Dosing & Uses
Dosage Forms & Strengths
injectable solution
- 20mg/mL (1.25-mL, 15-mL single-dose vials)
Hepatocellular Carcinoma
Indicated in combination with durvalumab for unresectable hepatocellular carcinoma (uHCC)
Each cycle is 28 days
Cycle 1 in combination with durvalumab
- Weight ≥30 kg: Tremelimumab 300 mg IV x 1 dose, THEN durvalumab 1500 mg IV
- Weight <30 kg: Tremelimumab 4 mg/kg IV x 1 dose, THEN durvalumab 20 mg/kg IV
Cycle 2 and thereafter
- Weight ≥30 kg: Durvalumab 1,500 mg IV q4Weeks as a single agent
- Weight <30 kg: Durvalumab 20 mg/kg IV q4Weeks as a single agent
- Continue until disease progression or unacceptable toxicity
Non-small Cell Lung Cancer
Indicated in combination with durvalumab and platinum-based chemotherapy for adults with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations
Weight based dose ≥30 kg
- Tremelimumab 75 mg IV
- Durvalumab: 1500 mg IV
Weight based dose <30 kg
- Tremelimumab 1 mg/kg IV
- Durvalumab: 20 mg/kg IV
Cycles 1-4
- Dose interval every 3 weeks
- Administer tremelimumab, durvalumab and chemotherapy
Cycle 5 (week 12)
- Starting at cycle 5, dose interval changes from every 3 weeks to every 4 weeks
- Administer durvalumab and chemotherapy
- Note: If ≤4 cycles of platinum-based chemotherapy received, the remaining cycles of tremelimumab (up to a total of 5) should be given after the platinum-based chemotherapy phase, in combination with durvalumab, every 4 weeks
- Optional pemetrexed therapy from week 12 until disease progression or intolerable toxicity for patients with nonsquamous disease who received treatment with pemetrexed and carboplatin/cisplatin
Cycle 6 (week 16)
- Administer tremelimumab, durvalumab and chemotherapy
Cycle 7 (week 20) and thereafter
- Administer durvalumab and chemotherapy
- Continue durvalumab until disease progression or intolerable toxicity
Platinum-based chemotherapy regimens
-
Non-squamous NSCLC
- Carboplatin plus nab-paclitaxel, OR
- Carboplatin or cisplatin plus pemetrexed
-
Squamous NSCLC
- Carboplatin plus nab-paclitaxel, OR
- Carboplatin or cisplatin plus gemcitabine
Dosage Modifications
No dose reductions are recommended
Intestinal perforation
- Any grade: Permanently discontinue
Pneumonitis, colitis, or neurological toxicities
- Grade 2: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 3 or 4: Permanently discontinue
Hepatitis with no tumor involvement of the liver
-
Withhold therapy
- ALT or AST increases to >3x and ≤8x ULN OR
- Total bilirubin [TB] increases to >1.5x and ≤3x ULN
- Resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
-
Permanently discontinue
- AST or ALT increases to >8x ULN or TB increases to >3x ULN
Hepatitis with tumor involvement of the liver
- If AST and ALT are ≤ULN at baseline, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement
-
Withhold therapy
- Baseline AST or ALT >1 and ≤3x ULN and increases to >5 and ≤10x ULN
- Baseline AST or ALT >3 and ≤5x ULN and increases to >8 and ≤10x ULN
- Resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
-
Permanently discontinue
- AST or ALT increases to >10x ULN or TB increases to >3x ULN
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 therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Grade 4 increased blood creatinine: Permanently discontinue
Exfoliative dermatologic conditions
- Suspected Stevens-Johnson Syndrome (SJS), toxic epidermal necrosis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: Withhold therapy; resume when complete or partial resolution occurs (Grade <1) after corticosteroid taper
- Permanently discontinue if no complete or partial resolution within 12 weeks of initiating steroids or inability to reduce prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating steroids
- Confirmed SJS, TEN, or DRESS syndrome: Permanently discontinue
Myocarditis
- Grade 2, 3, or 4: Permanently discontinue
Infusion-related reactions
- Grade 1 or 2: Interrupt or slow infusion rate
- Grade 3 or 4: Permanently discontinue
Renal impairment
- Mild-to-moderate (CrCl 30-89 mL/min): No dosage adjustment necessary
- Severe (CrCl 15-29 mL/min): Pharmacokinetics unknown
Hepatic impairment
- Mild-to-moderate (bilirubin <3x and any AST): No dosage adjustment necessary
- Severe (bilirubin >3x ULN and any AST): Pharmacokinetics unknown
Dosing Considerations
Verify pregnancy status of females of reproductive potential before initiating
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (0)
Serious - Use Alternative (0)
Monitor Closely (0)
Minor (0)
Adverse Effects
Listed Adverse Effects
uHCC: Adverse reactions listed are for tremelimumab combined with durvalumab
NSCLC: Adverse reactions listed are for tremelimumab combined with durvalumab and platinum-based chemotherapy
>10%
All grades (uHCC)
- AST increased (63%)
- ALT increased (56%)
- Hemoglobin decreased (52%)
- Sodium decreased (46%)
- Bilirubin increased (41%)
- Alkaline phosphatase increased (41%)
- Lymphocytes decreased (41%)
- Glucose increased (39%)
- Calcium decreased (34%)
- Rash (32%)
- Albumin decreased (31%)
- Platelets decreased (29%)
- Potassium increased (28%)
- Diarrhea (27%)
- Fatigue (26%)
- Pruritus (23%)
- Musculoskeletal pain (22%)
- Creatinine increased (21%)
- Abdominal pain (20%)
- Leukocytes decreased (20%)
- Decreased appetite (17%)
- Hypothyroidism (14%)
- Pyrexia (13%)
- Nausea (12%)
Grades 3 or 4 (uHCC)
- AST increased (27%)
- ALT increased (18%)
- Sodium decreased (15%)
- Glucose increased (14%)
All grades (NSCLC)
- Blood creatinine increased (89%)
- Anemia (84%)
- Leukopenia (77%)
- Neutropenia (71%)
- Lymphocytopenia (67%)
- Increased ALT (64%)
- Increased AST (63%)
- Hypocalcemia (58%)
- Hyponatremia (55%)
- Thrombocytopenia (53%)
- Hyperkalemia (49%)
- Nausea (42%)
- Hyperglycemia (42%)
- Amylase increased (41%)
- GGT increased (38%)
- Fatigue/asthenia (36%)
- Lipase increased (35%)
- Alkaline phosphatase increased (38%)
- Musculoskeletal pain (29%)
- Decreased appetite (28%)
- Rash (27%)
- Albumin decreased (27%)
- Diarrhea (22%)
- Hypokalemia (21%)
- Pyrexia (19%)
- Constipation (19%)
- Vomiting (18%)
- Pneumonia (17%)
- Bilirubinemia (16%)
- Upper respiratory tract infections (15%)
- Hypernatremia (15%)
- Hypothyroidism (13%)
- Cough/productive cough (12%)
- Hypomagnesemia (12%)
- Headache (11%)
- Pruritus (11%)
Grades 3 or 4 (NSCLC)
- Neutropenia (37%)
- Anemia (24%)
- Leukopenia (21%)
- Lymphocytopenia (20%)
- Lipase increased (14%)
- Hyponatremia (13%)
- Thrombocytopenia (11%)
1-10%
All grades (uHCC)
- Insomnia (10%)
Grades 3 or 4 (uHCC)
- Bilirubin increased (8%)
- Alkaline phosphatase increased (8%)
- Diarrhea (6%)
- Hemoglobin decreased (4.8%)
- Fatigue (3.9%)
- Potassium increased (3.8%)
- Rash (2.8%)
- Musculoskeletal pain (2.6%)
- Abdominal pain (1.8%)
- Platelets decreased (1.6%)
- Decreased appetite (1.3%)
- Creatinine increased (1.3%)
All grades (NSCLC)
- Stomatitis (10%)
- Alopecia (10%)
- Edema (10%)
Grades 3 or 4 (NSCLC)
- Amylase increased (9%)
- Pneumonia (8%)
- Hypokalemia (7%)
- Hyperglycemia (6%)
- Increased ALT (6%)
- Increased AST (5%)
- Blood creatinine increased (4%)
- Hypomagnesemia (4%)
- Increased alkaline phosphatase (3.4%)
- Rash (2.4%)
- GGT increased (2.2%)
- Hyperkalemia (2.2%)
- Albumin decreased (1.9%)
- Nausea (1.8%)
- Diarrhea (1.5%)
- Decreased appetite (1.5%)
- Vomiting (1.2%)
<1%
Grade 3 or 4 (uHCC)
- Leukocytes decreased (0.8%)
- Albumin decreased (0.5%)
- Pyrexia (0.3%)
- Insomnia (0.3%)
Grades 3 or 4 (NSCLC)
- Hypocalcemia (0.9%)
- Bilirubinemia (0.9%)
- Musculoskeletal pain (0.6%)
- Upper respiratory tract infection (0.6%)
Warnings
Contraindications
None
Cautions
May cause an infusion-related reactions; monitor for signs and symptoms of infusion-related reactions; interrupt, slow the rate of, or permanently discontinue tremelimumab; for Grade 1 or 2 infusion-related reactions, consider using premedications with subsequent doses
Based on findings from animal studies and its mechanism of action, fetal harm may occur when administered to pregnant females
Ocular side effects: May be associated with retinal detachment; various grades of visual impairment may occur; if events occur in combination with other immune-mediated adverse reactions, consider Vagt-Koyanagi-Harada-like syndrome; this may require treatment with systemic steroids to reduce risk of permanent vision loss
Severe or fatal immune-mediated adverse reactions
- Tremelimumab and durvalumab combined may potentiate risk of immune-mediated adverse reactions
- Severe or fatal immune-mediated adverse reactions may occur in any organ system or tissue at any time after starting both infusions
- Immune-mediated adverse reactions may manifest during treatment and after discontinuation
- Monitor for signs and symptoms of underlying immune-mediated adverse reactions
- Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone level, and thyroid function at baseline and before each dose
- Institute medical management promptly, including specialty consultation as appropriate
- Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy
-
Immune-mediated adverse reactions include the following
- Colitis, pneumonitis, hepatitis, endocrinopathies (eg, adrenal sufficiency, hypophysitis, thyroiditis, hyperthyroidism, hypothyroidism, type 1 diabetes), nephritis with renal dysfunction, and/or dermatology reactions
- Adrenal insufficiency: May cause primary or secondary adrenal insufficiency
- Hypophysitis can present with acute symptoms associated with mass effect (eg, headache, photophobia, visual field cuts); hypophysitis can cause hypopituitarism
- Thyroiditis can present with or without endocrinopathy; initiate hormone replacement therapy for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated
- May cause hyperthyroidism and/or hypothyroidism
- Monitor for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated
- Initiate symptomatic treatment including hormone replacement as clinically indicated
- Withhold or permanently discontinue tremelimumab in combination with durvalumab based on the severity
- Immune-mediated pancreatitis may occur when administered in combination with durvalumab
-
Other immune-mediated adverse reactions reported in <1% with durvalumab and tremelimumab combination and other immune-checkpoint inhibitors
- Cardiac or vascular: Myocarditis, pericarditis, vasculitis
- Nervous system: Meningitis, encephalitis, myelitis, and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy
- Ocular: Uveitis, iritis, and other ocular inflammatory toxicities can occur
- 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
Pregnancy & Lactation
Pregnancy
Based on its mechanism of action, can cause fetal harm if administered to pregnant females
No data are available on use in pregnant females
Verify pregnancy status of females of reproductive potential prior to initiating treatment
Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, tremelimumab and durvalumab has potential to be transmitted from mother to developing fetus
Animal data
- CTLA-4 blockade is associated with increased risk of immune-mediated rejection of developing fetus and fetal death
Contraception
- Females of reproductive potential: Use effective contraception during treatment and for 3 months after last dose
Lactation
There are no data on presence of tremelimumab in human milk, its effects on a breastfed child, or on milk production
Maternal IgG is known to be present in human milk
Effects of local gastrointestinal exposure and limited systemic exposure in breastfed child to tremelimumab are unknown
Advise females not to breastfeed during treatment and for 3 months after last dose
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Tremelimumab-actl, is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking human IgG2 monoclonal antibody, produced by recombinant DNA technology in NS0 cell suspension culture andhas a molecular weight of 149 kD
Monoclonal antibody binds to CTLA-4 and blocks the interaction with its ligands CD80 and CD86, releasing CTLA-4-mediated inhibition of T-cell activation
Absorption
Steady-state achieved at 12 weeks
AUC increased proportionally from 1-10 mg/kg q4Weeks
Distribution
Vd: 3.45 L (central, V1); 2.66 L (peripheral, V2)
Elimination
Clearance: 0.286 L/day (single dose); 0.263 L/day (steady-state)
Half-life: 16.9 days (single dose); 18.2 days (steady-state)
Administration
IV Incompatibilities
Do not coadminister other drugs through same infusion line
IV Compatibilities
0.9% NaCl
D5W
IV Preparation
Visually inspect for particulate matter and discoloration; discard if solution is cloudy, discolored, or visible particles are observed
Do not shake vial
Withdraw required volume from vial(s) and transfer into an IV bag containing 0.9% NaCl or D5W
Gently invert diluted solution to mix; do not shake solution; final concentration of diluted solution should not exceed 10 mg/mL
<30 kg (dose: tremelimumab 4 mg/kg): Maximum diluent volume = 80 mL
≥30 kg (dose: tremelimumab 300 mg): Maximum diluent volume = 150 mL
Discard partially used or empty vial(s)
IV Administration
Infuse IV over 60 minutes through an IV line containing a sterile, low-protein binding 0.2- or 0.22-micron filter
Use separate infusion bags and filters for each drug product
Administer all drug products as separate IV infusions; do not coadminister other drugs through same infusion line
For platinum-based chemotherapy or pemetrexed, refer to Prescribing Information for administration information
Observe for 60 minutes following completion of infusion; then administer durvalumab as a separate IV infusion over 60 minutes on same day
Order of infusions
- Combination with durvalumab: Infuse tremelimumab, followed by durvalumab on same day of dosing
- Combination with durvalumab and platinum-based or pemetrexed chemotherapy: Infuse tremelimumab first, followed by durvalumab and then platinum-based or pemetrexed chemotherapy on day of dosing
Storage
Unopened vial
- Refrigerate at 2-8ºC (36-46ºF) in original carton to protect from light
- Do not freeze
- Do not shake
Diluted solution
- Does not contain a preservative
- If not administered immediately, store for up to 24 hr in a refrigerator at 2-8ºC (36-46ºF) or at room temperature <30ºC (86ºF)
- Do not freeze
- Do not shake
Images
Formulary
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