Durvalumab

Immune-related adrenal insufficiency has been reported with durvalumab. Monitor for clinical signs/symptoms of adrenal insufficiency. If grade 2 or higher adrenal insufficiency occurs, administer systemic corticosteroids and hormone replacement as clinically indicated; interrupt durvalumab treatment (based on the severity).

Durvalumab has caused immune-mediated rash. Bullous dermatitis, Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported with other anti-PD-L1 monoclonal antibodies. Monitor for signs/symptoms of dermatologic toxicity. Initiate systemic corticosteroids for grade 2 rash or dermatitis lasting for more than 1 week or severe grade 3 or 4 rash/dermatitis, followed by a taper. May require treatment interruption or discontinuation (based on the severity).

Immune-related type 1 diabetes mellitus has occurred in patients receiving durvalumab. The median time to onset was 1.4 months. Monitor glucose and monitor for clinical signs/symptoms of diabetes. Initiate insulin for type 1 diabetes mellitus and interrupt durvalumab treatment (based on the severity) until clinically stable.

Immune-mediated colitis or diarrhea occurred in patients receiving durvalumab. Grades 3 and 4 diarrhea or colitis have been reported. The median time to onset was 1.4 months (range: 1 day to 14 months). Monitor for signs/symptoms of colitis or diarrhea and manage with treatment interruption or discontinuation, and systemic corticosteroids. In clinical studies, management with systemic corticosteroids, including high-dose corticosteroids was utilized in some patients; other immunosuppressants (eg, infliximab, mycophenolate) were required (rarely). Resolution occurred in approximately three-quarters of patients who experienced immune-mediated diarrhea/colitis.

Immune-mediated hepatitis has occurred in patients receiving durvalumab (some fatal). The median time to onset was ~1 month (range: 1 day to ~14 months). Monitor for signs/symptoms (including abnormal liver function tests) of hepatitis during durvalumab treatment and after discontinuation. Manage immune-mediated hepatitis with systemic corticosteroids and treatment interruption or discontinuation. In clinical studies, some patients experiencing immune-mediated hepatitis received high-dose corticosteroids; mycophenolate was required (rarely) to manage immune-mediated hepatitis. Recovery occurred in approximately half of patients experiencing immune-mediated hepatitis. Grade 3 or 4 ALT, AST, and/or total bilirubin elevations have been reported.

Immune-related hypophysitis/hypopituitarism has occurred in patients receiving durvalumab. Monitor for clinical signs/symptoms of hypophysitis or hypopituitarism. If grade 2 or higher hypophysitis occurs, administer corticosteroids and hormone replacement therapy as indicated; interrupt durvalumab (based on the severity). Hypopituitarism leading to adrenal insufficiency and diabetes insipidus has occurred (rarely).

Infections occurred in almost half of patients receiving durvalumab (some fatal). Severe infections, including sepsis, necrotizing fasciitis, and osteomyelitis have been reported. The most common grade 3 or 4 infections were urinary tract infections (urothelial carcinoma study) and pneumonia (non-small cell lung cancer [NSCLC] study). The overall incidence of infections was higher in a NSCLC study, compared to patients in other studies in whom radiation therapy was typically not administered immediately prior to durvalumab. Monitor for signs/symptoms of infection; if infection is suspected or confirmed, manage with anti-infectives. Withhold treatment for grade 3 or 4 infection.

Infusion reactions have been observed with durvalumab, including severe or life-threatening infusion-related reactions. Monitor for signs/symptoms of infusion reactions. Interrupt or slow the infusion rate for mild or moderate infusion reactions (consider premedications with subsequent infusions). Discontinue durvalumab permanently for grade 3 or 4 infusion reactions.

Durvalumab has caused immune-mediated nephritis (including fatal cases). Monitor renal function prior to initiating treatment and periodically during durvalumab treatment. Nephritis may require systemic corticosteroids and treatment interruption or discontinuation. Nephritis resolved in ~50% of patients. The median time to onset was 2 months (range: 1 day to ~14 months).

Immune-mediated pneumonitis or interstitial lung disease has occurred in patients receiving durvalumab (including fatal cases). The median time to onset was ~2 months (range: 1 day to ~19 months), and the median time to resolution was ~2 to 5 months (range up to ~19 months). In a non-small cell lung cancer study, the incidence of pneumonitis (including radiation pneumonitis) was higher in patients who completed definitive chemoradiation within 42 days prior to initiating durvalumab, compared to patients in other studies in whom radiation therapy was typically not administered immediately prior to durvalumab. Monitor for signs/symptoms of pneumonitis; evaluate suspected pneumonitis with radiographic imaging and manage with systemic corticosteroids and durvalumab treatment interruption or discontinuation. In clinical studies, resolution occurred in approximately half of patients experiencing immune-mediated pneumonitis.

Immune-related thyroid disorders have occurred in patients receiving durvalumab. Monitor thyroid function at baseline and periodically during treatment; monitor for clinical signs/symptoms of thyroid disorders. Hypothyroidism, hyperthyroidism, and thyroiditis (including grade 3 thyroiditis) have occurred in clinical trials. Hypothyroidism was preceded by thyroiditis or hyperthyroidism is some patients. Manage hypothyroidism with hormone replacement (if indicated) while continuing durvalumab. Initiate appropriate medical management for hyperthyroidism; withhold durvalumab (based on severity). Treatment with a beta-blocker and/or thioamide was administered for hyperthyroidism in some patients.

Ocular inflammatory toxicity including uveitis and keratitis have been reported. If uveitis occurs in combination with other immune-mediated reactions, evaluate for Vogt-Koyanagi-Harada syndrome; may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Other immune-related adverse reactions associated with durvalumab (rarely) include aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, and myositis. These immune-mediated toxicities usually occurred during treatment, although may occur after discontinuation. For suspected grade 2 immune-mediated reactions, exclude other causes and initiate systemic corticosteroids as clinically indicated. Administer systemic corticosteroids for grade 3 or 4 immune-mediated reactions. May require treatment interruption or discontinuation. Other immune-mediated reactions have also been reported with other anti-PD-L1 monoclonal antibodies, including pancreatitis, systemic inflammatory response syndrome, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, iritis, encephalitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatic, autoimmune neuropathy, Guillain-Barre syndrome and Vogt-Koyanagi-Harada syndrome. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage form specific issues:

Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.