Version May 2024
Hepatocellular carcinoma, unresectable:
Patients ≥30 kg: IV: 300 mg on day 1 of cycle 1 only (in combination with durvalumab), followed by durvalumab monotherapy until disease progression or unacceptable toxicity (Abou-Alfa 2022).
Patients <30 kg: IV: 4 mg/kg on day 1 of cycle 1 only (in combination with durvalumab), followed by durvalumab monotherapy until disease progression or unacceptable toxicity.
Non–small cell lung cancer, metastatic: Note: Weigh patients prior to each tremelimumab infusion. Tremelimumab is administered for a total of up to 5 doses; the tremelimumab schedule is dependent on cycle number. Refer to protocol (Johnson 2023) for further information.
Non-squamous tumor histology: Chemotherapy consisted of up to 4 cycles of carboplatin in combination with paclitaxel (protein bound) or pemetrexed in combination with either carboplatin or cisplatin. If the pemetrexed-based chemotherapy regimen is utilized, may administer optional pemetrexed maintenance therapy (in combination with durvalumab) starting at week 12 and continuing until disease progression or unacceptable toxicity.
Squamous tumor histology: Chemotherapy consisted of up to 4 cycles of carboplatin in combination with paclitaxel (protein bound) or gemcitabine in combination with either carboplatin or cisplatin.
Patients ≥30 kg:
Cycles 1 through 4: IV: 75 mg on day 1 every 3 weeks for cycles 1 through 4 (in combination with durvalumab and platinum-based chemotherapy).
Cycle 5: No tremelimumab dose is administered (see "Note" below). Durvalumab is administered during cycle 5; refer to durvalumab monograph for durvalumab dosing schedule.
Cycle 6: IV: 75 mg on day 1 (in combination with durvalumab); cycle 6 begins at week 16 (there is a 4-week interval between cycles 5 and 6). After cycle 6, continue durvalumab until disease progression or unacceptable toxicity.
Note: If patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining tremelimumab doses (up to a total of 5) should be administered after the platinum-based chemotherapy phase (in combination with durvalumab) every 4 weeks.
Patients <30 kg:
Cycles 1 through 4: IV: 1 mg/kg on day 1 every 3 weeks for cycles 1 through 4 (in combination with durvalumab and platinum-based chemotherapy).
Cycle 5: No tremelimumab dose is administered (see "Note" below). Durvalumab is administered during cycle 5; refer to durvalumab monograph for durvalumab dosing schedule.
Cycle 6: IV: 1 mg/kg on day 1 (in combination with durvalumab); cycle 6 begins at week 16 (there is a 4-week interval between cycles 5 and 6). After cycle 6, continue durvalumab until disease progression or unacceptable toxicity.
Note: If patients receive fewer than 4 cycles of platinum-based chemotherapy, the remaining tremelimumab doses (up to a total of 5) should be administered after the platinum-based chemotherapy phase (in combination with durvalumab) every 4 weeks.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Kidney impairment prior to treatment initiation:
CrCl 30 to 89 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, there is no clinically relevant effect on pharmacokinetics.
CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (effect on tremelimumab pharmacokinetics is unknown).
Kidney dysfunction during treatment:
Immune-mediated nephritis with kidney dysfunction: If tremelimumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper.
Grade 2 or grade 3 serum creatinine elevation: Withhold tremelimumab; resume tremelimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to <10 mg/day (prednisone or equivalent) within 12 weeks of corticosteroid initiation.
Grade 4 serum creatinine elevation: Permanently discontinue tremelimumab.
Hepatic impairment prior to treatment initiation:
Mild to moderate impairment (bilirubin <3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling; however, there is no clinically relevant effect on pharmacokinetics.
Severe impairment (bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (effect on tremelimumab pharmacokinetics is unknown).
Hepatotoxicity during treatment:
If tremelimumab treatment interruption or discontinuation is required, administer systemic corticosteroids (1 to 2 mg/kg/day prednisone [or equivalent]) or other appropriate therapy for immune-mediated adverse reactions until improvement to ≤ grade 1, then follow with a corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of last tremelimumab dose, or if unable to reduce prednisone to <10 mg/day (or equivalent) within 12 weeks of corticosteroid initiation. Also see "Dosing: Adjustment for Toxicity."
Hepatitis without tumor involvement of the liver:
AST or ALT increases to >3 and up to 8 times ULN or total bilirubin increases to >1.5 and up to 3 times ULN: Withhold tremelimumab; resume tremelimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to <10 mg/day (prednisone or equivalent) within 12 weeks of corticosteroid initiation.
AST or ALT increases to >8 times ULN or total bilirubin increases to >3 times ULN: Permanently discontinue tremelimumab.
Hepatitis with tumor involvement of the liver: Note: If AST and ALT are ≤ ULN at baseline, follow recommendations for hepatitis without tumor involvement of the liver.
If baseline AST or ALT is >1 up to 3 times ULN and increases to >5 and up to 10 times ULN or baseline AST or ALT is >3 up to 5 times ULN and increases to >8 and up to 10 times ULN: Withhold tremelimumab; resume tremelimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to <10 mg/day (prednisone or equivalent) within 12 weeks of corticosteroid initiation.
AST or ALT >10 times ULN or total bilirubin >3 times ULN: Permanently discontinue tremelimumab.
Note: Durvalumab may also require dosage modification.
Additional recommendations:
Grade 2 immune-mediated hepatitis: Withhold immune checkpoint inhibitor (ICI); if no improvement within 3 to 5 days after ICI is withheld, consider initiation of corticosteroids (prednisone 0.5 to 1 mg/kg/day or equivalent) (Ref).
Grade 3 or 4 immune-mediated hepatitis: Withhold ICI; initiate corticosteroids (methylprednisolone 1 to 2 mg/kg or equivalent) (Ref). Based on data from a retrospective cohort study in patients with grade 3 or 4 immune-mediated hepatitis, initial treatment with methylprednisolone 1 mg/kg/day demonstrated similar time to ALT normalization (compared with higher methylprednisolone doses), while reducing the potential for corticosteroid-related complications (Ref).
American Society of Clinical Oncology guidelines for appropriate systemic therapy dosing in adults with cancer with a BMI ≥30 kg/m2 : The dosing in the FDA-approved prescribing information should be followed in all patients, regardless of obesity status. If a patient with a BMI ≥30 kg/m2 experiences high-grade toxicity from systemic anticancer therapy, the same dosage modification recommendations should be followed for all patients, regardless of obesity status (Ref).
Note: No dose reduction for tremelimumab is recommended. Other concomitant combination anticancer therapies may also require treatment interruption and/or discontinuation.
Immune-mediated adverse reactions (general information): Withhold tremelimumab for severe (grade 3) immune-mediated adverse reactions. Permanently discontinue tremelimumab for life-threatening (grade 4) immune-mediated adverse reactions, recurrent severe (grade 3) immune-mediated reactions that require systemic immunosuppressive treatment, or inability to reduce corticosteroid dose to prednisone ≤10 mg/day (or equivalent) within 12 weeks of initiating corticosteroids. If tremelimumab treatment interruption or discontinuation is required, administer systemic corticosteroid therapy (prednisone 1 to 2 mg/kg/day [or equivalent]) until improvement to ≤ grade 1; upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with systemic corticosteroid therapy. Systemic corticosteroids may not be necessary for certain adverse reactions. Hormone replacement therapy may be required for endocrinopathies (if clinically indicated). See table for additional dosage modification guidance.
Additional management recommendations: Consider withholding checkpoint inhibitor therapy for most grade 2 toxicities and resume when symptoms and/or lab values resolve to ≤ grade 1; systemic corticosteroids (initial dose of prednisone 0.5 to 1 mg/kg/day [or equivalent]) may be administered if indicated for grade 2 toxicities (Ref). Refer to guideline for further information regarding management of immune-mediated adverse reactions associated with checkpoint inhibitor therapy.
|
Adverse reaction |
Severity |
Tremelimumab dosage modification |
|---|---|---|
|
a SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; DRESS = drug rash with eosinophilia and systemic symptoms. | ||
|
b Refer to prednisone monograph for tapering recommendations when used for immune-mediated adverse reactions associated with checkpoint inhibitor therapy. | ||
|
Immune-mediated adverse reactions | ||
|
Cardiovascular toxicity: Myocarditis |
Grade 2, 3, or 4 |
Permanently discontinue tremelimumab. |
|
Dermatologic toxicity |
Mild to moderate nonexfoliative rash |
May be managed with topical emollients and/or topical corticosteroids. Withhold or permanently discontinue tremelimumab depending on severity. |
|
Exfoliative dermatologic conditions: suspected SJS, TEN, or DRESSa |
Withhold tremelimumab; resume tremelimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to <10 mg/day (prednisone or equivalent) within 12 weeks of corticosteroid initiation. | |
|
Confirmed SJS, TEN, or DRESS |
Permanently discontinue tremelimumab. | |
|
Endocrinopathies |
Depending on the severity, withhold or discontinue tremelimumab. | |
|
Grade 3 or 4 |
Withhold tremelimumab until clinically stable or permanently discontinue (depending on the severity). | |
|
Adrenal insufficiency (≥ grade 2) |
Initiate symptomatic treatment (including hormone replacement therapy) as clinically indicated. | |
|
Diabetes (type 1) |
Initiate treatment with insulin as clinically indicated. | |
|
Hypophysitis |
Initiate symptomatic treatment (including hormone replacement therapy) as clinically indicated. | |
|
Hyperthyroidism |
Initiate medical management as clinically indicated. | |
|
Hypothyroidism |
Initiate thyroid hormone replacement therapy as clinically indicated. | |
|
Thyroiditis |
Initiate medical management as clinically indicated. | |
|
GI toxicity: Colitis |
Grade 2 |
Withhold tremelimumab; resume tremelimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to <10 mg/day (prednisone or equivalent) within 12 weeks of corticosteroid initiation. |
|
Grade 3 or 4 |
Permanently discontinue tremelimumab. | |
|
GI toxicity: Intestinal perforation |
Any grade |
Permanently discontinue tremelimumab. |
|
Neurologic toxicities |
Grade 2 |
Withhold tremelimumab; resume tremelimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to <10 mg/day (prednisone or equivalent) within 12 weeks of corticosteroid initiation. |
|
Grade 3 or 4 |
Permanently discontinue tremelimumab. | |
|
Ophthalmic toxicities |
Vogt-Koyanagi-Harada-like syndrome |
May require systemic corticosteroids to reduce the risk of permanent vision loss. |
|
Pulmonary toxicity: Pneumonitis |
Grade 2 |
Withhold tremelimumab; resume tremelimumab after complete or partial (to grade 0 or 1) resolution after corticosteroid taper. Permanently discontinue tremelimumab if no complete or partial response within 12 weeks of initiating corticosteroids, or if unable to reduce corticosteroid dose to <10 mg/day (prednisone or equivalent) within 12 weeks of corticosteroid initiation. |
|
Grade 3 or 4 |
Permanently discontinue tremelimumab. | |
|
Other adverse reactions | ||
|
Infusion reactions |
Grade 1 or 2 |
Interrupt or slow the rate of tremelimumab infusion. |
|
Grade 3 or 4 |
Permanently discontinue tremelimumab. | |
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for adults treated with tremelimumab in combination with durvalumab.
>10%:
Dermatologic: Pruritus (23%), skin rash (≤32%; including dermatitis)
Endocrine & metabolic: Decreased serum albumin (31%), decreased serum calcium (34%), decreased serum sodium (46%), hypothyroidism (11% to 14%), increased serum glucose (39%), increased serum potassium (28%)
Gastrointestinal: Abdominal pain (20%), decreased appetite (17%), diarrhea (≤27%; grades 3/4: ≤6%), nausea (12%)
Hematologic & oncologic: Decreased hemoglobin (52%; grades 3/4: 5%) decreased platelet count (29%; grades 3/4: 2%), leukopenia (20%; grades 3/4: <1%), lymphocytopenia (41%; grades 3/4: 11%)
Hepatic: Increased serum alanine aminotransferase (56%), increased serum alkaline phosphatase (41%), increased serum aspartate aminotransferase (63%), increased serum bilirubin (41%)
Immunologic: Antibody development (11%; of which 40% developed neutralizing antibodies)
Nervous system: Fatigue (26%)
Neuromuscular & skeletal: Musculoskeletal pain (22%)
Renal: Increased serum creatinine (21%)
Miscellaneous: Fever (13%)
1% to 10%:
Endocrine & metabolic: Adrenocortical insufficiency (2%), hyperthyroidism (5%), hypophysitis (≤1%), pituitary insufficiency (≤1%), thyroiditis (2%)
Gastrointestinal: Colitis (≤6%), pancreatitis (2%)
Hematologic & oncologic: Hemorrhage (serious: 6%)
Hepatic: Hepatitis (8%)
Hypersensitivity: Infusion-related reaction (3%)
Infection: Sepsis (2%)
Nervous system: Insomnia (10%)
Renal: Acute kidney injury (1%), nephritis (1%)
Respiratory: Pneumonia (serious: 2%), pneumonitis (1%)
<1%: Endocrine & metabolic: Hyperglycemia
Frequency not defined: Gastrointestinal: Intestinal perforation
Postmarketing:
Cardiovascular: Cardiac arrhythmia (Wang 2022), myocarditis (Mahmood 2018), pericarditis (Wang 2022), vasculitis (Comont 2018)
Dermatologic: Maculopapular rash (Singh 2020), vitiligo (Jolly 2009)
Gastrointestinal: Increased serum amylase (Fujiwara 2022), increased serum lipase (Singh 2020)
Nervous system: Myasthenia gravis (Fujiwara 2022), neuropathy (Comont 2018)
Neuromuscular & skeletal: Myopathy (John 2017), myositis (Mahmood 2018), polymyositis (John 2017)
Ophthalmic: Ocular toxicity (including blepharoptosis and diplopia) (Carrera 2017)
Renal: Interstitial nephritis (Jolly 2009)
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to tremelimumab or any component of the formulation.
Concerns related to adverse effects:
• Adverse reactions (immune-mediated): Tremelimumab blocks T-cell inhibitory signals induced by the CTLA-4 pathway, thus removing inhibition of the immune response with the potential for induction of immune-mediated adverse reactions. Severe and fatal immune-mediated adverse effects may occur in any organ system or tissue. While reactions generally occur during treatment, immune-mediated reactions may occur at any time after treatment initiation and may also manifest after tremelimumab discontinuation. Early identification and management of immune-mediated adverse reactions are necessary to ensure tremelimumab safety. Medically manage immune-mediated adverse reactions promptly and refer for specialty consultation as appropriate. Depending on the severity, withhold or permanently discontinue tremelimumab. In general, if treatment interruption or discontinuation are required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone [or equivalent]) until improvement to ≤ grade 1. Upon improvement to ≤ grade 1, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants if immune-mediated adverse reaction is not controlled with corticosteroid therapy.
• Dermatologic toxicity: Tremelimumab in combination with durvalumab may cause immune-mediated rash or dermatitis, including grade 3 and 4 events. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms has occurred with checkpoint inhibitors. Systemic corticosteroids were used to manage immune-mediated rash or dermatitis in all patients; other immunosuppressants were rarely required. Dermatologic events resolved in the majority of patients, although permanent discontinuation was required in some cases.
• Endocrinopathies: Immune-mediated endocrinopathies have occurred with tremelimumab in combination with durvalumab.
- Adrenal insufficiency: Primary and secondary adrenal insufficiency, including grade 3 events, has occurred (rarely) with tremelimumab in combination with durvalumab. Systemic corticosteroids were required in all patients. Adrenal insufficiency resolved in some patients.
- Diabetes mellitus: Type 1 diabetes, which can present with diabetic ketoacidosis, may occur. Some cases may require long-term insulin therapy.
- Hypophysitis: Tremelimumab in combination with durvalumab may rarely cause immune-mediated hypophysitis, which may present with acute symptoms associated with mass effect (eg, headache, photophobia, or visual field defects). Hypophysitis may lead to hypopituitarism. Some patients required endocrine therapy and/or systemic corticosteroids. Events resolved in approximately one-half of patients.
- Thyroid disorders: Immune-mediated hyperthyroidism, hypothyroidism, and thyroiditis have occurred with tremelimumab in combination with durvalumab. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Thyroiditis resolved in one-third of patients; systemic corticosteroids were required in some patients and all patients required other therapies (including hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blockers, or beta-blockers). Hyperthyroidism resolved in most patients, and most required other therapies (including systemic corticosteroids, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blockers, or beta-blockers). Hypothyroidism resolved in a small percentage of patients; systemic corticosteroids were occasionally required.
- Other endocrinopathies: Hypoparathyroidism has also been reported.
• GI toxicity: Tremelimumab in combination with durvalumab may cause immune-mediated colitis (including grade 3 or higher events); immune-mediated colitis is frequently associated with diarrhea. All patients received systemic corticosteroids to manage colitis; some patients required other immunosuppressants. Events resolved in a majority of patients, although resulted in permanent discontinuation in a small number of patients. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated diarrhea/colitis. In cases of corticosteroid-refractory diarrhea/colitis, consider repeating infectious workup to exclude alternative etiologies. Intestinal perforation and large intestine perforation have been observed with tremelimumab in combination with durvalumab. Pancreatitis (including grade 3 and 4 events) have occurred; all patients required management with systemic corticosteroids; pancreatitis resolved in some cases. Gastritis and duodenitis have also been reported (rarely).
• Hepatotoxicity: Immune-mediated hepatitis (including grade 3 and 4 and fatal events) has occurred with tremelimumab in combination with durvalumab. Systemic corticosteroids were used to manage immune-mediated hepatitis in all patients; some patients required other immunosuppressants. Hepatitis resolved in under half of patients, yet resulted in permanent discontinuation in some patients.
• Infusion-related reactions: Infusion-related reactions may occur with tremelimumab; may be severe or life-threatening.
• Nephrotoxicity: Immune-mediated nephritis with renal dysfunction (including grade 3 events) has occurred (rarely) with tremelimumab in combination with durvalumab. Systemic corticosteroids were used to manage immune-mediated nephritis. Nephritis with renal dysfunction resolved in some patients but resulted in treatment discontinuation in other patients.
• Ocular toxicity: Immune-mediated iritis, uveitis, and other ocular inflammatory conditions have been observed (rarely) with tremelimumab in combination with durvalumab or other checkpoint inhibitors. Some cases may be associated with retinal detachment. Visual impairment, including blindness, may occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome.
• Pulmonary toxicity: Immune-mediated pneumonitis (including grade 3 and fatal events) has occurred (rarely) with tremelimumab when used in combination with durvalumab. Systemic corticosteroids were used to treat immune-mediated pneumonitis; some patients required other immunosuppressants to manage pneumonitis. Pneumonitis resolved in most cases, although led to tremelimumab and durvalumab treatment discontinuation in some patients.
• Other immune-mediated toxicities: Other clinically significant immune-mediated adverse reactions have been observed (rarely although sometimes fatal) with tremelimumab in combination with durvalumab or with other checkpoint inhibitors, including autoimmune neuropathy, meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (MG), Guillain-Barré syndrome, nerve paresis, myocarditis, pericarditis, vasculitis, arthritis, myositis, polymyalgia rheumatica, polymyositis, rhabdomyolysis, aplastic anemia, hemolytic anemia, hemophagocytic lymphohistiocytosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), immune thrombocytopenia, sarcoidosis, and systemic inflammatory response syndrome.
Disease-related concerns:
• Myasthenia gravis: Checkpoint inhibitors may worsen or precipitate new MG, especially within the first 16 weeks of treatment; use with caution. Patients with well-controlled MG may be considered for checkpoint inhibitor therapy if MG treatment is maintained (or reinitiated in patients whose MG is in remission), combination therapy (eg, anti–CTLA-4 with anti–PD-a/PD-L1 monoclonal antibodies) is avoided, and respiratory and bulbar function are closely followed. In patients who develop overt MG during checkpoint inhibitor therapy, early aggressive treatment with plasma exchange or IVIG in combination with high-dose corticosteroids may be required (AAN [Narayanaswami 2021]).
Dosage form specific issues:
• Polysorbate 80: 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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous [preservative free]:
Imjudo: Tremelimumab-actl 300 mg/15 mL (15 mL); Tremelimumab-actl 25 mg/1.25 mL (1.25 mL) [contains edetate (edta) disodium, polysorbate 80]
No
Solution (Imjudo Intravenous)
25 mg/1.25 mL (per mL): $3,120.00
300 mg/15 mL (per mL): $3,120.00
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Imjudo: Tremelimumab-actl 20 mg/mL (1.25 mL, 15 mL) [contains edetate (edta) disodium dihydrate, polysorbate 80]
Tremelimumab is available through specialty pharmacies and various specialty institutions/accounts. Examples from the manufacturer may be found at: https://www.imfinzihcp.com/content/dam/website-services/us/434-imfinzi-com/or-new/sr-pdf/Speciality-Pharmacy-Providers.pdf.
IV: Infuse over 60 minutes through an IV line containing a sterile, low-protein binding 0.2- or 0.22-micron filter. Administer all concomitant combination medications as separate IV infusions; do not administer other medications through the same IV line. Use separate infusion bags and filters for each medication.
Tremelimumab in combination with durvalumab: Administer tremelimumab first and observe patient for 60 minutes following completion of tremelimumab infusion, then administer durvalumab as a separate infusion on the same day.
Tremelimumab in combination with durvalumab and platinum- based chemotherapy:
Cycle 1: Administer tremelimumab over 60 minutes; 1 to 2 hours after completion of tremelimumab infusion, administer durvalumab over 60 minutes. Administer platinum-based chemotherapy 1 to 2 hours after the completion of the durvalumab infusion.
Subsequent cycles: If no infusion reactions occur in cycle 1, durvalumab may be administered immediately following tremelimumab and the time between the end of the durvalumab infusion and the start of chemotherapy may be reduced to 30 minutes.
Tremelimumab in combination with durvalumab and pemetrexed: Administer tremelimumab first, followed by durvalumab, and then pemetrexed on the day of dosing.
Monitor for signs/symptoms of infusion reactions. Interrupt or slow the infusion for grade 1 or 2 infusion-related reactions; discontinue permanently for grade 3 or 4 reactions.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Imjudo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761289s002lbl.pdf#page=31
Hepatocellular carcinoma, unresectable: Treatment of unresectable hepatocellular carcinoma (in combination with durvalumab) in adults.
Non–small cell lung cancer, metastatic: Treatment of metastatic non–small cell lung cancer (in combination with durvalumab and platinum-based chemotherapy) in adults whose tumors have no sensitizing epidermal growth factor receptor mutations or anaplastic lymphoma kinase genomic tumor aberrations.
Imjudo may be confused with Imfinzi.
Tremelimumab may be confused with ipilimumab, teclistamab, tisotumab vedotin, toripalimab.
This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acetaminophen: May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Antibiotics: May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Corticosteroids (Systemic): May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Management: Carefully consider the need for corticosteroids, at doses of a prednisone-equivalent of 10 mg or more per day, during the initiation of immune checkpoint inhibitor therapy. Use of corticosteroids to treat immune related adverse events is still recommended Risk D: Consider therapy modification
Efgartigimod Alfa: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Inhibitors of the Proton Pump (PPIs and PCABs): May diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Ketoconazole (Systemic): Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies) may enhance the hepatotoxic effect of Ketoconazole (Systemic). Risk C: Monitor therapy
Rozanolixizumab: May diminish the therapeutic effect of Fc Receptor-Binding Agents. Risk C: Monitor therapy
Verify pregnancy status prior to use in patients who could become pregnant.
Patients who could become pregnant should use effective contraception during therapy and for 3 months after the last tremelimumab dose.
Tremelimumab is a humanized monoclonal antibody (IgG2). Human IgG crosses the placenta. Fetal exposure is dependent upon the IgG subclass, maternal serum concentrations, placental integrity, newborn birth weight, and GA, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis and the highest during the third trimester (Clements 2020; Palmeira 2012; Pentsuk 2009).
Based on the mechanism of action and data from animal reproduction studies, in utero exposure to tremelimumab may cause fetal harm, including a higher risk of pregnancy loss.
It is not known if tremelimumab is present in breast milk.
Tremelimumab is a humanized monoclonal antibody (IgG2). Human IgG is present in breast milk; concentrations are dependent upon IgG subclass and postpartum age (Anderson 2021).
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 3 months after the last tremelimumab dose.
Monitor liver enzymes (at baseline and prior to each dose); serum creatinine (at baseline and prior to each dose); adrenocorticotropic hormone (ACTH; at baseline and prior to each dose); thyroid function tests (at baseline and prior to each dose); blood glucose (for hyperglycemia). Evaluate pregnancy status prior to durvalumab initiation in patients who could become pregnant. Monitor closely for clinical signs/symptoms of immune-mediated adverse reactions, including adrenal insufficiency, colitis/diarrhea (consider initiating or repeating infectious workup in patients with corticosteroid-refractory immune-mediated colitis to exclude alternative causes), dermatologic toxicity, diabetes/hyperglycemia, hepatitis/hepatotoxicity, hypophysitis or hypopituitarism, pneumonitis, ocular toxicity, and thyroid disorders. Monitor for signs/symptoms of infusion reactions.
The American Society of Clinical Oncology hepatitis B virus (HBV) screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV screening with hepatitis B surface antigen, hepatitis B core antibody, total Ig or IgG, and antibody to hepatitis B surface antigen prior to beginning (or at the beginning of) systemic anticancer therapy; do not delay treatment for screening/results. Detection of chronic or past HBV infection requires a risk assessment to determine antiviral prophylaxis requirements, monitoring, and follow-up.
Cardiovascular monitoring: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking (ASCO [Armenian 2017]). Obtain baseline ECG, natriuretic peptides, and troponins in all patients; obtain a baseline echocardiogram in high-risk patients; consider serial ECGs and cardiac troponins prior to doses 2, 3, and 4, and if normal, reduce to every 3 doses until completion of therapy; cardiovascular risk assessment every 6 to 12 months in high-risk patients who require long-term (>12 months therapy, consider cardiovascular risk assessment every 6 to 12 months in all patients requiring long-term therapy) (ESC [Lyon 2022]). Refer to a cardiologist when clinically indicated.
Additional suggested monitoring (ASCO [Schneider 2021): Prior to therapy: CBC with differential, creatine kinase, comprehensive clinical assessment including performance status, weight, body mass index, heart rate, BP, and oxygen saturation; consider chest x-ray, electrocardiogram, and CT scan; assess history of autoimmune conditions, organ-specific disease, endocrinopathies, neuropathy, and infectious disease; assess bowel habits, respiratory symptoms, skin (for rash), arthralgias, and neurologic symptoms. During therapy: Assess BP, weight, heart rate, and oxygen saturation; assess for infections, screen for hyperglycemia/diabetes (polyuria, polydipsia, weight loss); eye exam (including intraocular pressure after 6 weeks), CBC with differential, and creatine kinase; monitor bone mineral density (with long-term therapy).
Tremelimumab is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking human IgG2 monoclonal antibody. CTLA-4 is a negative regulator of T-cell activity. Tremelimumab binds to CTLA-4 and blocks interaction with its ligands CD80 and CD86, releasing CTLA-4-mediated inhibition of T-cell activation. In animal tumor models, blocking CTLA-4 activity resulted in decreased tumor growth and increased proliferation of T-cells in tumors.
Distribution: Vd central: 3.45 L; Vd peripheral: 2.66 L.
Half-life elimination: ~17 days (following a single dose); ~18 days (at steady state).
Excretion: Clearance: 0.286 L/day (following a single dose); 0.263 L/day (at steady state).
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