Dosage and Administration

Serious and fatal immune-mediated adverse reactions (continued)

• Monitor for early identification and management. Assess liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate investigation to exclude alternative etiologies, including infection. Promptly institute medical management, including specialist consultation as appropriate.

• Withhold or permanently discontinue ZYTORVI®^based on the severity and type of reaction (see Dosage and Administration in the Prescribing Information). In general, if ZYTORVI®^requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. After improvement to Grade 1 or less, initiate a corticosteroid taper and continue the taper for at least one month. Consider administration of other systemic immunosuppressants in patients whose immune-related adverse reactions are not controlled with corticosteroid therapy.

Immune-mediated pneumonitis

ZYTORVI ^® may cause immune-mediated pneumonitis.

• In patients receiving ZYTORVI ^® in combination with cisplatin and gemcitabine, immune-mediated pneumonitis occurred in 2.1% (3/146) of patients, including Grade 2 adverse reactions (1.4%). Pneumonitis resolved in 67% (2/3) of these patients.

• In patients receiving ZYTORVI ^® monotherapy, immune-mediated pneumonitis occurred in 2.6% (22/851) of patients, including fatal (0.2%), Grade 3 (0.7%), and Grade 2 (1.1%) adverse reactions. Systemic corticosteroids were required in 82% (18/22) of patients with pneumonitis. Pneumonitis led to permanent discontinuation of ZYTORVI ^® in 1.2% (10/851) of patients. Pneumonitis resolved in 23% (5/22) of these patients.

Immune-mediated colitis

ZYTORVI^® can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeat infectious workup to exclude alternative etiologies. In patients receiving ZYTORVI^® monotherapy, immune-mediated colitis occurred in 0.4% (3/851) of patients, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. Colitis resolved in all 3 patients.

Hepatotoxicity and immune-mediated hepatitis

ZYTORVI^® can cause immune-mediated hepatitis.

• In patients receiving ZYTORVI^® in combination with cisplatin and gemcitabine, immune-mediated hepatitis occurred in 0.7% (1/146) of patients, which was a Grade 3 adverse reaction (0.7%). The patient with immune-mediated hepatitis required systemic corticosteroids.

• In patients receiving ZYTORVI^® monotherapy, immune-mediated hepatitis occurred in 3.3% (28/851) of patients, including Grade 4 (0.8%), Grade 3 (2.1%), and Grade 2 (0.4%) adverse reactions. Hepatitis led to permanent discontinuation of ZYTORVI^® in 1.1% of patients and discontinuation of ZYTORVI^® in 0.8% of patients. Hepatitis resolved in 54% (15/28) of these patients.

Immune-mediated endocrinopathies

Adrenal insufficiency:

ZYTORVI^® can cause primary or secondary adrenal insufficiency. For Grade 2 or greater adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue ZYTORVI^® depending on severity. In patients receiving ZYTORVI^® monotherapy, adrenal insufficiency occurred in 0.5% (4/851) of patients, including Grade 2 (0.4%) and Grade 1 (0.1%) adverse reactions. Systemic corticosteroids were required in 75% (3/4) of patients with adrenal insufficiency. Adrenal insufficiency led to discontinuation of ZYTORVI^® in 0.1% (1/851) of patients. Of the one patient in whom ZYTORVI^® was withheld, ZYTORVI^® was restarted after symptom improvement.

Hypophysitis:

ZYTORVI^® can cause immune-mediated hypophysitis. Hypophysitis may present with acute symptoms associated with mass effects such as headache, photophobia, or visual field defects. Hypophysitis may cause hypopituitarism. Initiate hormone replacement therapy as indicated. Withhold or permanently discontinue ZYTORVI^® depending on severity. In patients receiving ZYTORVI^® monotherapy, hypophysitis occurred in 0.4% (3/851) of patients receiving ZYTORVI^®, including Grade 3 (0.2%) and Grade 2 (0.1%) adverse reactions. All three patients received systemic corticosteroids. Hypophysitis led to permanent discontinuation of ZYTORVI^® in 0.1% (1/851) of patients and discontinuation of ZYTORVI^® in 0.1% (1/851) of patients. The only patient in whom ZYTORVI^® was discontinued restarted ZYTORVI^®.

Thyroid disorders:

ZYTORVI^® may cause immune-mediated thyroid disorders. Thyroiditis may present with or without endocrinopathy. Hypothyroidism may accompany hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical treatment for hyperthyroidism as clinically indicated. Discontinue or permanently discontinue ZYTORVI^® depending on severity.

• In patients receiving ZYTORVI^® in combination with cisplatin and gemcitabine, thyroiditis occurred in 2.1% (3/146) of patients receiving ZYTORVI, including Grade 2 (1.4%). Three patients required thyroid hormone replacement therapy. Thyroiditis resolved in one of the 3 patients. Hyperthyroidism occurred in 1.4% (2/146) of patients receiving ZYTORVI in combination with cisplatin and gemcitabine. Hyperthyroidism resolved in these 2 patients. Hypothyroidism occurred in 30% (44/146) of patients receiving ZYTORVI in combination with cisplatin and gemcitabine, including Grade 2 (24%) and Grade 1 (6%). Eighty percent of the 44 patients required thyroid hormone replacement therapy. ZYTORVI was discontinued in 2.1% (3/146) of patients. Of the 3 patients in whom ZYTORVI^® was discontinued, 2 patients restarted ZYTORVI^®.

• In patients receiving ZYTORVI^® monotherapy, thyroiditis occurred in 0.6% (5/851) of patients receiving ZYTORVI^®, including Grade 2 (0.1%). Two of these 5 patients received systemic corticosteroids and 2 required thyroid hormone replacement therapy. Thyroiditis resolved in 2 of the 5 patients. Hyperthyroidism occurred in 7% (55/851) of patients receiving ZYTORVI^®, including Grade 2 (1.9%). Hyperthyroidism resolved in 85% (47/55) of patients. Hypothyroidism occurred in 15% (128/851) of patients receiving ZYTORVI^®, including Grade 2 (8%). Sixty-three percent of the 128 patients required thyroid hormone replacement therapy. ZYTORVI^® was discontinued in 0.5% of patients. Of the 4 patients in whom ZYTORVI^® was discontinued, 3 patients restarted ZYTORVI^®.

Type 1 Diabetes Mellitus, which may present with diabetic ketoacidosis:

ZYTORVI^® can cause primary or secondary diabetes mellitus. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate insulin treatment as clinically indicated. Withhold or permanently discontinue ZYTORVI^® depending on severity. In patients receiving ZYTORVI^® monotherapy, diabetes mellitus occurred in 0.9% (8/851) of patients receiving ZYTORVI^®, including Grade 4 (0.1%), Grade 3 (0.7%), and Grade 2 (0.1%). Diabetes mellitus led to permanent discontinuation in 0.4% of patients. Six of 8 (75%) patients with diabetes mellitus required long-term insulin therapy.

Immune-mediated nephritis with renal dysfunction

ZYTORVI^® may cause immune-mediated nephritis.

• In patients receiving ZYTORVI^® in combination with cisplatin and gemcitabine, immune-mediated nephritis occurred in 0.7% (1/146) of patients receiving ZYTORVI^®. The one patient with immune-mediated nephritis (Grade 4) required systemic corticosteroids and the nephritis led to discontinuation of ZYTORVI^®. The nephritis resolved in this patient.

• In patients receiving ZYTORVI^® monotherapy, immune-mediated nephritis occurred in 0.5% (4/851) of patients, including Grade 3 adverse reactions (0.5%). Nephritis resolved in 75% (3/4) of these patients.

Immune-mediated dermatological adverse reactions

ZYTORVI^® may cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), drug rash with eosinophilia and systemic symptoms (DRESS), and toxic epidermal necrolysis (TEN), has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be appropriate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue ZYTORVI^® depending on severity.

• In patients receiving ZYTORVI^® in combination with cisplatin and gemcitabine, immune-mediated dermatologic adverse reactions occurred in 8% (12/146) of patients, including Grade 3 (3.4%) and Grade 2 (1.4%) adverse reactions. Systemic corticosteroids were required in 25% (3/12) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions led to permanent discontinuation of ZYTORVI^® in 2.1% (3) of patients. Immune-mediated dermatologic adverse reactions resolved in 92% (11/12) of these patients.

• In patients receiving ZYTORVI^® monotherapy, immune-mediated dermatologic adverse reactions occurred in 4% (34/851) of patients, including Grade 3 (0.4%) and Grade 2 (1.4%) adverse reactions. Immune-mediated dermatologic adverse reactions led to discontinuation of ZYTORVI^® in 0.4% (3) of patients. Systemic corticosteroids were required in 12% (4/34) of patients with immune-mediated dermatologic adverse reactions. Immune-mediated dermatologic adverse reactions resolved in 71% (24/34) of these patients.

Other immune-mediated adverse reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients receiving ZYTORVI^® or have been reported with the use of other PD-1/PD-L1 blocking antibodies. Serious or fatal outcomes have been reported for some of these adverse reactions.

• Cardiac/Vascular: Myocarditis, pericarditis, vasculitis, pericardial effusion

• Nervous system: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy

• Ocular: Uveitis, iritis, and other ocular inflammatory toxicities may occur. Some cases may be associated with retinal detachment. Varying degrees of visual impairment, including blindness, may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.

• Gastrointestinal: Pancreatitis, including increased serum amylase and lipase levels, gastritis, duodenitis

• Musculoskeletal and connective tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis, polymyalgia rheumatica, dermatomyositis

• Endocrine: Hypoparathyroidism

• Hematologic/Immune: hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection

Infusion-related reaction

ZYTORVI^® can cause serious or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis.

• In patients receiving ZYTORVI^® in combination with cisplatin and gemcitabine, infusion-related reactions were reported in 4.1% of patients, including Grade 2 reactions (0.7%).

• In patients receiving ZYTORVI^® monotherapy, infusion-related reactions occurred in 2% of 851 patients, including Grade 3 (0.1%) and Grade 2 (0.6%). ZYTORVI^® was discontinued due to a Grade 3 infusion-related reaction. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. Interrupt or slow the infusion rate for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. For severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions, interrupt the infusion and permanently discontinue ZYTORVI^®.

Complications of allogeneic HSCT

Fatal and other serious complications can occur in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications can occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT. Monitor patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 blocking antibody before or after allogeneic HSCT.

Embryo-fetal toxicity

ZYTORVI^® can cause fetal harm when administered to a pregnant woman. Animal studies have shown that inhibition of the PD-1/PD-L1 pathway may lead to an increased risk of immune-mediated rejection of the developing fetus, resulting in fetal death. Inform women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ZYTORVI^® and for 4 months after the last dose.

Lactation

There are no data on the presence of toripalimab-tpzi in human milk, its effects on the breastfed infant, or its effects on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure of the breastfed infant to toripalimab-tpzi are unknown. Because of the potential for serious adverse reactions in breastfed infants, advise nursing women not to breastfeed during treatment with ZYTORVI^® and for 4 months after the last dose.

Serious adverse reactions

• In JUPITER-02, when ZYTORVI^® was administered in combination with cisplatin and gemcitabine for the first-line treatment of recurrent, locally advanced or metastatic nasopharyngeal carcinoma, serious adverse reactions occurred in 43% of patients. Serious adverse drug reactions in ≥2% were thrombocytopenia (14%), decreased neutrophil count (10%), pneumonia (10%), anemia (9%), abnormal liver function (2.7%), and rash (2.1%). There were three fatal adverse reactions (2.1%): one due to epistaxis; one due to intracranial hemorrhage associated with immune-related thrombocytopenia and coagulopathy; and one due to pneumonia. Permanent discontinuation of ZYTORVI^® due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of ZYTORVI^® in ≥1% were pneumonia (2.1%), pulmonary tuberculosis (1.4%), rash (1.4%), and vomiting (1.4%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased neutrophils (58%), decreased lymphocytes (57%), decreased hemoglobin (50%), decreased platelets (33%), decreased potassium (10%), decreased sodium (9%), increased alanine aminotransferase (6%), increased or decreased magnesium (4.2% each), decreased calcium (3.5%), increased aspartate aminotransferase (2.7%), increased bilirubin (2.1%).

• In POLARIS-02, when ZYTORVI^® was administered as a single agent to patients with previously treated, unresectable or metastatic nasopharyngeal carcinoma, serious adverse reactions occurred in 24% of patients. Serious adverse drug reactions in ≥2% were pneumonia (4.7%), abnormal liver function (2.6%), and hyperbilirubinemia (2.1%). Fatal adverse reactions occurred in 3.7% of patients receiving ZYTORVI^®, including death not otherwise specified (1.6%), tumor hemorrhage (0.5%), hepatic failure and thrombocytopenia (0.5%), hyponatremia (0.5%), and sudden death (0.5%). Permanent discontinuation of ZYTORVI^® due to an adverse reaction occurred in 9% of patients. Adverse reactions resulting in permanent discontinuation of ZYTORVI^® in ≥1% included pneumonia (1.1%), abnormal liver function (1.1%), and hyperbilirubinemia (1.1%). The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased sodium (11%), decreased lymphocytes (9%), decreased hemoglobin (6%), increased aspartate aminotransferase (3.8%), decreased phosphate (3.2%), and increased alkaline phosphatase (2.2%).

Common adverse reactions

• In JUPITER-02, the most common adverse reactions (≥20%) were nausea (71%), vomiting (68%), decreased appetite (55%), constipation (39%), hypothyroidism (38%), rash (36%), pyrexia (32%), diarrhea (31%), peripheral neuropathy (30%), cough (26%), musculoskeletal pain (25%), upper respiratory infection (23%), insomnia (23%), dizziness (21%), and malaise (21%).

• In POLARIS-02, in patients with previously treated, unresectable or metastatic nasopharyngeal carcinoma, the most common adverse reactions (≥20%) were hypothyroidism (27%), fatigue (22%), and cough (20%).

See ZYTORVI^® Prescribing Information.