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: 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: 169)
Drupal\Core\EventSubscriber\DefaultExceptionHtmlSubscriber->makeSubrequest() (Line: 119)
Drupal\Core\EventSubscriber\CustomPageExceptionHtmlSubscriber->makeSubrequestToCustomPath() (Line: 71)
Drupal\Core\EventSubscriber\CustomPageExceptionHtmlSubscriber->on403() (Line: 109)
Drupal\Core\EventSubscriber\HttpExceptionSubscriberBase->onException() (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: 241)
Symfony\Component\HttpKernel\HttpKernel->handleThrowable() (Line: 91)
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: 203)
Drupal\page_cache\StackMiddleware\PageCache->fetch() (Line: 140)
Drupal\page_cache\StackMiddleware\PageCache->lookup() (Line: 89)
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)
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Nursing Drug Reference & Checker

🔍

Drug Reference Lookup

FDA label · Alerts · Nursing considerations · Beers · NIOSH

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Type 2+ letters for RxNorm autocomplete suggestions.

💊 DAPAGLIFLOZIN

ORAL FDA Label

Quick reference

RouteORAL

ManufacturerTeva Pharmaceuticals, Inc.

SourceFDA Label

✅ Indications & Usage ›

1 INDICATIONS AND USAGE Dapagliflozin tablets are indicated: To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus [see Warnings and Precautions ( 5.1 )]. Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . Dapagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action. Pediatric use information is approved for AstraZeneca AB’s Farxiga ® (dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information. Dapagliflozin tablets is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated: To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. ( 1 ) As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitations of use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 ) Not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2 . Dapagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action. ( 1 )

💉 Dosage & Administration ›

2 DOSAGE AND ADMINISTRATION Assess renal function prior to initiation and then as clinically indicated. Assess volume status and correct volume depletion before initiating. ( 2.1 ) To improve glycemic control, the recommended starting dosage is 5 mg orally once daily. Dosage can be increased to 10 mg orally once daily for additional glycemic control. ( 2.2 ) To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. The recommended dosage is 10 mg orally once daily. ( 2.3 ) See full prescribing information for dosage recommendations in patients with renal impairment. ( 2.2 , 2.3 ) Withhold dapagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. ( 2.4 )

2.1 Testing Prior to Initiation of Dapagliflozin Tablets Assess renal function prior to initiation of dapagliflozin tablets and then as clinically indicated [see Warnings and Precautions ( 5.2 )] . Assess volume status. In patients with volume depletion, correct this condition before initiating dapagliflozin tablets [see Warnings and Precautions ( 5.2 ) and Use in Specific Populations ( 8.5 , 8.6 )] .

2.2 Recommended Dosage for Glycemic Control in Adults with Type 2 Diabetes Mellitus In adults with type 2 diabetes mellitus, the recommended starting dosage of dapagliflozin tablets is 5 mg orally once daily to improve glycemic control. For additional glycemic control, the dosage can be increased to 10 mg orally once daily. For Adult Patients with Type 2 Diabetes Mellitus and Renal Impairment : The recommended dosage for dapagliflozin tablets in patients with an eGFR greater than or equal to 45 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function. Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 4... [See full FDA label]

🚫 Contraindications ›

4 CONTRAINDICATIONS Dapagliflozin is contraindicated in patients with a history of a serious hypersensitivity reaction to dapagliflozin or any of the excipients in dapagliflozin. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin [see Adverse Reactions ( 6.1 )] . History of serious hypersensitivity reaction to dapagliflozin or any of the excipients in dapagliflozin. ( 4 )

⚠️ Warnings & Precautions ›

5 WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue dapagliflozin if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.1 ) Volume depletion: Before initiating dapagliflozin, assess volume status and renal function in the elderly, patients with renal impairment or low systolic blood pressure, and in patients on diuretics. Monitor for signs and symptoms during therapy. ( 5.2 ) Urosepsis and Pyelonephritis: Evaluate for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.3 ) Hypoglycemia: Consider a lower dose of insulin or the insulin secretagogue to reduce the risk of hypoglycemia when used in combination with dapagliflozin. ( 5.4 ) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in patients with diabetes, both females and males. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment. ( 5.5 ) Genital Mycotic Infections: Monitor and treat if indicated. ( 5.6 )

5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, dapagliflozin significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo. Dapagliflozin is not indicated for glycemic control in patients wit... [See full FDA label]

🔴 Adverse Reactions ›

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions ( 5.1 )] Volume Depletion [see Warnings and Precautions ( 5.2 )] Urosepsis and Pyelonephritis [see Warnings and Precautions ( 5.3 )] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ( 5.4 )] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions ( 5.5 )] Genital Mycotic Infections [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (5% or greater incidence) were female genital mycotic infections, nasopharyngitis, and urinary tract infections. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Dapagliflozin has been evaluated in clinical trials in adult patients with type 2 diabetes mellitus. The overall safety profile of dapagliflozin was consistent across the studied indications. Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus. Clinical Trials for Glycemic Control in Adult Patients with Type 2 Diabetes Mellitus Pool of 12 Placebo-Controlled Adult Trials for Dapagliflozin 5 and 10 mg for Glycemic Control The data in Table 1 is derived from 12 glycemic control placebo-controlled trials in adult patients with type 2 diabetes mellitus ranging from 12 to 24 weeks. In 4 trials dapagliflozin was used as monotherapy, and in 8 trials dapagliflozin was used as add-on to background antidiabetic therapy or as combi... [See full FDA label]

💊 Drug Interactions ›

7 DRUG INTERACTIONS Table 4: Clinically Relevant Interactions with Dapagliflozin Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when dapagliflozin is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) [see Warnings and Precautions ( 5.4 )] . Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during dapagliflozin initiation and dosage changes. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control. See full prescribing information for information on drug interactions and interference of dapagliflozin with laboratory tests. ( 7 )

🤰 Pregnancy ›

8.1 Pregnancy Risk Summary Based on animal data showing adverse renal effects, dapagliflozin is not recommended during the second and third trimesters of pregnancy. Limited data with dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure in pregnancy (see Clinical Considerations) . In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data) . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown. 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. Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times th... [See full FDA label]

👶 Pediatric Use ›

8.4 Pediatric Use The safety and effectiveness of dapagliflozin for glycemic control in type 2 diabetes mellitus have not been established in pediatric patients less than 10 years of age. The safety and effectiveness of dapagliflozin have not been established in pediatric patients to reduce the risk of [see Indications and Usage ( 1 )] : hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. Pediatric use information is approved for AstraZeneca AB’s Farxiga ® (dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

👴 Geriatric Use ›

8.5 Geriatric Use No dapagliflozin dosage change is recommended based on age. A total of 1,424 (24%) of the 5,936 dapagliflozin-treated patients were 65 years and older and 207 (3.5%) patients were 75 years and older in a pool of 21 double-blind, controlled, clinical trials assessing the efficacy of dapagliflozin in improving glycemic control in type 2 diabetes mellitus. After controlling for level of renal function (eGFR), efficacy was similar for patients under age 65 years and those 65 years and older. In patients ≥65 years of age, a higher proportion of patients treated with dapagliflozin for glycemic control had adverse reactions of hypotension [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] .

🔬 Mechanism of Action ›

12.1 Mechanism of Action Sodium-glucose cotransporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Dapagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, dapagliflozin reduces reabsorption of filtered glucose and thereby promotes urinary glucose excretion. Dapagliflozin also reduces sodium reabsorption and increases the delivery of sodium to the distal tubule. This may influence several physiological functions including, but not restricted to, lowering both pre- and afterload of the heart and downregulation of sympathetic activity.

📊 Pharmacokinetics ›

12.3 Pharmacokinetics Absorption Following oral administration of dapagliflozin, the maximum plasma concentration (C max ) is usually attained within 2 hours under fasting state. The C max and AUC values increase dose proportionally with increase in dapagliflozin dose in the therapeutic dose range. The absolute oral bioavailability of dapagliflozin following the administration of a 10 mg dose is 78%. Administration of dapagliflozin with a high-fat meal decreases its C max by up to 50% and prolongs T max by approximately 1 hour but does not alter AUC as compared with the fasted state. These changes are not considered to be clinically meaningful and dapagliflozin can be administered with or without food. Distribution Dapagliflozin is approximately 91% protein bound. Protein binding is not altered in patients with renal or hepatic impairment. Metabolism The metabolism of dapagliflozin is primarily mediated by UGT1A9; CYP-mediated metabolism is a minor clearance pathway in humans. Dapagliflozin is extensively metabolized, primarily to yield dapagliflozin 3-O-glucuronide, which is an inactive metabolite. Dapagliflozin 3-O-glucuronide accounted for 61% of a 50 mg [ 14 C]-dapagliflozin dose and is the predominant drug-related component in human plasma. Elimination Dapagliflozin and related metabolites are primarily eliminated via the renal pathway. Following a single 50 mg dose of [ 14 C]-dapagliflozin, 75% and 21% total radioactivity is excreted in urine and feces, respectively. In urine, less than 2% of the dose is excreted as parent drug. In feces, approximately 15% of the dose is excreted as parent drug. The mean plasma terminal half-life (t 1/2 ) for dapagliflozin is approximately 12.9 hours following a single oral dose of dapagliflozin 10 mg. Specific Populations Effects of Age, Gender, Race, and Body Weight on Pharmacokinetics Based on a population pharmacokinetic analysis, age, gender, race, and body weight do not have a clinically meaningful effect on the pharmaco... [See full FDA label]

☠️ Overdosage ›

10 OVERDOSAGE There were no reports of overdose during the clinical development program for dapagliflozin. In the event of an overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. It is also reasonable to employ supportive measures as dictated by the patient’s clinical status. The removal of dapagliflozin by hemodialysis has not been studied.

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