kg in Trial 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3 to 4) occurred in 9 YERVOY-treated patients (1.8%). All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 patients (2.3%) and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 2.5 months and ranged up to 4.4 months after the initiation of YERVOY.
Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).
Adjuvant Treatment Of Melanoma
In patients receiving YERVOY 10 mg/kg in Trial 2, Grade 3 to 4 immune-mediated endocrinopathies occurred in 39 patients (8%) and Grade 2 immune-mediated endocrinopathies in 93 patients (20%). Of the 39 patients with Grade 3 to 4 immune-mediated endocrinopathies, 35 patients had hypopituitarism (associated with one or more secondary endocrinopathies, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 3 patients had hyperthyroidism, and 1 had primary hypothyroidism. The median time to onset of Grade 3 to 4 immune-mediated endocrinopathy was 2.2 months (range: 2 days to 8 months). Twenty-seven of the 39 patients (69%) were hospitalized for immune-mediated endocrinopathies, and 4 patients (10%) were reported to have resolution.
Of the 93 patients with Grade 2 immune-mediated endocrinopathy, 74 had primary hypopituitarism (associated with one or more secondary endocrinopathy, e.g., adrenal insufficiency, hypogonadism, and hypothyroidism), 9 had primary hypothyroidism, 3 had hyperthyroidism, 3 had thyroiditis with hypo-or hyperthyroidism, 2 had hypogonadism, 1 had both hyperthyroidism and hypopituitarism, and 1 subject developed Graves’ ophthalmopathy. The median time to onset of Grade 2 immune-mediated endocrinopathy was 2.1 months (range: 9 days to 19.3 months), and 20% were reported to have resolution.
One hundred twenty-four patients received systemic corticosteroids as immunosuppression and/or adrenal hormone replacement for Grade 2 to 4 immune-mediated endocrinopathy. Of these, 42 (34%) were able to discontinue corticosteroids. Seventy-three patients received thyroid hormones for treatment of Grade 2 to 4 immune-mediated hypothyroidism. Of these, 14 patients (19%) were able to discontinue thyroid replacement therapy.
Other Immune-Mediated Adverse Reactions, Including OcularManifestations
Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.
Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Haradalike syndrome, which has been observed in patients receiving YERVOY and may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Metastatic Melanoma
In Trial 1, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.
Adjuvant Treatment Of Melanoma
In Trial 2, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients unless specified: eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis.
Other Clinical Experience
Across 21 dose-ranging trials administering YERVOY at doses of 0.1 to 20 mg/kg (n=2478), the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, ocular myositis, hemolytic anemia, and nephritis.
Embryo-fetal Toxicity
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
Inform patients of the potential risk of immune-mediated adverse reactions.
Embryo-Fetal Toxicity
Advise female patients that YERVOY can cause fetal harm. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months after the last dose. Advise female patients to contact their healthcare provider with a known or suspected pregnancy. Advise females who may have been exposed to YERVOY during pregnancy to contact Bristol-Myers Squibb at 1-800-721-5072.
Advise patients that there is a Pregnancy Safety Surveillance Study that monitors pregnancy outcomes in women exposed to YERVOY during pregnancy, and they can be enrolled by calling 1-844-593-7869.
Lactation
Advise women not to breastfeed during treatment with YERVOY and for 3 months after the last dose.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
The carcinogenic potential of ipilimumab has not been evaluated in long-term animal studies, and the genotoxic potential of ipilimumab has not been evaluated.
Fertility studies have not been performed with ipilimumab.
Use In Specific Populations
Pregnancy
Risk Summary
Based on data from animal studies and its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of ipilimumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in higher incidences of abortion, stillbirth, premature delivery (with corresponding lower birth weight), and higher incidences of infant mortality in a dose-related manner (see Data). The effects of ipilimumab are likely to be greater during the second and third trimesters of pregnancy. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus. There is insufficient human data for YERVOY exposure in pregnant women. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
A Pregnancy Safety Surveillance Study has been established to collect information about pregnancies in women who have received YERVOY. Healthcare providers are encouraged to enroll patients or have their patients enroll directly by calling 1-844-593-7869.
Data
Animal Data
In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition. No treatment-related adverse effects on reproduction were detected during the first two trimesters of pregnancy. Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality. In addition, developmental abnormalities were identified in the urogenital system of 2 infant monkeys exposed in utero to 30 mg/kg of ipilimumab (7.2 times the AUC in humans at the 3 mg/kg dose). One female infant monkey had unilateral renal agenesis of the left kidney and ureter, and 1 male infant monkey had an imperforate urethra with associated urinary obstruction and subcutaneous scrotal edema.
Genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/−), the target for ipilimumab, appeared healthy and gave birth to healthy CTLA-4+/− heterozygous offspring. Mated CTLA-4+/− heterozygous mice also produced offspring deficient in CTLA-4 (homozygous negative, CTLA-4−/−). The CTLA-4−/− homozygous negative offspring appeared healthy at birth, exhibited signs of multiorgan lymphoproliferative disease by 2 weeks of age, and all died by 3 to 4 weeks of age with massive lymphoproliferation and multiorgan tissue destruction.
Lactation
Risk Summary
It is not known whether YERVOY is present in human milk. In monkeys, ipilimumab was present in milk (see Data). There are no data to assess the effects of YERVOY on milk production. Advise women to discontinue nursing during treatment with YERVOY and for 3 months following the final dose.
Data
In monkeys treated at dose levels resulting in exposures 2.6 and 7.2 times higher than those in humans at a 3 mg/kg dose, ipilimumab was present in milk at concentrations of 0.1 mcg/mL and 0.4 mcg/mL, representing a ratio of up to 0.3% of the steady-state serum concentration of the drug.
Females And Males Of Reproductive Potential
Contraception
Based on its mechanism of action, YERVOY can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with YERVOY and for 3 months following the last dose of YERVOY.
Pediatric Use
The safety and effectiveness of YERVOY have been established in pediatric patients 12 years and older. Use of YERVOY in this age group is supported by evidence from adequate and well-controlled studies of YERVOY in adults and population pharmacokinetic data demonstrating that the exposure at a dose of 3 mg/kg in the pediatric and adult populations is comparable. In addition, the tumor biology and course of advanced melanoma is sufficiently similar in adults and pediatric patients 12 years and older to allow extrapolation of data from adults to pediatric patients.
The safety and effectiveness for pediatric patients less than 12 years of age has not been established.
YERVOY was evaluated in a total of 45 pediatric patients across two clinical trials. In a dose-finding trial, 33 pediatric patients with relapsed or refractory solid tumors were evaluated. The median age was 13 years (range 2 to 21 years), and 20 patients were ≥12 years old. YERVOY was administered at doses of 1, 3, 5, and 10 mg/kg intravenously over 90 minutes every 3 weeks for 4 doses and then every 12 weeks thereafter until progression or treatment discontinuation.
YERVOY was also evaluated in an open-label, single-arm, trial in 12 pediatric patients ≥12 years old (range 12 to 16 years) with previously treated or untreated, unresectable Stage 3 or 4 malignant melanoma. Patients received YERVOY 3 mg/kg (4 patients) or 10 mg/kg (8 patients) intravenously over 90 minutes every 3 weeks for 4 doses.
Of the 17 patients ≥12 years of age with melanoma treated with YERVOY across both studies, two patients experienced objective responses including one partial response that was sustained for 16 months. There were no responses in patients with non-melanoma solid tumors.
The overall safety profile of YERVOY in children and adolescents was consistent with the safety profile in adults.
Pediatric Pharmacokinetics (PK)
Based on a population PK analysis using available pooled data from 565 patients from 4 phase 2 adult studies (N=521) and 2 pediatric studies (N=44), body weight normalized clearance of ipilimumab is comparable between adult and pediatric patients. In pediatric patients with a dosing regimen of 3 mg/kg every 3 weeks, the model simulated geometric mean (CV%) steady-state serum peak and trough concentrations of ipilimumab were 65.8 (17.6%) and 20.7 (33.1%) mcg/mL (for 2 to 6 years old), 70.1 (19.6%) and 19.6 (42.9%) mcg/mL (for 6 to <12 years old), and 73.3 (20.6%) and 17.8 (50.8%) mcg/mL (for 12 years and older), which are comparable to those in adult patients.
Geriatric Use
Of the 511 patients treated with YERVOY in Trial 1, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).
Trial 2 did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.
Renal Impairment
No dose adjustment is needed for patients with renal impairment.
Hepatic Impairment
No dose adjustment is needed for patients with mild hepatic impairment (total bilirubin [TB] >1.0 to 1.5 times the upper limit of normal [ULN] or AST >ULN). YERVOY has not been studied in patients with moderate (TB >1.5 to 3.0 times ULN and any AST) or severe (TB >3 times ULN and any AST) hepatic impairment.
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
- Immune-mediated enterocolitis.
- Immune-mediated hepatitis.
- Immune-mediated dermatitis.
- Immune-mediated neuropathies.
- Immune-mediated endocrinopathies.
- Other immune-mediated adverse reactions, including ocular manifestations.
In patients receiving YERVOY 3 mg/kg for unresectable or metastatic melanoma in Trial 1, 15% of patients receiving monotherapy and 12% of patients treated in combination with gp100 peptide vaccine experienced Grade 3 to 5 immune-mediated reactions. In patients receiving YERVOY 10 mg/kg for adjuvant treatment of melanoma in Trial 2, 41% experienced Grade 3 to 5 immune-mediated reactions.
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.
The data described below reflect exposure to YERVOY 3 mg/kg in Trial 1, a randomized trial in patients with unresectable or metastatic melanoma and to YERVOY 10 mg/kg in Trial 2, a randomized trial in patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma.
Clinically significant adverse reactions were evaluated in a total of 982 patients treated in Trials 1 and 2 and in 21 dose-ranging trials (n=2478) administering YERVOY at doses of 0.1 to 20 mg/kg.
Unresectable Or Metastatic Melanoma
The safety of YERVOY was evaluated in Trial 1, a randomized, double-blind clinical trial in which 643 previously treated patients with unresectable or metastatic melanoma received YERVOY 3 mg/kg for 4 doses given by intravenous infusion as a single agent (n=131), YERVOY with an investigational gp100 peptide vaccine (gp100) (n=380), or gp100 peptide vaccine as a single agent (n=132). Patients in the trial received a median of 4 doses (range: 1 to 4 doses).
Trial 1 excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation.
The trial population characteristics were: median age 57 years (range: 19 to 90), 59% male, 94% white, and baseline ECOG performance status 0 (56%).
YERVOY was discontinued for adverse reactions in 10% of patients.
Table 2 presents selected adverse reactions from Trial 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3 to 5 events.
Table 2: Selected Adverse Reactions in Trial 1
Percentage (%) of Patientsa | ||||||
YERVOY 3 mg/kg n=131 |
YERVOY 3 mg/kg+gp100 n=380 |
gp100 n=132 |
||||
System Organ Class/ Preferred Term | Any Grade | Grade 3 to 5 | Any Grade | Grade 3 to 5 | Any Grade | Grade 3 to 5 |
General Disorders and Administration-Site Conditions | ||||||
Fatigue | 41 | 7 | 34 | 5 | 31 | 3 |
Gastrointestinal Disorders | ||||||
Diarrhea | 32 | 5 | 37 | 4 | 20 | 1 |
Colitis | 8 | 5 | 5 | 3 | 2 | 0 |
Skin and Subcutaneous Tissue Disorders | ||||||
Pruritus | 31 | 0 | 21 | <1 | 11 | 0 |
Rash | 29 | 2 | 25 | 2 | 8 | 0 |
a Incidences presented in this table are based on reports of adverse events regardless of causality. |
Table 3: Severe to Fatal Immune-Mediated Adverse Reactions in Trial 1
Percentage (%) of Patients | ||
YERVOY 3 mg/kg n=131 |
YERVOY 3 mg/kg+gp100 n=380 |
|
Any Immune-Mediated Adverse Reaction | 15 | 12 |
Enterocolitisa,b | 7 | 7 |
Hepatotoxicitya | 1 | 2 |
Dermatitisa | 2 | 3 |
Neuropathya | 1 | <1 |
Endocrinopathy | 4 | 1 |
Hypopituitarism | 4 | 1 |
Adrenal insufficiency | 0 | 1 |
Other | ||
Pneumonitis | 0 | <1 |
Meningitis | 0 | <1 |
Nephritis | 1 | 0 |
Eosinophiliac | 1 | 0 |
Pericarditisa,c | 0 | <1 |
a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established |
Adjuvant Treatment Of Melanoma
The safety of YERVOY was evaluated in Trial 2, a randomized (1:1), double-blind, placebo-controlled trial in which 945 patients with resected Stage IIIA (>1 mm nodal involvement), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma received YERVOY 10 mg/kg (n=471) or placebo (n=474) administered as an intravenous infusion for 4 doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at Week 24 up to a maximum of 3 years. In this trial, 36% of patients received YERVOY for longer than 6 months and 26% of patients received YERVOY for longer than 1 year. YERVOY-treated patients in the trial received a median of 4 doses (range: 1 to 16).
Trial 2 excluded patients with prior systemic therapy for melanoma, autoimmune disease, a condition requiring systemic immunosuppression, or a positive test for hepatitis B, hepatitis C, or HIV.
The trial population characteristics were: median age 51 years (range: 18 to 84 years), 62% male, 99% white, and baseline ECOG performance status 0 (94%).
YERVOY was discontinued for adverse reactions in 52% of patients.
Table 4 presents selected adverse reactions from Trial 2 which occurred in at least 5% of YERVOY-treated patients and with at least 5% increased incidence over the placebo group for all-grade events.
Table 4: Selected Adverse Reactions in Trial 2
System Organ Class/ Preferred Term | Percentage (%) of Patientsa | |||
YERVOY 10 mg/kg n=471 |
Placebo n=474 |
|||
Any Grade | Grade 3 to 5 | Any Grade | Grade 3 to 5 | |
Skin and Subcutaneous Tissue Disorders | ||||
Rash | 50 | 2.1 | 20 | 0 |
Pruritus | 45 | 2.3 | 15 | 0 |
Gastrointestinal Disorders | ||||
Diarrhea | 49 | 10 | 30 | 2.1 |
Nausea | 25 | 0.2 | 18 | 0 |
Colitisb | 16 | 8 | 1.5 | 0.4 |
Vomiting | 13 | 0.4 | 6 | 0.2 |
Investigations | ||||
Weight Decreased | 32 | 0.2 | 9 | 0.4 |
General Disorders and Administration-Site Conditions | ||||
Fatigue | 46 | 2.3 | 38 | 1.5 |
Pyrexia | 18 | 1.1 | 4.9 | 0.2 |
Nervous System Disorders | ||||
Headache | 33 | 0.8 | 18 | 0.2 |
Metabolism and Nutrition Disorders | ||||
Decreased Appetite | 14 | 0.2 | 3.4 | 0.2 |
Psychiatric Disorders | ||||
Insomnia | 10 | 0 | 4.4 | 0 |
a Incidences presented in this table are based on reports of adverse events regardless of causality. b Includes 1 death |
Table 5 presents selected laboratory abnormalities from Trial 2 which occurred in at least 10% of YERVOY-treated patients at a higher incidence compared to placebo.
Table 5: Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of YERVOY-Treated Patients (Trial 2)
Test | Percentage of Patients with Worsening Laboratory Test from Baselinea | |||
YERVOY | Placebo | |||
All Grades | Grade 3 to 4 | All Grades | Grade 3 to 4 | |
Chemistry | ||||
Increased ALT | 46 | 10 | 16 | 0 |
Increased AST | 38 | 9 | 14 | 0.2 |
Increased lipaseb | 26 | 9 | 17 | 4.5 |
Increased amylaseb | 17 | 2.0 | 7 | 0.6 |
Increased alkaline phosphatase | 17 | 0.6 | 6 | 0.2 |
Increased bilirubin | 11 | 1.5 | 9 | 0 |
Increased creatinine | 10 | 0.2 | 6 | 0 |
Hematology | ||||
Decreased hemoglobin | 25 | 0.2 | 14 | 0 |
a Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available. Excluding lipase and amylase, YERVOY group (range: 466 to 470 patients) and placebo group (range: 472 to 474 patients). b For lipase and amylase, YERVOY group (range: 447 to 448 patients) and placebo group (range: 462 to 464 patients). |
Table 6 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Trial 2.
Table 6: Severe to Fatal Immune-Mediated Adverse Reactions in Trial 2
Percentage (%) of Patients | |
YERVOY 10 mg/kg n=471 |
|
Any Immune-Mediated Adverse Reaction | 41 |
Enterocolitisa,b | 16 |
Hepatitis | 11 |
Dermatitis | 4.0 |
Neuropathya | 1.7 |
Endocrinopathy | 8 |
Hypopituitarism | 7 |
Primary hypothyroidism | 0.2 |
Hyperthyroidism | 0.6 |
Other | |
Myocarditisa | 0.2 |
Meningitis | 0.4 |
Pericarditisc | 0.2 |
Pneumonitis | 0.2 |
Uveitis | 0.2 |
a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. |
Other Clinical Experience
Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of YERVOY. 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.
Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity.
Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab (TE-ADAs) in an electrochemiluminescent (ECL) based assay. This assay had substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Seven (4.9%) of 144 patients receiving ipilimumab and 7 (4.5%) of 156 patients receiving placebo for the adjuvant treatment of melanoma tested positive for TE-ADAs using an ECL assay with improved drug tolerance.
No patients tested positive for neutralizing antibodies. No infusion-related reactions occurred in patients who tested positive for TE-ADAs.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ipilimumab with the incidences of antibodies to other products may be misleading.
DRUG INTERACTIONS
No formal pharmacokinetic drug interaction studies have been conducted with YERVOY.
Risk Özeti
Hayvan çalışmalarından elde edilen verilere ve etki mekanizmasına dayanarak, YERVOY hamile bir kadına uygulandığında fetal zarara neden olabilir. Hayvan üreme çalışmalarında, organogenezin başlangıcından doğum yoluyla ipilimumabın sinomolgus maymunlarına uygulanması, daha yüksek kürtaj, ölü doğum, erken doğum (karşılık gelen düşük doğum ağırlığı ile) ve dozla ilgili bir şekilde daha yüksek bebek ölüm insidansı ile sonuçlanmıştır ( bakınız Veri). İpilimumab'ın etkilerinin gebeliğin ikinci ve üçüncü üç aylık dönemlerinde daha büyük olması muhtemeldir. İnsan IgG1'in plasenta bariyerini geçtiği bilinmektedir ve ipilimumab bir IgG1'dir; bu nedenle ipilimumab, anneden gelişmekte olan fetüse bulaşma potansiyeline sahiptir. Gebe kadınlarda YERVOY maruziyeti için yeterli insan verisi yoktur. Hamile kadınlara fetus için potansiyel risk konusunda tavsiyelerde bulunun.
ABD genel popülasyonunda, klinik olarak tanınan gebeliklerde majör doğum kusurları ve düşüklükle ilgili tahmini arka plan riski sırasıyla% 2 ila% 4 ve% 15 ila% 20'dir.
YERVOY alan kadınlarda hamilelikler hakkında bilgi toplamak için bir Gebelik Güvenliği Gözetim Çalışması kurulmuştur. Sağlık hizmeti sunucuları 1-844-593-7869 numaralı telefonu arayarak hastaları kaydetmeye veya hastalarını doğrudan kaydettirmeye teşvik edilir.
Veri
Hayvan Verileri
Embriyo-fetal ve peri-postnatal gelişimin birleşik bir çalışmasında, hamile sinomolgus maymunları, doğumdan itibaren ilk üç aylık dönemde organogenezin başlangıcından itibaren her 3 haftada bir ipilimumab aldı. Gebeliğin ilk iki trimesterinde tedaviye bağlı yan etkiler tespit edilmemiştir. Üçüncü üç aylık dönemden başlayarak, 3 mg / kg'lık bir dozda insan maruziyetinin yaklaşık 2.6 ila 7.2 katı maruziyetle sonuçlanan dozlarda ipilimumab uygulanması, kürtaj, ölü doğum, erken doğumda (karşılık gelen düşük doğum ağırlığı ile) doza bağlı artışlarla sonuçlanmıştır. ve bebek ölüm oranının artması. Ek olarak, maruz kalan 2 bebek maymunun ürogenital sisteminde gelişimsel anormallikler tespit edilmiştir utero 30 mg / kg ipilimumab'a (3 mg / kg dozda insanlarda AUC'nin 7.2 katı). Bir dişi bebek maymunun sol böbrek ve üreterin tek taraflı renal agenezi vardı ve 1 erkek bebek maymunun ilişkili idrar tıkanıklığı ve deri altı skrotal ödem ile delinmiş bir üretra vardı.
İpilimumab hedefi olan CTLA-4 (CTLA-4 + / -) için genetik olarak tasarlanmış fareler heterozigot sağlıklı görünüyordu ve sağlıklı CTLA-4 + / − heterozigot yavruları doğurdu. Eşleştirilmiş CTLA-4 + / - heterozigot fareler ayrıca CTLA-4'te (homozigot negatif, CTLA-4− / -) eksik yavrular üretmiştir. CTLA-4− / - homozigot negatif yavrular doğumda sağlıklı görünüyordu, 2 haftalıkken multiorgan lenfoproliferatif hastalık belirtileri sergiledi ve hepsi 3 ila 4 haftalıkken büyük lenfoproliferasyon ve multiorgan doku yıkımı ile öldü.
Aşağıdaki advers reaksiyonlar, etiketlemenin diğer bölümlerinde daha ayrıntılı olarak tartışılmaktadır.
- Bağışıklık aracılı enterokolit.
- Bağışıklık aracılı hepatit.
- Bağışıklık aracılı dermatit.
- Bağışıklık aracılı nöropatiler.
- Bağışıklık aracılı endokrinopatiler.
- Oküler belirtiler dahil olmak üzere diğer bağışıklık aracılı advers reaksiyonlar.
Deneme 1'de rezektabl veya metastatik melanom için 3 mg / kg YERVOY alan hastalarda, monoterapi alan hastaların% 15'i ve gp100 peptit aşısı ile kombinasyon halinde tedavi edilen hastaların% 12'sinde Derece 3 ila 5 bağışıklık aracılı reaksiyonlar görülmüştür. Deneme 2'de melanomun adjuvan tedavisi için 10 mg / kg YERVOY alan hastalarda,% 41'inde Derece 3 ila 5 bağışıklık aracılı reaksiyonlar görülmüştür.
Klinik Araştırmalar Deneyimi
Klinik araştırmalar çok çeşitli koşullar altında yapıldığından, gözlenen advers reaksiyon oranları, diğer klinik çalışmalardaki oranlarla veya aynı sınıftaki terapötiklerle ilgili deneyimlerle doğrudan karşılaştırılamaz ve klinik uygulamada gözlemlenen oranları yansıtmayabilir.
Aşağıda açıklanan veriler, Deneme 1'de 3 mg / kg YERVOY maruziyetini yansıtmaktadır, rezektabl veya metastatik melanomlu hastalarda ve Deneme 2'de 10 mg / kg YERVOY'a randomize bir çalışma, rezeke Evre IIIA hastalarında randomize bir çalışma (> 1 mm düğüm tutulumu) IIIB, ve IIIC (transit metastaz olmadan) kutanöz melanom.
Klinik olarak anlamlı advers reaksiyonlar, Denemeler 1 ve 2'de tedavi edilen toplam 982 hastada ve 0.1 ila 20 mg / kg dozlarında YERVOY uygulayan 21 doz aralıklı çalışmada (n = 2478) değerlendirildi.
İncelenemez veya Metastatik Melanom
YERVOY'un güvenliği Deneme 1'de değerlendirildi, randomize, daha önce tedavi edilemeyen veya metastatik melanomlu 643 hastanın tek bir ajan olarak intravenöz infüzyonla verilen 4 doz için 3 mg / kg YERVOY aldığı çift kör klinik çalışma (n = 131) Araştırma gp100 peptit aşısı ile YERVOY (gp100) (n = 380) veya tek bir ajan olarak gp100 peptit aşısı (n = 132). Çalışmadaki hastalara medyan 4 doz verildi (aralık: 1 ila 4 doz).
Deneme 1, aktif otoimmün hastalığı olan veya organ nakli için sistemik immünosupresyon alan hastaları hariç tutmuştur.
Deneme popülasyonu özellikleri: ortanca yaş 57 (aralık: 19 ila 90),% 59 erkek,% 94 beyaz ve başlangıç ECOG performans durumu 0 (% 56) idi.
YERVOY, hastaların% 10'unda advers reaksiyonlar nedeniyle kesildi.
Tablo 2, Deneme 1'den seçilen advers reaksiyonları göstermektedir, YERVOY içeren kollardaki hastaların en az% 5'inde meydana gelen ve tüm dereceli olaylar için kontrol gp100 kolu üzerinde en az% 5 artmış insidans ve Sınıf 3 ila 5 olayları için kontrol grubu üzerinde en az% 1 insidans.
Tablo 2: Deneme Sürecinde Seçilmiş Olumsuz Reaksiyonlar 1
Hastaların yüzdesi (%)a | ||||||
YERVOY 3 mg / kg n = 131 |
YERVOY 3 mg / kg + gp100 n = 380 |
gp100 n = 132 |
||||
Sistem Organ Sınıfı / Tercih Edilen Terim | Herhangi bir not | Sınıf 3 ila 5 | Herhangi bir not | Sınıf 3 ila 5 | Herhangi bir not | Sınıf 3 ila 5 |
Genel Bozukluklar ve Uygulama-Site Koşulları | ||||||
Yorgunluk | 41 | 7 | 34 | 5 | 31 | 3 |
Gastrointestinal Hastalıklar | ||||||
İshal | 32 | 5 | 37 | 4 | 20 | 1 |
Kolit | 8 | 5 | 5 | 3 | 2 | 0 |
Deri ve Deri Altı Doku Bozuklukları | ||||||
Kaşıntı | 31 | 0 | 21 | <1 | 11 | 0 |
Döküntü | 29 | 2 | 25 | 2 | 8 | 0 |
a Bu tabloda sunulan olaylar, nedensellikten bağımsız olarak olumsuz olayların raporlarına dayanmaktadır. |
Tablo 3: Denemede Ölümcül Bağışıklık Aracılı Olumsuz Reaksiyonlar 1
Hastaların yüzdesi (%) | ||
YERVOY 3 mg / kg n = 131 |
YERVOY 3 mg / kg + gp100 n = 380 |
|
Bağışıklık Aracılı Olumsuz Reaksiyon | 15 | 12 |
Enterokolita, b | 7 | 7 |
Hepatotoksisitea | 1 | 2 |
Dermatita | 2 | 3 |
Nöropatia | 1 | <1 |
Endokrinopati | 4 | 1 |
Hipopituitarizm | 4 | 1 |
Adrenal yetmezlik | 0 | 1 |
Diğer | ||
Pnömonit | 0 | <1 |
Menenjit | 0 | <1 |
Nefrit | 1 | 0 |
Eozinofilic | 1 | 0 |
Perikardita,c | 0 | <1 |
a Ölümcül sonuç dahil. b Bağırsak perforasyonu dahil. c Altta yatan etiyoloji belirlenmemiştir |
Melanomun Adjuvan Tedavisi
YERVOY'un güvenliği Deneme 2'de değerlendirildi, randomize (1: 1) çift kör, rezeke edilen 945 hastanın Evre IIIA'yı kontrol ettiği plasebo kontrollü çalışma (> 1 mm düğüm tutulumu) IIIB, ve IIIC (transit metastaz olmadan) kutanöz melanom 10 mg / kg YERVOY aldı (n = 471) veya plasebo (n = 474) 3 haftada bir 4 doz için intravenöz infüzyon olarak uygulanır, ardından 24. haftada başlayarak en fazla 3 yıla kadar her 12 haftada bir 10 mg / kg uygulanır. Bu çalışmada hastaların% 36'sı 6 aydan uzun süre YERVOY ve hastaların% 26'sı 1 yıldan uzun bir süre YERVOY aldı. YERVOY ile tedavi edilen hastalara medyan 4 doz verildi (aralık: 1 ila 16).
Deneme 2, melanom, otoimmün hastalık, sistemik immünosupresyon gerektiren bir durum veya hepatit B, hepatit C veya HIV için pozitif bir test için önceden sistemik tedavisi olan hastaları hariç tuttu
Deneme popülasyonu özellikleri: ortanca yaş 51 (aralık: 18 ila 84 yıl),% 62 erkek,% 99 beyaz ve başlangıç ECOG performans durumu 0 (% 94) idi.
YERVOY hastaların% 52'sinde advers reaksiyonlar nedeniyle kesildi.
Tablo 4, YERVOY ile tedavi edilen hastaların en az% 5'inde meydana gelen ve tüm dereceli olaylar için plasebo grubuna göre en az% 5 artmış insidans ile Deneme 2'den seçilen advers reaksiyonları göstermektedir.
Tablo 4: Deneme Sürecinde Seçilmiş Olumsuz Reaksiyonlar 2
Sistem Organ Sınıfı / Tercih Edilen Terim | Hastaların yüzdesi (%)a | |||
YERVOY 10 mg / kg n = 471 |
Plasebo n = 474 |
|||
Herhangi bir not | Sınıf 3 ila 5 | Herhangi bir not | Sınıf 3 ila 5 | |
Deri ve Deri Altı Doku Bozuklukları | ||||
Döküntü | 50 | 2.1 | 20 | 0 |
Kaşıntı | 45 | 2.3 | 15 | 0 |
Gastrointestinal Hastalıklar | ||||
İshal | 49 | 10 | 30 | 2.1 |
Bulantı | 25 | 0.2 | 18 | 0 |
Kolitb | 16 | 8 | 1.5 | 0.4 |
Kusma | 13 | 0.4 | 6 | 0.2 |
Soruşturmalar | ||||
Ağırlık azaldı | 32 | 0.2 | 9 | 0.4 |
Genel Bozukluklar ve Uygulama-Site Koşulları | ||||
Yorgunluk | 46 | 2.3 | 38 | 1.5 |
Pyrexia | 18 | 1.1 | 4.9 | 0.2 |
Sinir Sistemi Bozuklukları | ||||
Baş ağrısı | 33 | 0.8 | 18 | 0.2 |
Metabolizma ve Beslenme Bozuklukları | ||||
İştah azalması | 14 | 0.2 | 3.4 | 0.2 |
Psikiyatrik Bozukluklar | ||||
Uykusuzluk | 10 | 0 | 4.4 | 0 |
a Bu tabloda sunulan olaylar, nedensellikten bağımsız olarak olumsuz olayların raporlarına dayanmaktadır. b 1 ölüm içerir |
Tablo 5, YERVOY ile tedavi edilen hastaların en az% 10'unda plaseboya kıyasla daha yüksek bir insidansta meydana gelen, Deneme 2'den seçilen laboratuvar anormalliklerini göstermektedir.
Tablo 5: YERVOY ile Tedavi Edilen Hastaların% 10'unda meydana gelen Başlangıçtan Kaynaklanan Laboratuvar Anormallikleri (Deneme 2)
Test etmek | Baselinea'dan Kötüleştirici Laboratuvar Testi Olan Hastaların Yüzdesi | |||
YERVOY | Plasebo | |||
Tüm Sınıflar | Sınıf 3 ila 4 | Tüm Sınıflar | Sınıf 3 ila 4 | |
Kimya | ||||
Artan ALT | 46 | 10 | 16 | 0 |
Artan AST | 38 | 9 | 14 | 0.2 |
Artan lipazeb | 26 | 9 | 17 | 4.5 |
Amilaseb arttı | 17 | 2.0 | 7 | 0.6 |
Artan alkalin fosfataz | 17 | 0.6 | 6 | 0.2 |
Bilirubin arttı | 11 | 1.5 | 9 | 0 |
Artan kreatinin | 10 | 0.2 | 6 | 0 |
Hematoloji | ||||
Hemoglobin azaldı | 25 | 0.2 | 14 | 0 |
a Her test insidansı, hem başlangıç hem de en az bir çalışma içi laboratuvar ölçümü olan hasta sayısına dayanmaktadır. Lipaz ve amilaz hariç, YERVOY grubu (aralık: 466 ila 470 hasta) ve plasebo grubu (aralık: 472 ila 474 hasta). b Lipaz ve amilaz için YERVOY grubu (aralık: 447 ila 448 hasta) ve plasebo grubu (aralık: 462 ila 464 hasta). |
Tablo 6, Deneme 2'den kaynaklanan şiddetli, hayatı tehdit eden veya ölümcül bağışıklık aracılı advers reaksiyonların hasta başına insidansını göstermektedir.
Tablo 6: Deneme 2'de Ölümcül Bağışıklık Aracılı Olumsuz Reaksiyonlar
Hastaların yüzdesi (%) | |
YERVOY 10 mg / kg n = 471 |
|
Bağışıklık Aracılı Olumsuz Reaksiyon | 41 |
Enterokolita, b | 16 |
Hepatit | 11 |
Dermatit | 4.0 |
Nöropatia | 1.7 |
Endokrinopati | 8 |
Hipopituitarizm | 7 |
Birincil hipotiroidizm | 0.2 |
Hipertiroidizm | 0.6 |
Diğer | |
Miyokardita | 0.2 |
Menenjit | 0.4 |
Perikarditc | 0.2 |
Pnömonit | 0.2 |
Üveit | 0.2 |
a Ölümcül sonuç dahil. b Bağırsak perforasyonu dahil. c Altta yatan etiyoloji belirlenmemiştir. |
Diğer Klinik Deneyimler
0.3 ila 10 mg / kg arasında değişen YERVOY dozlarını kullanan klinik çalışmalarda, aşağıdaki advers reaksiyonlar da bildirilmiştir (aksi belirtilmedikçe% 1'den az insidans): ürtiker (% 2), büyük bağırsak ülseri, özofajit, akut solunum sıkıntısı sendromu , böbrek yetmezliği ve infüzyon reaksiyonu.
Pazarlama Sonrası Deneyim
YERVOY'un onay sonrası kullanımı sırasında aşağıdaki advers reaksiyonlar tespit edilmiştir. Bu reaksiyonlar belirsiz büyüklükteki bir popülasyondan gönüllü olarak bildirildiğinden, sıklıklarını güvenilir bir şekilde tahmin etmek veya ilaca maruz kalmayla nedensel bir ilişki kurmak her zaman mümkün değildir.
Deri ve Deri Altı Doku Bozuklukları: Eozinofili ve sistemik semptomlarla ilaç reaksiyonu (DRESS sendromu)
İmmünojenisite
Tüm terapötik proteinlerde olduğu gibi, immünojenisite potansiyeli vardır.
İncelenemeyen veya metastatik melanomlu 1024 değerlendirilebilir hastanın 11'i (% 1.1), elektrokimilüminesan (ECL) bazlı bir deneyde ipilimumab (TE-ADA) karşı tedaviye bağlı bağlanma antikorları için pozitif test edildi. Bu test, ipilimumab varlığında anti-ipilimumab antikorlarının saptanmasında önemli sınırlamalara sahipti. İpilimumab alan 144 hastanın yedisi (% 4.9) ve melanomun adjuvan tedavisi için plasebo alan 156 hastanın 7'si (% 4.5), ilaç toleransı iyileştirilmiş bir ECL testi kullanılarak TE-ADA'lar için pozitif test edildi.
Hiçbir hasta nötralize edici antikorlar için pozitif test etmedi. TE-ADA'lar için pozitif test edilen hastalarda infüzyonla ilişkili reaksiyon görülmemiştir.
İmmünojenisite test sonuçları, test duyarlılığı ve özgüllüğü, test metodolojisi, numune işleme, numune toplama zamanlaması, eşlik eden ilaçlar ve altta yatan hastalık gibi çeşitli faktörlere büyük ölçüde bağlıdır. Bu nedenlerden dolayı, antikor insidansının ipilimumab ile antikor insidansının diğer ürünlere karşılaştırılması yanıltıcı olabilir.
YERVOY ile aşırı doz hakkında bilgi yoktur
The pharmacokinetics (PK) of ipilimumab was studied in 785 patients with unresectable or metastatic melanoma who received doses of 0.3, 3, or 10 mg/kg once every 3 weeks for 4 doses. The PK of ipilimumab is linear in the dose range of 0.3 to 10 mg/kg. Following administration of YERVOY every 3 weeks, the systemic accumulation was 1.5-fold or less. Steady-state concentrations of ipilimumab were reached by the third dose; the mean Cmin at steady state was 19.4 mcg/mL at 3 mg/kg and 58.1 mcg/mL at 10 mg/kg every 3 weeks. The mean value (percent coefficient of variation) based on population PK analysis for the terminal half-life (t1/2) was 15.4 days (34%) and for clearance (CL) was 16.8 mL/h (38%).