Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Refer to section 4.2, Table 2 for recommended treatment modifications. For suspected immunemediated adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude alternate aetiologies. Based on the severity of the adverse reaction, IMJUDO or IMJUDO in combination with durvalumab should be withheld and corticosteroids administered. Upon improvement to ≤ Grade 1, corticosteroid taper should be initiated and continued over at least 1 month. Consider increasing dose of corticosteroids and/or using additional systemic immunosuppressants if there is worsening or no improvement.
In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.
Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Suspected pneumonitis should be confirmed with radiographic imaging and other infectious and disease-related aetiologies excluded, and managed as recommended in section 4.2. For Grade 2 events, an initial dose of 1-2 mg/kg/day prednisone or equivalent should be initiated followed by a taper. For Grade 3 or 4 events, an initial dose of 2-4 mg/kg/day methylprednisolone or equivalent should be initiated followed by a taper.
Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Monitor alanine aminotransferase, aspartate aminotransferase, total bilirubin, and alkaline phosphatase levels prior to initiation of treatment and prior to each subsequent infusion. Additional monitoring is to be considered based on clinical evaluation. Immune-mediated hepatitis should be managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for all grades.
Immune-mediated colitis or diarrhoea, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Intestinal perforation and large intestine perforation were reported in patients receiving tremelimumab in combination with durvalumab. Patients should be monitored for signs and symptoms of colitis/diarrhoea and intestinal perforation and managed as recommended in section 4.2. Corticosteroids should be administered at an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper for Grades 2-4. Consult a surgeon immediately if intestinal perforation of ANY grade is suspected.
Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy, and hypothyroidism may follow hyperthyroidism (see section 4.8). Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and as indicated based on clinical evaluation. Immune-mediated hypothyroidism, hyperthyroidism, and thyroiditis should be managed as recommended in section 4.2. For immune-mediated hypothyroidism, initiate thyroid hormone replacement as clinically indicated for Grades 2-4. For immune-mediated hyperthyroidism/thyroiditis, symptomatic management can be implemented for Grades 2-4.
Immune-mediated adrenal insufficiency occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should be monitored for clinical signs and symptoms of adrenal insufficiency. For symptomatic adrenal insufficiency, patients should be managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper and a hormone replacement as clinically indicated for Grades 2-4.
Immune-mediated type 1 diabetes mellitus, which can first present as diabetic ketoacidosis that can be fatal if not detected early, occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should be monitored for clinical signs and symptoms of type 1 diabetes mellitus. For symptomatic type 1 diabetes mellitus, patients should be managed as recommended in section 4.2. Treatment with insulin can be initiated as clinically indicated for Grades 2-4.
Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. For symptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in section 4.2. Corticosteroids should be administered for with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper and a hormone replacement as clinically indicated for Grades 2-4.
Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should be monitored for abnormal renal function tests prior to and periodically during treatment and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.
Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Events of Stevens-Johnson Syndrome or toxic epidermal necrolysis have been reported in patients treated with PD-1 and CTLA-4 inhibitors. Patients should be monitored for signs and symptoms of rash or dermatitis and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grade 2 > 1 week or Grade 3 and 4.
Immune-mediated myocarditis, which can be fatal, occurred in patients receiving tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated myocarditis and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 2-4 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4. If no improvement within 2 to 3 days despite corticosteroids, promptly start additional immunosuppressive therapy. Upon resolution (Grade 0), corticosteroid taper should be initiated and continued over at least 1 month.
Immune-mediated pancreatitis, occurred in patients receiving tremelimumab in combination with durvalumab and chemotherapy (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated pancreatitis and managed as recommended in section 4.2.
Given the mechanism of action of tremelimumab in combination with durvalumab, other potential immune-mediated adverse reactions may occur. The following immune-related adverse reactions have been observed in patients treated with tremelimumab in combination with durvalumab, or with durvalumab and chemotherapy: myasthenia gravis, myositis, polymyositis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, cystitis noninfective, immune-mediated arthritis and uveitis (see section 4.8). Patients should be monitored for signs and symptoms and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.
Patients should be monitored for signs and symptoms of infusion-related reactions. Severe infusion-related reactions have been reported in patients receiving tremelimumab in combination with durvalumab (see section 4.8). Infusion-related reactions should be managed as recommended in section 4.2. For Grade 1 or 2 severity, may consider pre-medications for prophylaxis of subsequent infusion reactions. For Grade 3 or 4, manage severe infusion-related reactions per insititutional standard, appropriate clinical practice guidelines and/or society guidelines.
Limited data are available in elderly patients (≥ 75 years) treated with tremelimumab in combination with durvalumab and platinum-based chemotherapy (see sections 4.8 and 5.1). Careful consideration of the potential benefit/risk of this regimen on an individual basis is recommended.
Patients with the following were excluded from clinical studies: Child-Pugh Score B or C, main portal vein thrombosis, liver transplant, uncontrolled hypertension, history of, or current brain metastases, spinal cord compression, 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. In the absence of data, tremelimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
Patients with the following were excluded from clinical studies: active or prior documented autoimmune disease; active and/or untreated brain metastases; a history of immunodeficiency; administration of systemic immunosuppression within 14 days before the start of tremelimumab or durvalumab, except physiological dose of systemic corticosteroids (< 10 mg/day prednisone or equivalent); uncontrolled intercurrent illness; active tuberculosis or hepatitis B or C or HIV infection or patients receiving live attenuated vaccine within 30 days before or after the start of tremelimumab or durvalumab. In the absence of data, tremelimumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.
The use of systemic corticosteroids or immunosuppressants before starting tremelimumab, except physiological dose of systemic corticosteroids (≤10 mg/day prednisone or equivalent), is not recommended because of their potential interference with the pharmacodynamic activity and efficacy of tremelimumab. However, systemic corticosteroids or other immunosuppressants can be used after starting tremelimumab to treat immune-related adverse reactions (see section 4.4).
No formal pharmacokinetic (PK) drug-drug interaction studies have been conducted with tremelimumab. Since the primary elimination pathways of tremelimumab are protein catabolism via reticuloendothelial system or target-mediated disposition, no metabolic drug-drug interactions are expected. PK drug-drug interactions between tremelimumab in combination with durvalumab and platinum-based chemotherapy were assessed in the POSEIDON study and showed no clinically meaningful PK interactions between tremelimumab, durvalumab, nab-paclitaxel, gemcitabine, pemetrexed, carboplatin or cisplatin in the concomitant treatment.
Women of childbearing potential should use effective contraception during treatment with tremelimumab and for at least 3 months after the last dose of tremelimumab.
There are no data on the use of tremelimumab in pregnant women. Based on its mechanism of action, and placental transfer of human IgG2, tremelimumab has the potential to impact maintenance of pregnancy and may cause foetal harm when administered to a pregnant woman. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). IMJUDO is not recommended during pregnancy and in women of childbearing potential not using effective contraception during treatment and for at least 3 months after the last dose.
There is no information regarding the presence of tremelimumab in human milk, the absorption and effects on the breast-fed infant, or the effects on milk production. Human IgG2 is known to be excreted in human milk. A risk to the breastfed child cannot be excluded. Breast-feeding should be discontinued during treatment with IMJUDO and for at least 3 months after the last dose.
There are no data on the potential effects of tremelimumab on fertility in humans or animals. However, mononuclear cell infiltration in prostate and uterus was observed in repeat-dose toxicity studies (see Section 5.3). The clinical relevance of these findings for fertility is unknown.
Tremelimumab has no or negligible influence on the ability to drive and use machines.
The safety of tremelimumab 300 mg as a single dose in combination with durvalumab, is based on pooled data in 462 HCC patients (HCC pool) from the HIMALAYA Study and another study in HCC patients, Study 22. The most common (>10%) adverse reactions were rash (32.5%), pruritus (25.5%), diarrhoea (25.3%), abdominal pain (19.7%), aspartate aminotransferase increased/alanine aminotransferase increased (18.0%), pyrexia (13.9%), hypothyroidism (13.0%), cough/productive cough (10.8%) and oedema peripheral (10.4%) (see Table 3).
The most common (>3%) severe adverse reactions (NCI CTCAE Grade ≥3) were aspartate aminotransferase increased/alanine aminotransferase increased (8.9%), lipase increased (7.1%), amylase increased (4.3%) and diarrhoea (3.9%).
The most common (>2%) serious adverse reactions were colitis (2.6%), diarrhoea (2.4%) and pneumonia (2.2%).
The frequency of treatment discontinuation due to adverse reactions is 6.5%. The most common adverse reactions leading to treatment discontinuation were hepatitis (1.5%) and aspartate aminotransferase increased/alanine aminotransferase increased (1.3%).
The safety of tremelimumab given in combination with durvalumab and chemotherapy is based on data in 330 patients with metastatic NSCLC. The most common (> 10%) adverse reactions were anaemia (49.7%), nausea (41.5%), neutropenia (41.2%), fatigue (36.1%), decreased appetite (28.2%), rash (25.8%), thrombocytopenia (24.5%), diarrhoea (21.5%), leukopenia (19.4%), constipation (19.1%), vomiting (18.2%), aspartate aminotransferase increased/alanine aminotransferase increased (17.6%), pyrexia (16.1%), upper respiratory tract infections (15.5%), pneumonia (14.8%), hypothyroidism (13.3%), arthralgia (12.4%), cough/productive cough (12.1%) and pruritus (10.9%).
The most common (>3%) severe adverse reactions (NCI CTCAE Grade ≥ 3) were neutropenia (23.9%), anaemia (20.6%), pneumonia (9.4%), thrombocytopenia (8.2%), leukopenia (5.5%), fatigue (5.2%), lipase increased (3.9%) and amylase increased (3.6%).
The most common (>2%) serious adverse reactions were pneumonia (11.5%), anaemia (5.5%), thrombocytopenia (3%), colitis (2.4%), diarrhoea (2.4%), pyrexia (2.4%) and febrile neutropenia (2.1%).
Tremelimumab was discontinued due to adverse reactions in 4.5% of patients. The most common adverse reactions leading to treatment discontinuation were pneumonia (1.2%) and colitis (0.9%).
Tremelimumab was interrupted due to adverse reactions in 40.6% of patients. The most common adverse reactions leading to dose interruption were neutropenia (13.6%), thrombocytopenia (5.8%), leukopenia (4.5%), diarrhoea (3.0%), pneumonia (2.7%), aspartate aminotransferase increased/alanine aminotransferase increased (2.4%), fatigue (2.4%), lipase increased (2.4%), colitis (2.1%), hepatitis (2.1%) and rash (2.1%).
Table 3, unless otherwise stated, lists the incidence of adverse reactions (ADRs) in patients treated with tremelimumab 300 mg in combination with durvalumab in the HCC pool of 462 patients, and IMJUDO in combination with durvalumab and platinum-based chemotherapy in the POSEIDON Study, in which 330 patients received tremelimumab. In the POSEIDON study, patients were exposed to tremelimumab during a median of 20 weeks.
Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, the ADRs are presented in decreasing frequency. The corresponding frequency category for each ADR is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, ADRs are presented in order of decreasing seriousness.
Table 3. Adverse reactions in patients treated with tremelimumab in combination with durvalumab:
| Tremelimumab 75 mg in combination with durvalumab and platinum-based chemotherapy | Tremelimumab 300 mg in combination with durvalumab | |||||
|---|---|---|---|---|---|---|
| Any Grade (%) | Grade 3-4 (%) | Any Grade (%) | Grade 3-4 (%) | |||
| Infections and infestations | ||||||
| Upper respiratory tract infectionsa | Very common | 15.5 | 0.6 | Common | 8.4 | 0 |
| Pneumoniab | Very common | 14.8 | 7.3 | Common | 4.3 | 1.3 |
| Influenza | Common | 3.3 | 0 | Common | 2.2 | 0 |
| Oral candidiasis | Common | 2.4 | 0.3 | Uncommon | 0.6 | 0 |
| Dental and oral soft tissue infectionsc | Uncommon | 0.6 | 0.3 | Common | 1.3 | 0 |
| Blood and lymphatic system disorders | ||||||
| Anaemiad | Very common | 49.7 | 20.6 | |||
| Neutropeniad,e | Very common | 41.2 | 23.9 | |||
| Thrombocytopeniad,f | Very common | 24.5 | 8.2 | |||
| Leukopeniad,g | Very common | 19.4 | 5.5 | |||
| Febrile neutropeniad | Common | 3.0 | 2.1 | |||
| Pancytopeniad | Common | 1.8 | 0.6 | |||
| Immune thrombocytopenia | Uncommon | 0.3 | 0 | Uncommonh | 0.3 | 0 |
| Endocrine disorders | ||||||
| Hypothyroidismi | Very common | 13.3 | 0 | Very common | 13.0 | 0 |
| Hyperthyroidismj | Common | 6.7 | 0 | Common | 9.5 | 0.2 |
| Adrenal insufficiency | Common | 2.1 | 0.6 | Common | 1.3 | 0.2 |
| Hypopituitarism/ Hypophysitis | Common | 1.5 | 0.3 | Uncommon | 0.9 | 0 |
| Thyroiditisk | Common | 1.2 | 0 | Common | 1.7 | 0 |
| Diabetes insipidus | Uncommon | 0.3 | 0.3 | Rarel | <0.1 | 0 |
| Type 1 diabetes mellitus | Uncommon | 0.3 | 0.3 | Uncommonl | 0.3 | <0.1 |
| Eye disorders | ||||||
| Uveitis | Uncommon | 0.3 | 0 | Rarel | <0.1 | 0 |
| Metabolism and nutrition disorders | ||||||
| Decreased appetited | Very common | 28.2 | 1.5 | |||
| Nervous system disorders | ||||||
| Neuropathy peripherald,m | Common | 6.4 | 0 | |||
| Encephalitisn | Uncommon | 0.6 | 0.6 | Rarel | <0.1 | 0 |
| Myasthenia gravis | Rare° | <0.1 | <0.1 | Uncommon | 0.4 | 0 |
| Guillain-Barré syndrome | Rarep | <0.1 | 0 | Rarep | <0.1 | 0 |
| Meningitis | Rare° | 0.1 | 0 | Uncommon | 0.2 | 0.2 |
| Cardiac disorders | ||||||
| Myocarditisq | Uncommon | 0.3 | 0 | Uncommon | 0.4 | 0 |
| Respiratory, thoracic, and mediastinal disorders | ||||||
| Cough/Productive cough | Very common | 12.1 | 0 | Very common | 10.8 | 0.2 |
| Pneumonitisr | Common | 4.2 | 1.2 | Common | 2.4 | 0.2 |
| Dysphonia | Common | 2.4 | 0 | Uncommon | 0.9 | 0 |
| Interstitial lung disease | Uncommon | 0.6 | 0 | Uncommon | 0.2 | 0 |
| Gastrointestinal disorders | ||||||
| Nausead | Very common | 41.5 | 1.8 | |||
| Diarrhoea | Very common | 21.5 | 1.5 | Very common | 25.3 | 3.9 |
| Constipationd | Very common | 19.1 | 0 | |||
| Vomitingd | Very common | 18.2 | 1.2 | |||
| Stomatitisd,s | Common | 9.7 | 0 | |||
| Amylase increased | Common° | 8.5 | 3.6 | Common | 8.9 | 4.3 |
| Abdominal paint | Common | 7.3 | 0 | Very common | 19.7 | 2.2 |
| Lipase increased | Common° | 6.4 | 3.9 | Common | 10.0 | 7.1 |
| Colitisu | Common | 5.5 | 2.1 | Common | 3.5 | 2.6 |
| Pancreatitisv | Common | 2.1 | 0.3 | Common | 1.3 | 0.6 |
| Intestinal perforation | Rarep | <0.1 | <0.1 | Rarep | <0.1 | <0.1 |
| Large intestine perforation | Uncommonp | 0.1 | <0.1 | Uncommonp | 0.1 | <0.1 |
| Hepatobiliary disorders | ||||||
| Aspartate aminotransferase increased/Alanine aminotransferase increasedw | Very common | 17.6 | 2.1 | Very common | 18.0 | 8.9 |
| Hepatitisx | Common | 3.9 | 0.9 | Common | 5.0 | 1.7 |
| Skin and subcutaneous tissue disorders | ||||||
| Alopeciad | Very common | 10.0 | 0 | |||
| Rashy | Very common | 25.8 | 1.5 | Very common | 32.5 | 3.0 |
| Pruritus | Very common | 10.9 | 0 | Very common | 25.5 | 0 |
| Dermatitisz | Uncommon | 0.6 | 0 | Common | 1.3 | 0 |
| Night sweats | Uncommon | 0.6 | 0 | Common | 1.3 | 0 |
| Pemphigoid | Uncommon | 0.3 | 0.3 | Uncommon | 0.2 | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | Very common | 12.4 | 0.3 | |||
| Myalgia | Common | 4.2 | 0 | Common | 3.5 | 0.2 |
| Myositis | Uncommon | 0.3 | 0.3 | Uncommon | 0.6 | 0.2 |
| Polymyositis | Uncommon | 0.3 | 0.3 | Uncommon | 0.2 | 0.2 |
| Immune-mediated arthritis | Uncommon° | 0.2 | 0 | Uncommon | 0.6 | 0 |
| Renal and urinary disorders | ||||||
| Blood creatinine increased | Common | 6.4 | 0.3 | Common | 4.5 | 0.4 |
| Dysuria | Common | 1.5 | 0 | Common | 1.5 | 0 |
| Nephritisaa | Uncommon | 0.6 | 0 | Uncommon | 0.6 | 0.4 |
| Cystitis noninfective | Uncommon | 0.3 | 0 | Rarel | <0.1 | 0 |
| General disorders and administration site conditions | ||||||
| Fatigued | Very common | 36.1 | 5.2 | |||
| Pyrexia | Very common | 16.1 | 0 | Very common | 13.9 | 0.2 |
| Oedema peripheralbb | Common | 8.5 | 0 | Very common | 10.4 | 0.4 |
| Injury, poisoning and procedural complications | ||||||
| Infusion-related reactioncc | Common | 3.9 | 0.3 | Common | 1.3 | 0 |
a Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection.
b Includes pneumocystis jirovecii pneumonia, pneumonia and pneumonia bacterial.
c Includes periodontitis, pulpitis dental, tooth abscess and tooth infection.
d Adverse reaction only applies to chemotherapy ADRs in the Poseidon study.
e Includes neutropenia and neutrophil count decreased.
f Includes platelet count decreased and thrombocytopenia.
g Includes leukopenia and white blood cell count decreased.
h Reported in studies outside of the HCC pool. Frequency is based on the POSEIDON study.
i Includes blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.
j Includes blood thyroid stimulating hormone decreased and hyperthyroidism.
k Includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis and thyroiditis subacute.
l Reported in studies outside of the HCC pool. Frequency is based on a pooled data set of patients treated with tremelimumab in combination with durvalumab.
m Includes neuropathy peripheral, parasthesia and peripheral sensory neuropathy.
n Includes encephalitis and encephalitis autoimmune.
° Reported in studies outside of the POSEIDON study. Frequency is based on a pooled data set of patients treated with tremelimumab in combination with durvalumab.
p Reported in studies outside of the POSEIDON study and HCC pool. Frequency is based on a pooled data set of patients treated with tremelimumab in combination with durvalumab.
q Includes autoimmune myocarditis.
r Includes immune-mediated pneumonitis and pneumonitis.
s Includes mucosal inflammation and stomatitis.
t Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
u Includes colitis, enteritis and enterocolitis.
v Includes autoimmune pancreatitis, pancreatitis and pancreatitis acute.
w Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.
x Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity, hepatitis acute and immunemediated hepatitis.
y Includes eczema, erythema, rash, rash macular, rash maculopapular, rash papular, rash pruritic and rash pustular.
z Includes dermatitis and immune-mediated dermatitis.
aa Includes autoimmune nephritis and immune-mediated nephritis.
bb Includes oedema peripheral and peripheral swelling.
cc Includes infusion-related reaction and urticaria.
Tremelimumab is associated with immune-mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of tremelimumab. The data for the following immune-mediated adverse reactions are based on 2280 patients from nine studies across multiple tumour types who received tremelimumab 75 mg every 4 weeks or 1 mg/kg every 4 weeks in combination with durvalumab 1500 mg every 4 weeks, 20 mg/kg every 4 weeks or 10 mg/kg every 2 weeks. This combined safety dataset excludes the POSEIDON Study (and patients treated with tremelimumab in combination with durvalumab and platinum-based chemotherapy). Details for the significant adverse reactions for tremelimumab when given in combination with durvalumab and platinum-based chemotherapy are presented if clinically relevant differences were noted in comparison to tremelimumab in combination with durvalumab.
The data below also reflects information for significant adverse reactions for tremelimumab 300 mg in combination with durvalumab in the HCC pool (n=462).
The management guidelines for these adverse reactions are described in section 4.4.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated pneumonitis occurred in 86 (3.8%) patients, including Grade 3 in 30 (1.3%) patients, Grade 4 in 1 (<0.1%) patient, and Grade 5 (fatal) in 7 (0.3%) patients. The median time to onset was 57 days (range: 8 – 912 days). All patients received systemic corticosteroids and 79 of the 86 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seven patients also received other immunosuppressants. Treatment was discontinued in 39 patients. Resolution occurred in 51 patients.
In the HCC pool (n=462), immune-mediated pneumonitis occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient and Grade 5 (fatal) in 1 (0.2%) patient. The median time to onset was 29 days (range: 5-774 days). All patients received systemic corticosteroids, and 5 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received other immunosuppressants. Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated hepatitis occurred in 80 (3.5%) patients, including Grade 3 in 48 (2.1%) patients, Grade 4 in 8 (0.4%) patients and Grade 5 (fatal) in 2 (<0.1%) patients. The median time to onset was 36 days (range: 1 – 533 days). All patients received systemic corticosteroids and 68 of the 80 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients also received other immunosuppressants. Treatment was discontinued in 27 patients. Resolution occurred in 47 patients.
In the HCC pool (n=462), immune-mediated hepatitis occurred in 34 (7.4%) patients, including Grade 3 in 20 (4.3%) patients, Grade 4 in 1 (0.2%) patient and Grade 5 (fatal) in 3 (0.6%) patients. The median time to onset was 29 days (range: 13-313 days). All patients received systemic corticosteroids, and 32 of the 34 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Nine patients also received other immunosuppressants. Treatment was discontinued in 10 patients. Resolution occurred in 13 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated colitis or diarrhoea occurred in 167 (7.3%) patients, including Grade 3 in 76 (3.3%) patients and Grade 4 in 3 (0.1%) patients. The median time to onset was 57 days (range: 3 – 906 days). All patients received systemic corticosteroids and 151 of the 167 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty-two patients also received other immunosuppressants. Treatment was discontinued in 54 patients. Resolution occurred in 141 patients.
In the HCC pool (n=462), immune-mediated colitis or diarrhoea occurred in 31 (6.7%) patients, including Grade 3 in 17 (3.7%) patients. The median time to onset was 23 days (range: 2-479 days). All patients received systemic corticosteroids, and 28 of the 31 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also received other immunosuppressants. Treatment was discontinued in 5 patients. Resolution occurred in 29 patients.
Intestinal perforation was observed in patients receiving tremelimumab in combination with durvalumab (rare) in studies outside of the HCC pool.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated hypothyroidism occurred in 209 (9.2%) patients, including Grade 3 in 6 (0.3%) patients. The median time to onset was 85 days (range: 1 – 624 days). Thirteen patients received systemic corticosteroids and 8 of the 13 received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment discontinued in 3 patients. Resolution occurred in 52 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 25 patients or immune-mediated thyroiditis in 2 patients.
In the HCC pool (n=462), immune-mediated hypothyroidism occurred in 46 (10.0%) patients. The median time to onset was 85 days (range: 26-763 days). One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy. Resolution occurred in 6 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 4 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated hyperthyroidism occurred in 62 (2.7%) patients, including Grade 3 in 5 (0.2%) patients. The median time to onset was 33 days (range: 4 – 176 days). Eighteen patients received systemic corticosteroids, and 11 of the 18 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Fifty-three patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker). One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 47 patients.
In the HCC pool (n=462), immune-mediated hyperthyroidism occurred in 21 (4.5%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 30 days (range: 13-60 days). Four patients received systemic corticosteriods, and all of the four patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 17 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated thyroiditis occurred in 15 (0.7%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 57 days (range: 22 – 141 days). Five patients received systemic corticosteroids and 2 of the 5 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Thirteen patients required other therapy including, hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. No patients discontinued treatment due to immune-mediated thyroiditis. Resolution occurred in 5 patients.
In the HCC pool (n=462), immune-mediated thyroiditis occurred in 6 (1.3%) patients. The median time to onset was 56 days (range: 7-84 days). Two patients received systemic corticosteroids, and 1 of the 2 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy. Resolution occurred in 2 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated adrenal insufficiency occurred in 33 (1.4%) patients, including Grade 3 in 16 (0.7%) patients and Grade 4 in 1 (<0.1%) patient. The median time to onset was 105 days (range: 20 – 428 days). Thirty-two patients received systemic corticosteroids, and 10 of the 32 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in one patient. Resolution occurred in 11 patients.
In the HCC pool (n=462), immune-mediated adrenal insufficiency occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 64 days (range: 43-504 days). All patients received systemic corticosteroids, and 1 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 2 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated type 1 diabetes mellitus occurred in 6 (0.3%) patients, including Grade 3 in 1 (<0.1%) patient and Grade 4 in 2 (<0.1%) patients. The median time to onset was 58 days (range: 7 – 220 days). All patients required insulin. Treatment was discontinued for 1 patient. Resolution occurred in 1 patient.
Immune-mediated type 1 diabetes mellitus was observed in patients receiving tremelimumab in combination with durvalumab (uncommon) in studies outside of the HCC pool.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated hypophysitis/hypopituitarism occurred in 16 (0.7%) patients, including Grade 3 in 8 (0.4%) patients. The median time to onset for the events was 123 days (range: 63 – 388 days). All patients received systemic corticosteroids and 8 of the 16 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy. Treatment was discontinued in 2 patients. Resolution occurred in 7 patients.
In the HCC pool (n=462), immune-mediated hypophysitis/hypopituitarism occurred in 5 (1.1%) patients. The median time to onset for the events was 149 days (range: 27-242 days). Four patients received systemic corticosteroids, and 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. Resolution occurred in 2 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated nephritis occurred in 9 (0.4%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 79 days (range: 39 – 183 days). All patients received systemic corticosteroids and 7 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 3 patients. Resolution occurred in 5 patients.
In the HCC pool (n=462), immune-mediated nephritis occurred in 4 (0.9%) patients, including Grade 3 in 2 (0.4%) patients. The median time to onset was 53 days (range: 26-242 days). All patients received systemic corticosteroids, and 3 of the 4 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), immune-mediated rash or dermatitis (including pemphigoid) occurred in 112 (4.9%) patients, including Grade 3 in 17 (0.7%) patients. The median time to onset was 35 days (range: 1 – 778 days). All patients received systemic corticosteroids, and 57 of the 112 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 10 patients. Resolution occurred in 65 patients.
In the HCC pool (n=462), immune-mediated rash or dermatitis (including pemphigoid) occurred in 26 (5.6%) patients, including Grade 3 in 9 (1.9%) patients and Grade 4 in 1 (0.2%) patient. The median time to onset was 25 days (range: 2-933 days). All patients received systemic corticosteroids and 14 of the 26 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants. Treatment was discontinued in 3 patients. Resolution occurred in 19 patients.
In the combined safety database with tremelimumab in combination with durvalumab (n=2280), infusion-related reactions occurred in 45 (2.0%) patients, including Grade 3 in 2 (<0.1%) patients. There were no Grade 4 or 5 events.
In patients treated with tremelimumab in combination with durvalumab and platinum-based chemotherapy in the POSEIDON study (n=330), the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 6.2% for alanine aminotransferase increased, 5.2% for aspartate aminotransferase increased, 4.0% for blood creatinine increased, 9.4% for amylase increased and 13.6% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was 24.8% and a TSH shift from baseline that was ≥ LLN to < LLN was 32.9%.
As with all therapeutic proteins, there is a potential for immunogenicity. Immunogenicity of tremelimumab is based on pooled data in 2075 patients who were treated with tremelimumab 75 mg or 1 mg/kg and evaluable for the presence of anti-drug antibodies (ADAs). Two-hundred fifty-two patients (12.1%) tested positive for treatment-emergent ADAs. Neutralising antibodies against tremelimumab were detected in 10.0% (208/2075) patients. The presence of ADAs did not impact tremelimumab pharmacokinetics, and there was no apparent effect on safety.
In the HIMALAYA study, of the 182 patients who were treated with tremelimumab 300 mg as a single dose in combination with durvalumab and evaluable for the presence of ADAs against tremelimumab, 20 (11.0%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies against tremelimumab were detected in 4.4% (8/182) patients. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.
In the POSEIDON study, of the 278 patients who were treated with tremelimumab 75 mg in combination with durvalumab 1500 mg every 3 weeks and platinum-based chemotherapy and evaluable for the presence of ADAs, 38 (13.7%) patients tested positive for treatment-emergent ADAs. Neutralising antibodies against tremelimumab were detected in 11.2% (31/278) of patients. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.
Data from HCC patients 75 years of age or older are limited.
In the POSEIDON study in patients treated with tremelimumab in combination with durvalumab and platinum-based chemotherapy, some differences in safety were reported between elderly (≥65 years) and younger patients. The safety data from patients 75 years of age or older are limited to a total of 74 patients. There was a higher frequency of serious adverse reactions and discontinuation of any study treatment due to adverse reactions in 35 patients aged 75 years of age or older treated with tremelimumab in combination with durvalumab and platinum-based chemotherapy (45.7% and 28.6%, respectively) relative to 39 patients aged 75 years of age or older who received platinum-based chemotherapy only (35.9% and 20.5%, respectively).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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