User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 253)
Drupal\Core\Render\Renderer->doRenderRoot() (Line: 143)
Drupal\Core\Render\Renderer->{closure:Drupal\Core\Render\Renderer::renderInIsolation():142}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 142)
Drupal\Core\Render\Renderer->renderInIsolation() (Line: 169)
Drupal\Core\Render\Renderer->doRenderPlaceholder() (Line: 206)
Drupal\Core\Render\Renderer->renderPlaceholder() (Line: 797)
Drupal\Core\Render\Renderer->replacePlaceholders() (Line: 265)
Drupal\Core\Render\Renderer->doRenderRoot() (Line: 143)
Drupal\Core\Render\Renderer->{closure:Drupal\Core\Render\Renderer::renderInIsolation():142}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 142)
Drupal\Core\Render\Renderer->renderInIsolation() (Line: 113)
Drupal\Core\Render\Renderer->renderRoot() (Line: 253)
Drupal\Core\Render\HtmlResponseAttachmentsProcessor->renderPlaceholders() (Line: 74)
Drupal\big_pipe\Render\BigPipeResponseAttachmentsProcessor->processAttachments() (Line: 106)
Drupal\canvas\Render\ImportMapResponseAttachmentsProcessor->processAttachments() (Line: 45)
Drupal\Core\EventSubscriber\HtmlResponseSubscriber->onRespond() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 216)
Symfony\Component\HttpKernel\HttpKernel->filterResponse() (Line: 204)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 501)
Drupal\Core\Template\TwigExtension->escapeFilter() (Line: 73)
__TwigTemplate_903f906915f560ffb5a631ed1395e98b->doDisplay() (Line: 402)
Twig\Template->yield() (Line: 386)
Twig\Template->render() (Line: 51)
Twig\TemplateWrapper->render() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 513)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 556)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 242)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::prepare():235}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 235)
Drupal\Core\Render\MainContent\HtmlRenderer->prepare() (Line: 131)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
Drupal\Core\Render\Renderer->doRender() (Line: 230)
Drupal\Core\Render\Renderer->render() (Line: 162)
Drupal\Core\Render\MainContent\HtmlRenderer->{closure:Drupal\Core\Render\MainContent\HtmlRenderer::renderResponse():157}() (Line: 634)
Drupal\Core\Render\Renderer::{closure:Drupal\Core\Render\Renderer::executeInRenderContext():634}()
Fiber->start() (Line: 635)
Drupal\Core\Render\Renderer->executeInRenderContext() (Line: 157)
Drupal\Core\Render\MainContent\HtmlRenderer->renderResponse() (Line: 90)
Drupal\Core\EventSubscriber\MainContentViewSubscriber->onViewRenderArray() (Line: 246)
Symfony\Component\EventDispatcher\EventDispatcher::{closure:Symfony\Component\EventDispatcher\EventDispatcher::optimizeListeners():241}() (Line: 206)
Symfony\Component\EventDispatcher\EventDispatcher->callListeners() (Line: 56)
Symfony\Component\EventDispatcher\EventDispatcher->dispatch() (Line: 188)
Symfony\Component\HttpKernel\HttpKernel->handleRaw() (Line: 76)
Symfony\Component\HttpKernel\HttpKernel->handle() (Line: 53)
Drupal\Core\StackMiddleware\Session->handle() (Line: 48)
Drupal\Core\StackMiddleware\KernelPreHandle->handle() (Line: 28)
Drupal\Core\StackMiddleware\ContentLength->handle() (Line: 32)
Drupal\big_pipe\StackMiddleware\ContentLength->handle() (Line: 118)
Drupal\page_cache\StackMiddleware\PageCache->pass() (Line: 92)
Drupal\page_cache\StackMiddleware\PageCache->handle() (Line: 48)
Drupal\Core\StackMiddleware\ReverseProxyMiddleware->handle() (Line: 51)
Drupal\Core\StackMiddleware\NegotiationMiddleware->handle() (Line: 53)
Drupal\Core\StackMiddleware\AjaxPageState->handle() (Line: 54)
Drupal\Core\StackMiddleware\StackedHttpKernel->handle() (Line: 745)
Drupal\Core\DrupalKernel->handle() (Line: 19)

User warning: mkdir(): Permission Denied in Drupal\Component\PhpStorage\FileStorage->createDirectory() (line 125 of core/lib/Drupal/Component/PhpStorage/FileStorage.php).

Drupal\Component\PhpStorage\FileStorage->createDirectory() (Line: 73)
Drupal\Component\PhpStorage\FileStorage->ensureDirectory() (Line: 66)
Drupal\Component\PhpStorage\MTimeProtectedFastFileStorage->save() (Line: 116)
Drupal\Core\Template\TwigPhpStorageCache->write() (Line: 410)
Twig\Environment->loadTemplate() (Line: 370)
Twig\Environment->load() (Line: 35)
Drupal\Core\Template\TwigThemeEngine->renderTemplate() (Line: 428)
Drupal\Core\Theme\ThemeManager->render() (Line: 500)
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Nursing Drug Reference & Checker

🔍

Drug Reference Lookup

FDA label · Alerts · Nursing considerations · Beers · NIOSH

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💊 METHOTREXATE

☠ BLACK BOX WARNING

ORAL FDA Label

☠

FDA BLACK BOX WARNING

WARNING: EMBRYO-FETAL TOXICITY, HYPERSENSITIVITY REACTIONS, and SEVERE ADVERSE REACTIONS • Methotrexate tablets can cause embryo-fetal toxicity, including fetal death. For non-neoplastic diseases, methotrexate tablets are contraindicated in pregnancy. For neoplastic diseases, advise females and ma…

⚗

NIOSH 2024 HAZARDOUS DRUG — Table 1

Requires double chemotherapy gloves, gown, and eye protection. May require negative pressure compounding. Full USP <800> compliance required.

Full NIOSH entry →

Quick reference

RouteORAL

ManufacturerAlembic Pharmaceuticals Inc.

SourceFDA Label

✅ Indications & Usage ›

1 INDICATIONS AND USAGE Methotrexate tablets are a diydrofolate reductase inhibitor indicated for the: • Treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen (1.1) • Treatment of adults with mycosis fungoides (1.1) • Treatment of adults with relapsed or refractory non-Hodgkin lymphoma as part of a metronomic combination regimen (1.1) • Treatment of adults with rheumatoid arthritis (1.2) • Treatment of pediatric patients with polyarticular juvenile idiopathic arthritis (pJIA) (1.3) • Treatment of adults with severe psoriasis (1.4)

1.1 Neoplastic Diseases Methotrexate tablets are indicated for the: • treatment of adults and pediatric patients with acute lymphoblastic leukemia (ALL) as part of a combination chemotherapy maintenance regimen • treatment of adults with mycosis fungoides (cutaneous T-cell lymphoma) as a single agent or as part of a combination chemotherapy regimen • treatment of adults with relapsed or refractory non-Hodgkin lymphomas as part of a metronomic combination chemotherapy regimen

1.2 Rheumatoid Arthritis Methotrexate tablets are indicated for the treatment of adults with rheumatoid arthritis.

1.3 Polyarticular Juvenile Idiopathic Arthritis Methotrexate tablets are indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).

1.4 Psoriasis Methotrexate tablets are indicated for the treatment of adults with severe psoriasis.

💉 Dosage & Administration ›

2 DOSAGE AND ADMINISTRATION • Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths. (2.1, 5.9) • Verify pregnancy status in females of reproductive potential before starting methotrexate tablets. (4, 5.1) • ALL: The recommended dosage is 20 mg/m 2 orally once weekly as a part of a combination chemotherapy maintenance regimen. (2.2) • Mycosis fungoides: The recommended dosage is 25 to 75 mg orally once weekly as monotherapy
10 mg/m 2 orally twice weekly as part of combination chemotherapy. (2.2) • Relapsed or refractory non-Hodgkin lymphoma: The recommended dosage is 2.5 mg orally two to four times per week as part of metronomic combination chemotherapy. (2.2) • Rheumatoid Arthritis: The recommended starting dosage is 7.5 mg orally once weekly
adjust dose to achieve an optimal response. (2.3) • pJIA: The recommended starting dosage is 10 mg/m 2 orally once weekly
adjust dose to achieve an optimal response. (2.4) • Psoriasis: The recommended dosage is 10 to 25 mg orally once weekly until adequate response is achieved. (2.5)

2.1 Important Dosage and Safety Information Verify pregnancy status in females of reproductive potential before starting methotrexate tablets [see Contraindications (4), Warnings and Precautions (5.1)]. Instruct patients and caregivers to take the recommended dosage as directed, because medication errors have led to deaths [see Warnings and Precautions (5.9)]. When switching the dosing regimen from oral administration to intravenous, intramuscular, or subcutaneous administration, an alternative dosing regimen may be necessary. Do not administer to patients who are unable to swallow a tablet. Methotrexate tablets are a cytotoxic drug. Follow applicable special handling and disposal procedures. 1

2.2 Recommended Dosage for Neoplastic Diseases Acute Lymphoblastic Leukemia The recommended starting dosage of methotrexate tablets is 20 mg/m 2 orally once weekly, as pa... [See full FDA label]

🚫 Contraindications ›

4 CONTRAINDICATIONS Methotrexate tablets are contraindicated in: • Pregnant women receiving methotrexate tablets for treatment of non-neoplastic diseases [see Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.3)]. • Patients with a history of severe hypersensitivity reactions, including anaphylaxis, to methotrexate. [see Warnings and Precautions (5.2)]. • In pregnancy for non-neoplastic diseases (4) • History of severe hypersensitivity to methotrexate (4)

⚠️ Warnings & Precautions ›

5 WARNINGS AND PRECAUTIONS • Serious Infections : Monitor patients for infection during and after treatment with methotrexate. Withhold or discontinue methotrexate for serious infections as appropriate. (5.11) • Neurotoxicity : Monitor patients for neurotoxicity and withhold or discontinue methotrexate as appropriate. (5.12) • Secondary Malignancies : Can occur with methotrexate. (5.13) • Tumor Lysis Syndrome : Institute appropriate prophylactic measures in patients at risk for tumor lysis syndrome prior to initiation of methotrexate (5.14) • Immunizations and Risk Live Vaccines : Immunizations with live vaccines is not recommended. Follow current vaccination practice guidelines. (5.15) • Infertility : Can cause impairment of fertility, oligospermia, and menstrual dysfunction. (5.16, 8.3)

5.1 Embryo-Fetal Toxicity Based on published reports and its mechanism of action, methotrexate can cause fetal harm, including fetal death, when administered to a pregnant woman. Methotrexate is contraindicated for use in pregnant women receiving methotrexate for the treatment of non-malignant diseases. Advise pregnant women with neoplastic diseases of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with methotrexate and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during methotrexate treatment and for 3 months after the final dose [see Contraindications (4), Use in Specific Populations (8.1, 8.3)].

5.2 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, can occur with methotrexate [see Contraindications (4), Adverse Reactions (6.1)]. If anaphylaxis or other serious hypersensitivity reaction occurs, immediately and permanently discontinue methotrexate [see Dosage and Administration (2.6)].

5.3 Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancy... [See full FDA label]

🔴 Adverse Reactions ›

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.2)] Myelosuppression [see Warnings and Precautions (5.3)] Gastrointestinal Toxicity [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Pulmonary Toxicity [see Warnings and Precautions (5.6)] Dermatologic Reactions [see Warnings and Precautions (5.7)] Renal Toxicity [see Warnings and Precautions (5.8)] Serious Infections [see Warnings and Precautions (5.11)] Neurotoxicity [see Warnings and Precautions (5.12)] Secondary Malignancies [see Warnings and Precautions (5.13)] Tumor Lysis Syndrome [see Warnings and Precautions (5.14)] Increased Risk of Adverse Reactions Due to Third-Space Accumulation [see Warnings and Precautions (5.17)] Common adverse reactions include ulcerative stomatitis, leukopenia, nausea, abdominal distress. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials and other studies 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. Common adverse reactions were: ulcerative stomatitis, leukopenia, nausea, and abdominal distress. Other clinically relevant adverse reactions were infection, malaise, fatigue, chills, fever, and dizziness. Rheumatoid Arthritis The most common adverse reactions of methotrexate that exceeded the rate of placebo in 12- to 18-week double-blind studies in patients (n=128) with rheumatoid arthritis are listed below. Patients received methotrexate 7.5 to 15 mg orally once weekly. Most patients received concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and some also received cortico... [See full FDA label]

💊 Drug Interactions ›

7 DRUG INTERACTIONS Refer to the full prescribing information for drug interactions with methotrexate. (7)

7.1 Effects of Other Drugs on Methotrexate Drugs that Increase Methotrexate Exposure Coadministration of methotrexate with the following products may increase methotrexate plasma concentrations, which may increase the risk of methotrexate severe adverse reactions. In some cases, the coadministration of methotrexate with these products may also subsequently reduce active metabolite formation, which may decrease the clinical effectiveness of methotrexate. Increased organ specific adverse reactions may also occur when methotrexate is coadministered with hepatotoxic or nephrotoxic products. If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions when coadministered with: Oral antibiotics (including neomycin) Antifolate drugs (e.g., dapsone, pemetrexed, pyrimethamine and sulfonamides) Oral or intravenous penicillin or sulfonamide antibiotics Aspirin and other nonsteroidal anti- inflammatory drugs Hepatotoxic products Highly protein-bound drugs (e.g., oral anticoagulants, phenytoin, salicylates, sulfonamides, sulfonylureas, and tetracyclines) Proton pump inhibitors Weak acids (e.g., salicylates) Nephrotoxic products Probenecid Nitrous Oxide Coadministration of methotrexate with nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, which may increase the risk of severe methotrexate adverse reactions. Avoid nitrous oxide anesthesia in patients receiving methotrexate. Consider alternative therapies in patients who have received prior nitrous oxide anesthesia. Folic Acid Coadministration of methotrexate with folic acid or its derivatives decreases the clinical effectiveness of methotrexate in patients with neoplastic diseases. Methotrexate competes with reduced folates for active transport across cell membranes. Instruct patients to take folic or folinic acid only as directed by their hea... [See full FDA label]

🤰 Pregnancy ›

8.1 Pregnancy Risk Summary Methotrexate is contraindicated in pregnant women with non-neoplastic diseases [see Contraindications (4)]. Based on published reports and its mechanism of action [see Clinical Pharmacology (12.1)] , methotrexate can cause embryo-fetal toxicity and fetal death when administered to a pregnant woman. There are no animal data that meet current standards for nonclinical developmental toxicity studies. Advise pregnant women with neoplastic diseases 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. Data Human Data Published data from case reports, literature reviews, and observational studies report that methotrexate exposure during pregnancy is associated with an increased risk of embryo-fetal toxicity and fetal death. Methotrexate exposure during the first trimester of pregnancy is associated with an increased incidence of spontaneous abortions and multiple adverse developmental outcomes, including skull anomalies, facial dysmorphism, central nervous system abnormalities, limb abnormalities, and sometimes cardiac anomalies and intellectual impairment. Adverse outcomes associated with exposure during second and third trimesters of pregnancy include intrauterine growth restriction and functional abnormalities. Because methotrexate is widely distributed and persists in the body for a prolonged period, there is a potential risk to the fetus from preconception methotrexate exposure. A prospective multicenter study evaluated pregnancy outcomes in women taking methotrexate less than or equal to 30 mg/week after conception. The rate of spontaneous abortion and miscarriage in pregnant women exposed to methotrexate was 42% (95% confidence interval [95% CI] 29, 59), which was higher than in unexposed patients with autoimmune disease (22%; 95% CI: 17, 30) and unexposed patients with nonautoimmu... [See full FDA label]

👶 Pediatric Use ›

8.4 Pediatric Use The safety and effectiveness of methotrexate in pediatric patients have been established for the treatment of ALL as part of the combination chemotherapy maintenance regimen and the treatment of pJIA [see Indications and Usage (1), Dosage and Administration (2)] . No new safety signals have been observed in pediatric patients in clinical studies [see Adverse Reactions (6.1)] . The safety and effectiveness of methotrexate have not been established in pediatric patients for the other indications [see Indications and Usage (1)] .

👴 Geriatric Use ›

8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

🔬 Mechanism of Action ›

12.1 Mechanism of Action Methotrexate inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be utilized as carriers of one-carbon groups in the synthesis of purine nucleotides and thymidylate. Therefore, methotrexate interferes with DNA synthesis, repair, and cellular replication. Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. The mechanism of action in rheumatoid arthritis and in psoriasis is unknown.

📊 Pharmacokinetics ›

12.3 Pharmacokinetics Absorption At doses of 30 mg/m 2 or less, the mean bioavailability is approximately 60%. Peak plasma concentrations are reached within 0.75 to 6 hours following oral administration. Methotrexate may undergo enterohepatic recirculation; however, this pathway has not been fully characterized. Effect of Food Food has been shown to delay absorption and reduce peak concentration. Distribution Methotrexate in serum is approximately 50% protein bound. Methotrexate does not penetrate the blood-cerebrospinal fluid barrier at concentrations achieved with the recommended dosages. Elimination The elimination half-life of methotrexate is approximately 3 to 10 hours. Small amounts of methotrexate polyglutamates may remain in tissues for extended periods. The retention and prolonged drug action of these active metabolites vary among different cells, tissues, and tumors. Nonlinear elimination due to saturation of renal tubular reabsorption has been observed in studies of patients with psoriasis receiving methotrexate doses between 7.5 mg and 30 mg. Metabolism Methotrexate is partially metabolized by intestinal flora after oral administration. Methotrexate primarily undergoes hepatic and intracellular metabolism to active polyglutamated forms which can be converted back to methotrexate by hydrolase enzymes. Methotrexate also undergoes minor metabolism to active 7-hydroxymethotrexate. Excretion Methotrexate primarily undergoes renal excretion by glomerular filtration and active tubular secretion that is dependent upon dosage and route of administration. Biliary excretion accounts for ≤10% of the methotrexate dose. Specific Populations The effect of hepatic impairment on the pharmacokinetics of methotrexate is unknown. Pediatric Patients In pediatric patients with leukemia, oral absorption (23% to 95%) of methotrexate is variable and dose-dependent. The difference between highest and lowest peak methotrexate concentrations (C max 0.11 to 2.3 micromolar after a ... [See full FDA label]

☠️ Overdosage ›

10 OVERDOSAGE Overdosage, including fatal overdosage, has occurred with methotrexate [see Warnings and Precautions (5. 9)] . Manifestations Manifestations of methotrexate overdosage include adverse reactions reported at pharmacologic doses, particularly hematologic and gastrointestinal reactions (e.g., leukopenia, thrombocytopenia, anemia, pancytopenia, myelosuppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, or gastrointestinal bleeding). In some cases, no symptoms were reported; however, sepsis or septic shock, renal failure, and aplastic anemia were also reported. Management Leucovorin and levoleucovorin are indicated for diminishing the methotrexate adverse reactions of methotrexate overdosage. Administer leucovorin or levoleucovorin as soon as possible after methotrexate overdosage). Monitor serum creatinine and methotrexate levels to guide leucovorin or levoleucovorin therapy. Refer to the leucovorin or levoleucovorin prescribing information for additional dosage information. Glucarpidase is indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function. Refer to the glucarpidase prescribing information for additional dosage information. Administer concomitant hydration and urinary alkalinization. Neither hemodialysis nor peritoneal dialysis has been shown to improve methotrexate elimination; however, methotrexate has been effectively cleared with acute, intermittent hemodialysis using a high-flux dialyzer.

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💊 METHOTREXATE

1.2 Rheumatoid Arthritis Methotrexate tablets are indicated for the treatment of adults with rheumatoid arthritis.

1.3 Polyarticular Juvenile Idiopathic Arthritis Methotrexate tablets are indicated for the treatment of pediatric patients with polyarticular Juvenile Idiopathic Arthritis (pJIA).

1.4 Psoriasis Methotrexate tablets are indicated for the treatment of adults with severe psoriasis.

2.2 Recommended Dosage for Neoplastic Diseases Acute Lymphoblastic Leukemia The recommended starting dosage of methotrexate tablets is 20 mg/m 2 orally once weekly, as pa... [See full FDA label]

5.3 Myelosuppression Methotrexate suppresses hematopoiesis and can cause severe and life-threatening pancy... [See full FDA label]

7 DRUG INTERACTIONS Refer to the full prescribing information for drug interactions with methotrexate. (7)

8.5 Geriatric Use Clinical studies of methotrexate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.