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

Patient Age

Used for Beers Criteria (65+) across both panels.

Drug Name (Brand or Generic)

Type 2+ letters for RxNorm autocomplete suggestions.

💊 CARBIDOPA AND LEVODOPA

Generic: CARBIDOPA AND LEVODOPA

ORAL FDA Label

Quick reference

RouteORAL

ManufacturerSafecor Health, LLC

SourceFDA Label

✅ Indications & Usage ›

INDICATIONS AND USAGE Carbidopa and levodopa extended-release tablets are indicated in the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and symptomatic parkinsonism that may follow carbon monoxide intoxication or manganese intoxication.

💉 Dosage & Administration ›

DOSAGE AND ADMINISTRATION Carbidopa and levodopa extended-release tablets contain carbidopa and levodopa in a 1:4 ratio as either the 50-200 tablet or the 25-100 tablet. The daily dosage of carbidopa and levodopa extended-release tablets must be determined by careful titration. Patients should be monitored closely during the dose adjustment period, particularly with regard to appearance or worsening of involuntary movements, dyskinesias or nausea. Carbidopa and levodopa extended-release tablets should not be chewed or crushed. Standard drugs for Parkinson’s disease, other than levodopa without a decarboxylase inhibitor, may be used concomitantly while carbidopa and levodopa extended-release tablets are being administered, although their dosage may have to be adjusted. Since carbidopa prevents the reversal of levodopa effects caused by pyridoxine, carbidopa and levodopa extended-release tablets can be given to patients receiving supplemental pyridoxine (vitamin B 6 ). Initial Dosage Patients Currently Treated with Conventional Carbidopa-Levodopa Preparations Studies show that peripheral dopa-decarboxylase is saturated by the bioavailable carbidopa at doses of 70 mg a day and greater. Because the bioavailabilities of carbidopa and levodopa in carbidopa and levodopa immediate-release tablets and carbidopa and levodopa extended-release tablets are different, appropriate adjustments should be made, as shown in Table 2. Table 2: Approximate Bioavailabilities at Steady State This table is only a guide to bioavailabilities since other factors such as food, drugs, and inter-patient variabilities may affect the bioavailability of carbidopa and levodopa. Tablet Amount of Levodopa (mg) in Each Tablet Approximate Bioavailability Approximate Amount of Bioavailable Levodopa (mg) in Each Tablet Carbidopa and Levodopa Extended-Release Tablets 50 mg/200 mg 200 0.70-0.75 The extent of availability of levodopa from carbidopa and levodopa extended-release tablets was about 70-75% rela... [See full FDA label]

🚫 Contraindications ›

CONTRAINDICATIONS Nonselective monoamine oxidase (MAO) inhibitors are contraindicated for use with carbidopa and levodopa extended-release tablets. These inhibitors must be discontinued at least two weeks prior to initiating therapy with carbidopa and levodopa extended-release. Carbidopa and levodopa extended-release may be administered concomitantly with the manufacturer’s recommended dose of an MAO inhibitor with selectivity for MAO type B (e.g., selegiline HCl) (see

PRECAUTIONS

Drug Interactions ). Carbidopa and levodopa extended-release is contraindicated in patients with known hypersensitivity to any component of this drug and in patients with narrow-angle glaucoma.

⚠️ Warnings ›

WARNINGS When patients are receiving levodopa without a decarboxylase inhibitor, levodopa must be discontinued at least twelve hours before carbidopa and levodopa extended-release is started. In order to reduce adverse reactions, it is necessary to individualize therapy. See DOSAGE AND ADMINISTRATION section before initiating therapy. Carbidopa and levodopa extended-release should be substituted at a dosage that will provide approximately 25% of the previous levodopa dosage (see DOSAGE AND ADMINISTRATION ). Carbidopa does not decrease adverse reactions due to central effects of levodopa. By permitting more levodopa to reach the brain, particularly when nausea and vomiting is not a dose-limiting factor, certain adverse central nervous system (CNS) effects, e.g., dyskinesias, will occur at lower dosages and sooner during therapy with carbidopa and levodopa extended-release than with levodopa alone. Patients receiving carbidopa and levodopa extended-release may develop increased dyskinesias compared to carbidopa and levodopa immediate-release. Dyskinesias are a common side effect of carbidopa-levodopa treatment. The occurrence of dyskinesias may require dosage reduction. All patients should be observed carefully for the development of depression with concomitant suicidal tendencies. Carbidopa and levodopa extended-release should be administered cautiously to patients with severe cardiovascular or pulmonary disease, bronchial asthma, renal, hepatic or endocrine disease. As with levodopa, care should be exercised in administering carbidopa and levodopa extended-release to patients with a history of myocardial infarction who have residual atrial, nodal, or ventricular arrhythmias. In such patients, cardiac function should be monitored with particular care during the period of initial dosage adjustment, in a facility with provisions for intensive cardiac care. As with levodopa, treatment with carbidopa and levodopa extended-release may increase the possibility of upper gas... [See full FDA label]

🔴 Adverse Reactions ›

ADVERSE REACTIONS In controlled clinical trials, patients predominantly with moderate to severe motor fluctuations while on carbidopa and levodopa immediate-release were randomized to therapy with either carbidopa and levodopa immediate-release or carbidopa and levodopa extended-release. The adverse experience frequency profile of carbidopa and levodopa extended-release did not differ substantially from that of carbidopa and levodopa immediate-release, as shown in Table 1. Table 1: Clinical Adverse Experiences Occurring in 1% or Greater of Patients Adverse Experience Carbidopa and Levodopa Extended-Release n = 491 % Carbidopa and Levodopa Immediate-Release n = 524 % Dyskinesia 16.5

12.2 Nausea 5.5

5.7 Hallucinations 3.9

3.2 Confusion 3.7

2.3 Dizziness 2.9

2.3 Depression 2.2

1.3 Urinary tract infection 2.2

2.3 Headache 2.0

1.9 Dream abnormalities 1.8

0.8 Dystonia 1.8

0.8 Vomiting 1.8

1.9 Upper respiratory infection 1.8

1.0 Dyspnea 1.6 0.4 ‘On-Off’ phenomena 1.6

1.1 Back pain 1.6

0.6 Dry mouth 1.4

1.1 Anorexia 1.2

1.1 Diarrhea 1.2

0.6 Insomnia 1.2

1.0 Orthostatic hypotension 1.0

1.1 Shoulder pain 1.0

0.6 Chest pain 1.0

0.8 Muscle cramps 0.8

1.0 Paresthesia 0.8

1.1 Urinary frequency 0.8

1.1 Dyspepsia 0.6

1.1 Constipation 0.2

1.5 Abnormal laboratory findings occurring at a frequency of 1% or greater in approximately 443 patients who received carbidopa and levodopa extended-release and 475 who received carbidopa and levodopa immediate-release during controlled clinical trials included: decreased hemoglobin and hematocrit; elevated serum glucose; white blood cells, bacteria and blood in the urine. The adverse experiences observed in patients in uncontrolled studies were similar to those seen in controlled clinical studies. Other adverse experiences reported overall in clinical trials in 748 patients treated with carbidopa and levodopa extended-release, listed by body system in order of decreasing frequency, include: Body as a Whole: Asthenia, fatigue, abdominal pain, ... [See full FDA label]

💊 Drug Interactions ›

Drug Interactions Caution should be exercised when the following drugs are administered concomitantly with carbidopa and levodopa extended-release. Symptomatic postural hypotension has occurred when carbidopa-levodopa preparations were added to the treatment of patients receiving some antihypertensive drugs. Therefore, when therapy with carbidopa and levodopa extended-release is started, dosage adjustment of the antihypertensive drug may be required. For patients receiving MAO inhibitors (Type A or B), see CONTRAINDICATIONS . Concomitant therapy with selegiline and carbidopa-levodopa may be associated with severe orthostatic hypotension not attributable to carbidopa-levodopa alone (see CONTRAINDICATIONS ). There have been rare reports of adverse reactions, including hypertension and dyskinesia, resulting from the concomitant use of tricyclic antidepressants and carbidopa-levodopa preparations. Dopamine D 2 receptor antagonists (e.g., phenothiazines, butyrophenones, risperidone) and isoniazid may reduce the therapeutic effects of levodopa. In addition, the beneficial effects of levodopa in Parkinson’s disease have been reported to be reversed by phenytoin and papaverine. Patients taking these drugs with carbidopa and levodopa extended-release should be carefully observed for loss of therapeutic response. Use of carbidopa and levodopa extended-release with dopamine-depleting agents (e.g., reserpine and tetrabenazine) or other drugs known to deplete monoamine stores is not recommended. Carbidopa and levodopa extended-release and iron salts or multivitamins containing iron salts should be coadministered with caution. Iron salts can form chelates with levodopa and carbidopa and consequently reduce the bioavailability of carbidopa and levodopa. Although metoclopramide may increase the bioavailability of levodopa by increasing gastric emptying, metoclopramide may also adversely affect disease control by its dopamine receptor antagonistic properties.

🤰 Pregnancy ›

Pregnancy No teratogenic effects were observed in a study in mice receiving up to 20 times the maximum recommended human dose of carbidopa and levodopa immediate-release. There was a decrease in the number of live pups delivered by rats receiving approximately two times the maximum recommended human dose of carbidopa and approximately five times the maximum recommended human dose of levodopa during organogenesis. Carbidopa and levodopa immediate-release caused both visceral and skeletal malformations in rabbits at all doses and ratios of carbidopa/levodopa tested, which ranged from 10 times/5 times the maximum recommended human dose of carbidopa/levodopa to 20 times/10 times the maximum recommended human dose of carbidopa/levodopa. There are no adequate or well-controlled studies in pregnant women. It has been reported from individual cases that levodopa crosses the human placental barrier, enters the fetus, and is metabolized. Carbidopa concentrations in fetal tissue appeared to be minimal. Use of carbidopa and levodopa extended-release in women of childbearing potential requires that the anticipated benefits of the drug be weighed against possible hazards to mother and child.

🤱 Nursing / Lactation ›

Nursing Mothers Levodopa has been detected in human milk. Caution should be exercised when carbidopa and levodopa extended-release is administered to a nursing woman.

👶 Pediatric Use ›

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Use of the drug in patients below the age of 18 is not recommended.

👴 Geriatric Use ›

Geriatric Use In the clinical efficacy trials for carbidopa and levodopa immediate-release, almost half of the patients were older than 65, but few were older than 75. No overall meaningful differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals to adverse drug reactions such as hallucinations cannot be ruled out. There is no specific dosing recommendation based upon clinical pharmacology data as carbidopa and levodopa immediate-release and carbidopa and levodopa extended-release are titrated as tolerated for clinical effect.

🔬 Mechanism of Action ›

Mechanism of Action Parkinson’s disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility. Current evidence indicates that symptoms of Parkinson’s disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson’s disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson’s disease.

📊 Pharmacokinetics ›

Pharmacokinetics Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. Elimination half-life of levodopa in the presence of carbidopa is about 1.5 hours. Following carbidopa and levodopa extended-release, the apparent half-life of levodopa may be prolonged because of continuous absorption. In healthy elderly subjects (56-67 years old) the mean time-to-peak concentration of levodopa after a single dose of 50 mg/200 mg carbidopa and levodopa extended-release was about 2 hours as compared to 0.5 hours after standard carbidopa and levodopa immediate-release. The maximum concentration of levodopa after a single dose of carbidopa and levodopa extended-release was about 35% of the standard carbidopa and levodopa immediate-release (1151 vs. 3256 ng/mL). The extent of availability of levodopa from carbidopa and levodopa extended-release was about 70-75% relative to intravenous levodopa or standard carbidopa and levodopa immediate-release in the elderly. The absolute bioavailability of levodopa from carbidopa and levodopa extended-release (relative to I.V.) in young subjects was shown to be only about 44%. The extent of availability and the peak concentrations of levodopa were comparable in the elderly after a single dose and at steady state after t.i.d. administration of 50 mg/200 mg carbidopa and levodopa extended-release. In elderly subjects, the average trough levels of levodopa at steady state after the extended-release tablet were about 2-fold higher than after the standard carbidopa and levodopa immediate-release (163 vs. 74 ng/mL). In these studies, using similar total daily doses of levodopa, plasma levodopa concentrations with carbidopa and levodopa extended-release fluctuated in a narrower range than with carbidopa and levodopa immediate-release. Because the bio... [See full FDA label]

☠️ Overdosage ›

OVERDOSAGE Management of acute overdosage with carbidopa and levodopa extended-release is the same as with levodopa. Pyridoxine is not effective in reversing the actions of carbidopa and levodopa extended-release. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered judiciously and an adequate airway maintained. Electrocardiographic monitoring should be instituted and the patient carefully observed for the development of arrhythmias
if required, appropriate antiarrhythmic therapy should be given. The possibility that the patient may have taken other drugs as well as carbidopa and levodopa extended-release should be taken into consideration. To date, no experience has been reported with dialysis
hence, its value in overdosage is not known. Based on studies in which high doses of levodopa and/or carbidopa were administered, a significant proportion of rats and mice given single oral doses of levodopa of approximately 1500-2000 mg/kg are expected to die. A significant proportion of infant rats of both sexes are expected to die at a dose of 800 mg/kg. A significant proportion of rats are expected to die after treatment with similar doses of carbidopa. The addition of carbidopa in a 1:10 ratio with levodopa increases the dose at which a significant proportion of mice are expected to die to 3360 mg/kg.

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💊 CARBIDOPA AND LEVODOPA

12.2 Nausea 5.5

5.7 Hallucinations 3.9

3.2 Confusion 3.7

2.3 Dizziness 2.9

2.3 Depression 2.2

1.3 Urinary tract infection 2.2

2.3 Headache 2.0

1.9 Dream abnormalities 1.8

0.8 Dystonia 1.8

0.8 Vomiting 1.8

1.9 Upper respiratory infection 1.8

1.0 Dyspnea 1.6 0.4 ‘On-Off’ phenomena 1.6

1.1 Back pain 1.6

0.6 Dry mouth 1.4

1.1 Anorexia 1.2

1.1 Diarrhea 1.2

0.6 Insomnia 1.2

1.0 Orthostatic hypotension 1.0

1.1 Shoulder pain 1.0

0.6 Chest pain 1.0

0.8 Muscle cramps 0.8

1.0 Paresthesia 0.8

1.1 Urinary frequency 0.8

1.1 Dyspepsia 0.6

1.1 Constipation 0.2