IMJUDO- tremelimumab injection, solution
AstraZeneca Pharmaceuticals LP
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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use IMJUDO safely and effectively. See full prescribing information for IMJUDO.
IMJUDO (tremelimumab-xxxx) injection, for intravenous use Initial U.S. Approval: 20XX INDICATIONS AND USAGEIMJUDO is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody indicated in combination with durvalumab, for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC). (1.1) (1.1) DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHSCONTRAINDICATIONSNone. (4) WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSMost common adverse reactions (≥ 20%) of patients with uHCC are rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain. Most common laboratory abnormalities (≥ 40%) of patients with uHCC are AST increased, ALT increased, hemoglobin decreased, sodium decreased, bilirubin increased, alkaline phosphatase increased, and lymphocytes decreased. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. USE IN SPECIFIC POPULATIONSLactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 10/2022 |
The recommended dosage of IMJUDO is presented in Table 1.
Administer IMJUDO as an intravenous infusion after dilution as recommended [see Dosage and Administration (2.3)].
Indication |
Recommended IMJUDO dosage |
Duration of Therapy |
uHCC |
Patients with a body weight of 30 kg and more:
Patients with a body weight of less than 30 kg: |
After Cycle 1 of combination therapy, administer durvalumab as a single agent every 4 weeks until disease progression or unacceptable toxicity |
No dose reduction for treatment is recommended. In general, withhold treatment regimen for severe (Grade 3) immune-mediated adverse reactions. Permanently discontinue treatment regimen for life-threatening (Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating corticosteroids.
Recommended treatment modifications are presented in Table 2.
Adverse Reaction | Severity* | Dosage Modification |
---|---|---|
|
||
Immune-Mediated Adverse Reactions [see Warnings and Precautions (5.1)] |
||
Pneumonitis |
Grade 2 |
Withhold† |
Grade 3 or 4 |
Permanently discontinue |
|
Colitis |
Grade 2 |
Withhold† |
Grade 3 or 4 |
Permanently discontinue |
|
Intestinal perforation |
Any grade |
Permanently discontinue |
Hepatitis with no tumor involvement of the liver |
ALT or AST increases to more than 3 and up to 8 times the ULN or total bilirubin increases to more than 1.5 and up to 3 times ULN |
Withhold† |
ALT or AST increases to more than 8 times ULN or total bilirubin increases to more than 3 times the ULN |
Permanently discontinue |
|
Hepatitis with tumor involvement of the liver‡ |
AST or ALT is more than 1 and up to 3 times ULN at baseline and increases to more than 5 and up to 10 times ULN or AST or ALT is more than 3 and up to 5 times ULN at baseline and increases to more than 8 and up to 10 times ULN |
Withhold† |
AST or ALT increases to more than 10 times ULN or Total bilirubin increases to more than 3 times ULN |
Permanently discontinue |
|
Endocrinopathies |
Grade 3 or 4 |
Withhold until clinically stable or permanently discontinue depending on severity |
Nephritis with Renal Dysfunction |
Grade 2 or 3 increased blood creatinine |
Withhold† |
Grade 4 increased blood creatinine |
Permanently discontinue |
|
Exfoliative Dermatologic Conditions |
Suspected SJS, TEN, or DRESS |
Withhold† |
Confirmed SJS, TEN, or DRESS |
Permanently discontinue |
|
Myocarditis |
Grade 2, 3, or 4 |
Permanently discontinue |
Neurological Toxicities |
Grade 2 |
Withhold† |
Grade 3 or 4 |
Permanently discontinue |
|
Other Adverse Reactions |
||
Infusion-related reactions [see Warnings and Precautions (5.2)] |
Grade 1 or 2 |
Interrupt or slow the rate of infusion |
Grade 3 or 4 |
Permanently discontinue |
|
ALT = alanine aminotransferase, AST = aspartate aminotransferase, DRESS = Drug Rash with Eosinophilia and Systemic Symptoms, SJS = Stevens Johnson Syndrome, TEN = toxic epidermal necrolysis, ULN = upper limit normal |
Preparation
Dose | Patient Weight | Maximum diluent volume |
---|---|---|
300 mg |
≥ 30 kg |
150 mL |
4 mg/kg |
< 30 kg |
80 mL |
Storage of Diluted IMJUDO
Administration
Injection: 25 mg/1.25mL (20mg/mL) and 300 mg/15 mL (20 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial
IMJUDO is a monoclonal antibody that blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thereby removing inhibition of the immune response. In combination with durvalumab, a PD-L1 inhibitor, these drugs have the potential for induction of immune-mediated adverse reactions. Immune-mediated adverse reactions listed herein may not be inclusive of all possible severe and fatal immune-mediated reactions.
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. Immune-mediated adverse reactions can occur at any time after starting IMJUDO in combination with durvalumab. While immune-mediated adverse reactions usually manifest during treatment, immune-mediated adverse reactions can also manifest after discontinuation of IMJUDO and/or durvalumab.
Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of IMJUDO in combination with durvalumab. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and before each dose. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue IMJUDO and durvalumab depending on severity [see Dosage and Administration (2.2)]. In general, if combination of IMJUDO and durvalumab requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy.
Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.
Immune-Mediated Pneumonitis
IMJUDO in combination with durvalumab can cause immune-mediated pneumonitis, which may be fatal.
Immune mediated pneumonitis occurred in 1.3% (5/388) of patients receiving IMJUDO in combination with durvalumab, including fatal (0.3%) and Grade 3 (0.2%) adverse reactions. Events resolved in 3 of the 5 patients and resulted in permanent discontinuation in 1 patient. Systemic corticosteroids were required in all patients, of these 4 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient (1/5) required other immunosuppressants.
Immune-Mediated Colitis
IMJUDO in combination with durvalumab can cause immune-mediated colitis that is frequently associated with diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.
Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (3.6%) adverse reactions. Events resolved in 22 of the 23 patients and resulted in permanent discontinuation in 5 patients. All patients received systemic corticosteroids, and 20 of the 23 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also received other immunosuppressants.
Intestinal perforation has been observed in other studies of IMJUDO in combination with durvalumab..
Immune-Mediated Hepatitis
IMJUDO in combination with durvalumab can cause immune-mediated hepatitis, which may be fatal.
Immune-mediated hepatitis occurred in 7.5% (29/388) of patients receiving IMJUDO in combination with durvalumab, including fatal (0.8%), Grade 4 (0.3%), and Grade 3 (4.1%) adverse reactions. Events resolved in 12 of the 29 patients and resulted in permanent discontinuation in 9 patients. Systemic corticosteroids were required in all 29 patients and all 29 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients (8/29) required other immunosuppressants.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency: IMJUDO in combination with durvalumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold or permanently discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2)].
Immune-mediated adrenal insufficiency occurred in 1.5% (6/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (0.3%) adverse reactions. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in all 6 patients and of these, 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
Hypophysitis: IMJUDO in combination with durvalumab can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field cuts. Hypophysitis can cause hypopituitarism. Initiate symptomatic treatment including hormone replacement as clinically indicated. Withhold or permanently discontinue IMJUDO in combination with durvalumab depending on severity [see Dosage and Administration (2.2)].
Immune-mediated hypophysitis/hypopituitarism occurred in 1.1% (5/462) of patients receiving STRIDE. Events resolved in 2 of the 5 patients. Systemic corticosteroids were required in 4 patients (4/5) with hypophysitis, of these 1 of the 4 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also required endocrine therapy.
Thyroid Disorders: IMJUDO in combination with durvalumab can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2)].
Thyroiditis: Immune-mediated thyroiditis occurred in 1.5% (6/388) of patients receiving IMJUDO in combination with durvalumab. Events resolved in 2 of the 6 patients. Systemic corticosteroids were required in 2 patients (2/6) with immune-mediated thyroiditis, of these 1 patient required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker.
Hyperthyroidism: Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (0.3%) adverse reactions. Events resolved in 15 of the 18 patients. Two patients (2/18) required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seventeen patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).
Hypothyroidism: Immune-mediated hypothyroidism occurred in 11% (42/388) of patients receiving IMJUDO in combination with durvalumab. Events resolved in 5 of the 42 patients. One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker).
Type 1 Diabetes Mellitus: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold or permanently discontinue IMJUDO in combination with durvalumab based on the severity [see Dosage and Administration (2.2)].
Two patients (0.5%, 2/388) had events of hyperglycemia requiring insulin therapy that had not resolved at last follow-up.
Immune-Mediated Nephritis with Renal Dysfunction
IMJUDO in combination with durvalumab can cause immune-mediated nephritis.
Immune-mediated nephritis occurred in 1% (4/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 3 (0.5%) adverse reactions. Events resolved in 3 of the 4 patients and resulted in permanent discontinuation in 2 patients. Systemic corticosteroids were required in all patients with immune-mediated nephritis, of these 3 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
Immune-Mediated Dermatology Reactions
IMJUDO in combination with durvalumab can 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 CTLA-4 and PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes. Withhold or permanently discontinue IMJUDO in combination with durvalumab depending on severity [see Dosage and Administration (2.2)].
Immune-mediated pancreatitis occurred in 2.3% (9/388) of patients receiving IMJUDO in combination with durvalumab, including Grade 4 (0.3%) and Grade 3 (1.5%) adverse reactions. Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all 9 patients and of these, 7 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
Other Immune-Mediated Pancreatitis
IMJUDO in combination with durvalumab can cause immune-mediated pancreatitis.
Immune-mediated pancreatitis occurred in 1.9% (9/462) of patients receiving STRIDE, including Grade 4 (0.2%) and Grade 3 (1.3%) adverse reactions. Events resolved in 6 of the 9 patients. Systemic corticosteroids were required in all patients with immune-mediated pancreatitis, of these 7 patients required high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day).
Other Immune-Mediated Adverse Reactions
The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in patients who received IMJUDO in combination with durvalumab or were reported with the use of other immune-checkpoint inhibitors.
Cardiac/vascular: Myocarditis, pericarditis, vasculitis.
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 can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment to include blindness can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss.
Gastrointestinal: Gastritis, duodenitis.
Musculoskeletal and connective tissue disorders: Myositis/polymyositis, rhabdomyolysis and associated sequelae including renal failure, arthritis, polymyalgia rheumatica.
Endocrine: Hypoparathyroidism.
Other (hematologic/immune): Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, and immune thrombocytopenia.
IMJUDO in combination with durvalumab can cause severe or life-threatening infusion-related reactions.
Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue IMJUDO and durvalumab based on the severity [see Dosage and Administration (2.2)]. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses.
Infusion-related reactions occurred in 10 (2.6%) patients receiving IMJUDO in combination with durvalumab.
Based on findings from animal studies and its mechanism of action, IMJUDO can cause fetal harm when administered to a pregnant woman. In animal studies, CTLA-4 blockade is associated with higher incidence of pregnancy loss.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IMJUDO and for 3 months after the last dose of IMJUDO [see Use in Specific Populations (8.1, 8.3)].
The following adverse reactions are discussed in greater detail in other sections of the labeling.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hepatocellular Carcinoma
The safety of IMJUDO administered in combination with durvalumab was evaluated in a total of 388 patients with uHCC in HIMALAYA, a randomized, open-label, multicenter study [see Clinical Studies (14.1)].
Patients received IMJUDO 300 mg administered as a single intravenous infusion in combination with durvalumab 1,500 mg on the same day, followed by durvalumab every 4 weeks or sorafenib 400 mg given orally twice daily.
Serious adverse reactions occurred in 41% of patients who received IMJUDO in combination with durvalumab. Serious adverse reactions in > 1% of patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%), pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury (1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8% of patients who received IMJUDO in combination with durvalumab, including death (1%), hemorrhage intracranial (0.5%), cardiac arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and immune-mediated hepatitis (0.5%). The most common adverse reactions (occurring in ≥ 20% of patients) were rash, diarrhea, fatigue, pruritus, musculoskeletal pain, and abdominal pain.
Permanent discontinuation of the treatment regimen due to an adverse reaction occurred in 14% of patients; the most common adverse reactions leading to treatment discontinuation (≥ 1%) were hemorrhage (1.8%), diarrhea (1.5%), AST increased (1%), and hepatitis (1%).
Dosage interruptions or delay of the treatment regimen due to an adverse reaction occurred in 35% of patients. Adverse reactions which required dosage interruption or delay in ≥ 1% of patients included ALT increased (3.6%), diarrhea (3.6%), rash (3.6%), amylase increased (3.4%), AST increased (3.1%), lipase increased (2.8%), pneumonia (1.5%), hepatitis (1.5%), pyrexia (1.5%), anemia (1.3%), thrombocytopenia (1%), hyperthyroidism (1%), pneumonitis (1%), and blood creatinine increased (1%).
Table 4 summarizes the adverse reactions that occurred in patients treated with IMJUDO in combination with durvalumab in the HIMALAYA study.
IMJUDO and Durvalumab
(N=388) | Sorafenib
(N=374) |
|||
---|---|---|---|---|
Adverse Reaction | All Grades (%) | Grade 3-4 (%) | All Grades (%) | Grade 3-4 (%) |
|
||||
Gastrointestinal disorders | ||||
Diarrhea* |
27 |
6 |
45 |
4.3 |
Abdominal pain* |
20 |
1.8 |
24 |
4 |
Nausea |
12 |
0 |
14 |
0 |
Skin and subcutaneous tissue disorders |
||||
Rash* |
32 |
2.8 |
57 |
12 |
Pruritus |
23 |
0 |
6 |
0.3 |
Metabolism and nutrition disorders |
||||
Decreased appetite |
17 |
1.3 |
18 |
0.8 |
General disorders and administration site conditions |
||||
Fatigue* |
26 |
3.9 |
30 |
6 |
Pyrexia* |
13 |
0.3 |
9 |
0.3 |
Psychiatric disorders | ||||
Insomnia |
10 |
0.3 |
4.3 |
0 |
Endocrine disorders |
||||
Hypothyroidism* |
14 |
0 |
6 |
0 |
Musculoskeletal and Connective Tissue Disorders |
||||
Musculoskeletal pain* |
22 |
2.6 |
17 |
0.8 |
Table 5 summarizes the laboratory abnormalities that occurred in patients treated with IMJUDO in combination with durvalumab in the HIMALAYA study.
IMJUDO and Durvalumab | Sorafenib | |||
---|---|---|---|---|
Laboratory Abnormality | Any grade*
(%)† | Grade 3* or 4
(%)† | Any grade*
(%)† | Grade 3* or 4
(%)† |
Chemistry | ||||
Aspartate Aminotransferase increased |
63 |
27 |
55 |
21 |
Alanine Aminotransferase increased |
56 |
18 |
53 |
12 |
Sodium decreased |
46 |
15 |
40 |
11 |
Bilirubin increased |
41 |
8 |
47 |
11 |
Alkaline Phosphatase increased |
41 |
8 |
44 |
5 |
Glucose increased |
39 |
14 |
29 |
4 |
Calcium decreased |
34 |
0 |
43 |
0.3 |
Albumin decreased |
31 |
0.5 |
37 |
1.7 |
Potassium increased |
28 |
3.8 |
21 |
2.6 |
Creatinine increased |
21 |
1.3 |
15 |
0.9 |
Hematology | ||||
Hemoglobin decreased |
52 |
4.8 |
40 |
6 |
Lymphocytes decreased |
41 |
11 |
39 |
10 |
Platelets decreased |
29 |
1.6 |
35 |
3.1 |
Leukocytes decreased |
20 |
0.8 |
30 |
1.1 |
Risk summary
Based on findings from animal studies and its mechanism of action, IMJUDO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IMJUDO in pregnant women. In animal studies, CTLA-4 blockade is associated with increased risk of immune-mediated rejection of the developing fetus and fetal death (see Data).
Human immunoglobulin G2 (IgG2) is known to cross the placental barrier; therefore, IMJUDO has the potential to be transmitted from the mother to the developing fetus. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In reproduction studies, administration of tremelimumab-actl to pregnant cynomolgus monkeys during the period of organogenesis through delivery was not associated with maternal toxicity or effects on embryo-fetal development at exposure levels approximately 31-times higher than those observed at a recommended dose of 300 mg (based on AUC). CTLA-4 plays a role in maintaining maternal immune tolerance to the fetus to preserve pregnancy and in immune regulation of the newborn. In a murine model of pregnancy, CTLA-4 blockade resulted in increased resorptions and reduced live fetuses. Mated genetically engineered mice heterozygous for CTLA-4 (CTLA-4+/-) gave birth to CTLA-4+/- offspring and offspring deficient in CTLA-4 (homozygous negative, CTLA-4-/-) that appeared healthy at birth. The CTLA-4-/- homozygous negative offspring developed signs of a lymphoproliferative disorder and died by 3 to 4 weeks of age with multiorgan tissue destruction. Based on its mechanism of action, fetal exposure to tremelimumab-actl may increase the risk of developing immune-mediated disorders or altering the normal immune response.
Risk Summary
There are no data on the presence of tremelimumab-actl in human milk, its effects on a breastfed child, or on milk production. Maternal IgG is known to be present in human milk. The effects of local gastrointestinal exposure and limited systemic exposure in the breastfed child to IMJUDO are unknown. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with IMJUDO and for 3 months after the last dose. Refer to the Prescribing Information for agents administered in combination with IMJUDO for breastfeeding recommendations, as appropriate.
IMJUDO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Pregnancy Testing
Verify pregnancy status of females of reproductive potential prior to initiating treatment with IMJUDO.
Contraception
Advise females of reproductive potential to use effective contraception during treatment with IMJUDO and for 3 months after the last dose. Refer to the Prescribing Information for the agents administered in combination with IMJUDO for recommended contraception duration, as appropriate.
The safety and effectiveness of tremelimumab-actl have not been established in pediatric patients.
Of the 393 patients with uHCC treated with IMJUDO in combination with durvalumab, 50% of patients were 65 years or older and 13% of patients were 75 years or older. No overall differences in safety or efficacy of IMJUDO have been observed between patients 65 years or older and younger adult patients.
Tremelimumab-actl, a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking human IgG2 monoclonal antibody, is produced by recombinant DNA technology in NS0 cell suspension culture and has a molecular weight of 149 kDa.
IMJUDO (tremelimumab-actl) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial for intravenous infusion after dilution. IMJUDO contains tremelimumab-actl at a concentration of 20 mg/mL in either a 25 mg/1.25 mL or a 300 mg/15 mL single-dose vial.
Each mL contains 20 mg of tremelimumab-actl, and edetate disodium (0.09 mg), histidine (0.68 mg), L histidine hydrochloride monohydrate (3.3 mg), polysorbate 80 (0.2 mg), trehalose (76 mg), and Water for Injection, USP. The pH is approximately 5.5.
CTLA-4 is a negative regulator of T-cell activity. Tremelimumab-actl is a monoclonal antibody that binds to CTLA-4 and blocks the interaction with its ligands CD80 and CD86, releasing CTLA-4-mediated inhibition of T-cell activation. In synergistic mouse tumor models, blocking CTLA-4 activity resulted in decreased tumor growth and increased proliferation of T cells in tumors.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of tremelimumab-actl have not been fully characterized.
The pharmacokinetics of tremelimumab-actl was studied in patients with other solid tumors following administration of doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) administered once every 4 weeks for 4 doses. The pharmacokinetics of tremelimumab-actl as a single dose of 300 mg were evaluated in patients with HCC.
The AUC of tremelimumab-actl increased proportionally from 1 mg/kg to 10 mg/kg every 4 weeks (1 to 10-times the approved recommended dosage) and steady state was achieved at approximately 12 weeks.
Distribution
The geometric mean (% coefficient of variation [CV%]) of tremelimumab-actl for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively.
Elimination
The geometric mean (CV%) terminal half-life of tremelimumab-actl was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady state. The geometric mean (CV%) clearance of tremelimumab-actl was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady state.
Specific Populations
There were no clinically significant differences in the pharmacokinetics of tremelimumab-actl based on body weight (34 to149 kg), age (18 to 87 years), sex, race (White, Black, Asian, Native Hawaiian, Pacific Islander, or American Indian), serum albumin levels (0.3 to 396 g/L), lactate dehydrogenase levels (12 to 5570 U/L), soluble PD-L1 (67 to 349 pg/mL), organ dysfunction including mild to moderate renal impairment (CLcr 30 to 89 mL/min), and mild to moderate hepatic impairment (bilirubin < 3 x ULN and any AST).
The effect of severe renal impairment (CLcr 15 to 29 mL/min) or severe hepatic impairment (bilirubin > 3 x ULN and any AST) on the pharmacokinetics of tremelimumab-actl is unknown.
The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in other studies, including those of tremelimumab-actl.
In the HIMALAYA study, of the 182 patients who were treated with a single dose of tremelimumab-actl in combination with durvalumab once in every 4 weeks therapy and evaluable for the presence of ADAs against tremelimumab-actl at predose week 0 and week 4, 11% (20/182) of patients tested positive for anti-tremelimumab-actl antibodies. Among the 20 patients who tested positive for ADAs 40% (8/20) tested positive for neutralizing antibodies against tremelimumab-actl. There was no identified clinically significant effect of anti-tremelimumab antibodies on the pharmacokinetics or safety of tremelimumab-actl; however, the effect of ADAs and neutralizing antibodies on the effectiveness of tremelimumab-actl is unknown.
The efficacy of IMJUDO in combination with durvalumab was evaluated in the HIMALAYA study (NCT03298451), a randomized (1:1:1), open-label, multicenter study in patients with confirmed uHCC who had not received prior systemic treatment for HCC. Patients were randomized to one of two investigational arms (IMJUDO plus durvalumab or durvalumab) or sorafenib. Study treatment consisted of IMJUDO as a one-time single intravenous infusion of 300 mg in combination with durvalumab 1,500 mg on the same day, followed by durvalumab every 4 weeks; durvalumab 1,500 mg every 4 weeks (an unapproved regimen for uHCC); or sorafenib 400 mg given orally twice daily, until disease progression or unacceptable toxicity. The efficacy assessment of IMJUDO is based on patients randomized to the IMJUDO plus durvalumab arm versus the sorafenib arm. Randomization was stratified by macrovascular invasion (MVI) (yes or no), etiology of liver disease (hepatitis B virus vs. hepatitis C virus vs. others) and ECOG performance status (0 vs. 1).
The study enrolled patients with BCLC Stage C or B (not eligible for locoregional therapy). The study excluded patients with co-infection of viral hepatitis B and hepatitis C; active or prior documented gastrointestinal (GI) bleeding within 12 months; ascites requiring non-pharmacologic intervention within 6 months; hepatic encephalopathy within 12 months before the start of treatment; active or prior documented autoimmune or inflammatory disorders. Esophagogastroduodenoscopy was not mandated prior to enrollment but adequate endoscopic therapy, according to institutional standards, was required for patients with a history of esophageal variceal bleeding or those assessed as high risk for esophageal variceal bleeding by the treating physician.
Study treatment was permitted beyond disease progression if the patient was clinically stable and was deriving clinical benefit as determined by the investigator.
The major efficacy outcome measure was overall survival (OS) between the IMJUDO plus durvalumab arm versus the sorafenib arm. Additional efficacy outcomes were investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) according to RECIST v1.1. Tumor assessments were conducted every 8 weeks for the first 12 months and then every 12 weeks thereafter.
The baseline demographics of the IMJUDO plus durvalumab and sorafenib arms were as follows: male (85%), age < 65 years (50%), median age of 65 years (range: 18 to 88 years), White (46%), Asian (49%), Black or African American (2%), Native Hawaiian or other Pacific Islander (0.1%), race Unknown (2%), Hispanic or Latino (5%), Not Hispanic or Latino (94%), ethnicity Unknown (1%), ECOG PS 0 (62%); Child-Pugh Class score A (99%), macrovascular invasion (26%), extrahepatic spread (53%), viral etiology hepatitis B (31%), hepatitis C (27%), uninfected (42%).
Efficacy results are presented in Table 6 and Figure 1.
Endpoint | IMJUDO and Durvalumab
(N=393) | Sorafenib
(N=389) |
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OS |
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Number of deaths (%) |
262 (66.7) |
293 (75.3) |
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16.4 (14.2, 19.6) |
13.8 (12.3, 16.1) |
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0.78 (0.66, 0.92) |
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0.0035 |
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PFS |
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Number of events (%) |
335 (85.2) |
327 (84.1) |
Median PFS (months) (95% CI) |
3.8 (3.7, 5.3) |
4.1 (3.7, 5.5) |
HR (95% CI)* |
0.90 (0.77, 1.05) |
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ORR |
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20.1 (16.3, 24.4) |
5.1 (3.2, 7.8) |
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12 (3.1) |
0 |
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67 (17.0) |
20 (5.1) |
DoR |
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22.3 (13.7, NR) |
18.4 (6.5, 26.0) |
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82.3 |
78.9 |
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65.8 |
63.2 |
CI=Confidence Interval, HR=Hazard Ratio, NR=Not Reached |
Figure 1. Kaplan-Meier curve of OS
IMJUDO (tremelimumab-actl) Injection is a clear to slightly opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial in the following concentrations:
Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.
Do not freeze. Do not shake.
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Immune-Mediated Adverse Reactions
Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of IMJUDO in combination with durvalumab, including [see Warnings and Precautions (5.1)]:
Infusion-Related Reactions:
Embryo-Fetal Toxicity:
Lactation:
Manufactured for:
AstraZeneca Pharmaceuticals LP
Wilmington, DE 19850
Manufactured By:
AstraZeneca AB
Södertälje, Sweden SE-15185
US License No. 2059
IMJUDO® is a registered trademark of AstraZeneca group of companies.
©AstraZeneca 2022 AstraZeneca 2022
MEDICATION GUIDE
(tremelimumab-actl) injection |
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What is the most important information I should know about IMJUDO? IMJUDO is a medicine that may treat certain cancers by working with your immune system. IMJUDO in combination with durvalumab can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during treatment or even after your treatment has ended. Call or see your healthcare provider right away if you develop any new or worsening signs or symptoms, including: Lung problems. |
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Intestinal problems. |
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Liver problems. |
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Hormone gland problems. |
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Kidney problems. |
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Skin problems. |
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Pancreas problems. |
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Problems can also happen in other organs and tissues. These are not all of the signs and symptoms of immune system problems that can happen with IMJUDO. Call or see your healthcare provider right away for any new or worsening signs or symptoms, which may include:
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Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include: |
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Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with IMJUDO. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with IMJUDO , if you have severe side effects. |
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What is IMJUDO?
It is not known if IMJUDO is safe and effective in children. |
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Before you receive IMJUDO, tell your healthcare provider about all of your medical conditions, including if you:
Females who are able to become pregnant
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. |
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How will I receive IMJUDO?
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What are the possible side effects of IMJUDO? IMJUDO can cause serious side effects, including: See “What is the most important information I should know about IMJUDO?” |
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The most common side effects of IMJUDO when used in combination with durvalumab include:
Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of IMJUDO. Ask your healthcare provider or pharmacist for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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General information about the safe and effective use of IMJUDO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. If you would like more information about IMJUDO, talk with your healthcare provider. You can ask your healthcare provider for information about IMJUDO that is written for health professionals. |
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What are the ingredients in IMJUDO? Active ingredient: tremelimumab-actl Inactive ingredients: edetate disodium, histidine, L-histidine hydrochloride monohydrate, polysorbate 80, trehalose, and Water for Injection, USP. |
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Manufactured for: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 By: AstraZeneca AB, Södertälje, Sweden SE-15185 US License No. 2059 IMJUDO is a registered trademark of AstraZeneca group of companies. For more information, call 1-800-236-9933 or go to www.IMJUDO.com © AstraZeneca 2022 |
IMJUDO
tremelimumab injection, solution |
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IMJUDO
tremelimumab injection, solution |
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Labeler - AstraZeneca Pharmaceuticals LP (054743190) |
Registrant - AstraZeneca PLC (230790719) |