Описание
Ревлимид (Revlimid) — представитель нового класса противоопухолевых иммуномодуляторов, оказывает иммуномодулирующее и антиангиогенное действие. Входит в стандарты оказания медицинской помощи пациентам с миеломой и прочими различными злокачественными плазмоклеточными новообразованиями, а также при проведении в качестве поддерживающей терапии после трансплантации костного мозга.
Основное действующее вещество Ревлимида — Леналидомид. Леналидомид одобрен для применения в качестве средства комбинированной терапии в сочетании с дексаметазоном у больных с множественной миеломой, которые уже получали стандартное лечение. Леналидомид получил одобрение для лечения нуждающихся в трансфузии пациентов с миелодиспластическим синдромом, из групп с «промежуточным» или «низким» риском и цитогенетической абберацией 5q хромосомы.
Состав
Капсулы, 5 мг, 10 мг, 15 мг и 25 мг
- вспомогательные вещества: лактоза; МКЦ; кроскармеллоза натрия; магния стеарат;
- краситель индигокармин FD&с синий 2 (в капсулах, содержащих 10 мг и 15 мг вещества); краситель железа оксид желтый (в капсулах, содержащих 10 мг); титана диоксид; желатин;
- чернила черные: шеллак, изопропанол, этанол, пропиленгликоль, бутанол, аммиак водный, калия гидроксид, краситель железа оксид черный, вода.
Показания к применению
- в сочетании с дексаметазоном при лечении множественной миеломы, получивших, по меньшей мере, одну линию терапии
Фармакодинамика
До настоящего времени механизм действия ревлимида не был полностью изучен. Тем не менее, известно, что вещество препарата воздействует на различные участки тела и его механизм действия леналидомида основан на антиангиогенных, проэритропоэтических, противоопухолевых и
иммуномодулирующих свойствах.
Иммуномодулирующие и антиангиогенетические особенности вещества влияют на высвобождение воспалительных веществ и повышают выработку противовоспалительных веществ. Ингибируется образование опухолей в кровеносных сосудах. В результате ухудшается снабжение раковых клеток питательными веществами. Леналидомид также оказывает прямое воздействие на опухолевые клетки за счет подавления их роста.
Леналидомид способен индуцировать пролиферацию Т-лимфоцитов и повышать синтез противовоспалительного цитокина — интерлейкина-2 и гамма интерферона, а также увеличивает цитотоксическую активность собственных Т-киллеров. Индуцирует размножение клеток различных линий гемопоэтических опухолей, главным образом тех, которые имеют цитогенетические дефекты хромосомы 5.
Блокируя образование микрососудов и эндотелиальных каналов, ингибирует процесс ангиогенеза, миграцию и адгезию эндотелиальных клеток на модели ангиогенеза in vitro. Кроме того, леналидомид ингибирует секрецию провоспалительных цитокинов, включая ФНО-альфа, интерлейкин 1бета, 6 и 12 из липосахарид-стимулированных периферических мононуклеарных клеток крови. На модели дифференциации эритроидных клеток-предшественниц индуцировал экспрессию фетального Hb (которую оценивали по дифференциации CD34+ стволовых гемопоэтических клеток).
Леналидомид относится к веществам класса IMiDs. Эта обозначение используется для иммуномодулирующих препаратов, которые могут модулировать иммунную систему. IMiDs — это соединения, полученные из талидомида. Считается, что такие препараты характеризуются гораздо меньшим числом побочных эффектов и улучшенной эффективностью.
Тем не менее, терапия леналидомидом также имеет побочные эффекты. Во многих случаях при использовании ревлимида картина крови временно меняется. Может понижаться число как тромбоцитов (тромбоцитопения), так и белых кровяных пластинок (нейтропения). Данные анализов крови могут свидетельствовать на необходимость прерывания курса лечения или снижения дозы препарата.
Леналидомид, являясь структурным аналогом талидомида, также обладает выраженным тератогенным действием. Известно, что прием талидомида беременными женщинами вызывает тяжелые и несопоставимые с жизнью нарушения внутренних органов плода.
Другой побочный эффектом препарата связан с повышенным риском тромбообразования (тромбоз вен и эмболия легких). Возможно назначение профилактической терапии пациентам с тромбозом вен или эмболией легких в зависимости от индивидуального риска образования кровяных сгустков. Другие нежелательные эффекты, которые могут быть вызваны приемом ревлимида, представлены диареей, кожной сыпью и зудом.
Фармакокинетика
Леналидомид может существовать двух в оптически активных формах S( ) и R(+), ввиду того, что в его структуру входит асимметричный атом углерода. Леналидомид представляет собой рацемическую смесь этих изомеров.
Леналидомид хорошо растворим в органических растворителях, достигает максимальной растворимости в буферном растворе 0.1N HCl.
Всасывание
Леналидомид быстро всасывается из жкт после приема внутрь натощак здоровыми лицами, после приема максимальная концентрация в плазме достигается между 0,5 и 2 часами. Фармакокинетическое распределение имеет линейный характер. Максимальные концентрации (Cmax) и площадь под кривой концентрация-время (AUC) повышаются пропорционально повышению дозы. Прием многократных доз не приводит к накоплению лекарственного препарата.
Прием жирной и высококалорийной пищи снижает величину всасывания лекарства у здоровых добровольцев, что приводит, приблизительно, к 20% снижению значения площади под кривой концентрация-время (AUC) и 50% снижению концентрации Cmax в плазме. Вместе с тем, в проведенных регистрационных испытаниях для установления эффективности и безопасности леналидомида у больных с множественной миеломой, лекарственное средство принимали вне зависимости от приема пищи. Считается, что препарат ревлимид можно принимать как натощак, так и с едой.
Распределение
In vitro связывание (14C)-леналидомида с белками плазмы крови больных множественной миеломой и здоровых добровольцев составляет 23% и 29%, соответственно.
После приема дозы 25 мг/сутки Леналидомид обнаруживается в семенной жидкости (< 0,01% принятой дозы) и не наблюдается спустя 3 дня после прекращения приема препарата у здоровых лиц.
Метаболизм и выведение
Леналидомид практически не метаболизируется в организме, т.к. 82% его дозы выделяется почками в неизмененном виде. Период полувыведения, лекарства при приеме в рекомендованных дозах (5–25 мг/день), составляла около 3 часов у здоровых добровольцев и больных множественной миеломой.
Пожилые пациенты
Согласно фармакокинетическим данным популяционного анализа (в который были включены фармакокинетические данные больных в возрасте от 39 до 85 лет) не показал влияния возраста на клиренс леналидомида. Следует соблюдать осторожность в пожилом возрасте с учетом повышенной вероятности нарушения функций почек при подборе дозы препарата и вести тщательный контроль функции почек на фоне терапии.
Почечная недостаточность
Фармакокинетика Ревлимида была изучена у больных с нарушением функции почек неопухолевой природы. Максимальная концентрация не отличается у пациентов с нормальной и с нарушенной функцией почек. При этом выведение леналидомида замедляется пропорционально степени нарушения почечной дисфункции. Снижение клиренса креатинина ниже 50 мл/мин сопровождается повышением AUC. Период полураспада леналидомида повышается примерно с 3,5 ч (у пациентов с клиренсом креатинина выше 50 мл/мин) до приблизительно 9 часов (у пациентов с клиренсом креатинина менее 50 мл/мин). Данных о поступлении леналидомида в грудное молоко нет.
Показано, что при снижении функции почек (< 50 мл/мин), общий клиренс вещества снижается пропорционально, приводя к увеличению значения AUC. Значения AUC повышались примерно в 2,5, 4 и 5 раз у больных с умеренной почечной недостаточностью, тяжелой почечной недостаточностью и терминальной стадией почечной недостаточности соответственно, по сравнению с группой, объединяющей больных с легкой почечной недостаточностью и больных с нормальной функцией почек.
Однако нарушение почечной функции не влияет на всасывание леналидомида из жкт. Не наблюдается различий по значению максимальной концентрации между здоровыми добровольцами и больными множественной миеломой. Примерно 30% препарата выводилось из организма в ходе 4-часового сеанса диализа.
Печеночная недостаточность
Анализ фармакокинетических данных больных с легкой степенью печеночной недостаточностью (N=16, общий билирубин >1 и ≤1,5 x ВГН, АСТ > ВГН, верхняя граница нормы) показал отсутствие влияния легкой степени печеночной недостаточности на клиренс леналидомида. Фармакокинетических данных в отношении лиц со средней и тяжелой степенью печеночной недостаточностью не получено.
Другие внутренние факторы
Фармакокинетические данные популяционного анализа показал отсутствие клинически значимого влияния расы, массы тела, пола и типа онкогематологического заболевания на клиренс леналидомида у взрослых больных.
Фармацевтические характеристики
Капсулы с порошком почти белого или бледно-желтого цвета. Непрозрачные, твердые, желатиновые, цилиндрической формы. С маркировкой «REV» (на крышечке).
- Капсулы 5 мг: №2, из корпуса и крышечки белого или почти белого цвета, на корпусе имеется гравирока черного цвета «5 mg».
- Капсулы 10 мг: №0, состоящие из корпуса бледно-желтого цвета и сине-зеленой крышечки, с черного цвета маркировкой «10 mg» (на корпусе).
- Капсулы 15 мг: №0, состоящие из корпуса белого или практически белого цвета и крышечки голубого цвета, с маркировкой черного цвета «15 mg» (на корпусе).
- Капсулы 25 мг: №0, состоящие из корпуса и крышечки белого или практически белого цвета, с маркировкой черного цвета «25 mg» (на корпусе).
Упаковка, срок годности, условия хранения
Капсулы 5 мг, 10 мг, 15 мг и 25 мг. По 7 капсул помещены в контурную ячейковую упаковку из ПВХ/ ПХТФЭ и алюминиевой фольги. По 3 контурных ячейковых упаковки вместе с инструкцией помещены в картонную пачку.
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Срок хранения 3 года
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