Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
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 (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.
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 (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.
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 (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.
Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis occurred in patients receiving tremelimumab in combination with durvalumab, 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.
Immune-mediated adrenal insufficiency occurred in patients receiving tremelimumab in combination with durvalumab (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.
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 (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.
Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving tremelimumab in combination with durvalumab (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.
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 (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.
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 (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.
Immune-mediated myocarditis, which can be fatal, occurred in patients receiving tremelimumab in combination with durvalumab (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated myocarditis 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: myasthenia gravis, myositis, polymyositis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, cystitis noninfective and pancreatitis (see section 4.8). Patients should be monitored for signs and symptoms and managed as recommended in section 4.2.
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.
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.
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.
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, tremelimumab has the potential to impact maintenance of pregnancy and may cause foetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tremelimumab to pregnant cynomolgus monkeys during the period of organogenesis was not associated with maternal toxicity or any effects on maintenance of pregnancy or embryofoetal development (see section 5.3). Human IgG2 is known to cross the placental barrier. Tremelimumab 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 excreted in human milk. Because of the potential for adverse reactions from tremelimumab in breast-fed infants, breastfeeding women are advised not to breast-feed during treatment 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%), oedema peripheral (10.4%) and lipase increased (10.0%) (see Table 3).
The most common severe adverse reactions (NCI CTCAE Grade ≥ 3) are aspartate aminotransferase increased/alanine aminotransferase increased (8.9%), lipase increased (7.1%), amylase increased (4.3%) and diarrhoea (3.9%).
The most common serious adverse reactions are colitis (2.6%), diarrhoea (2.4%), pneumonia (2.2%), and hepatitis (1.7%).
The frequency of treatment discontinuation due to adverse reactions is 6.5%. The most common adverse reactions leading to treatment discontinuation are hepatitis (1.5%) and aspartate aminotransferase increased/alanine aminotransferase increased (1.3%).
The severity of adverse drug reactions was assessed based on the CTCAE, defining grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life threatening and grade 5=death.
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. 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 with HCC treated with tremelimumab 300 mg in combination with durvalumab:
| Tremelimumab 300 mg in combination with durvalumab (n=462) | ||||
|---|---|---|---|---|
| Adverse Reaction | Frequency of any Grade | Frequency of Grade 3-4 | ||
| Infections and infestations | ||||
| Upper respiratory tract infectionsa | Common | 39 (8.4%) | ||
| Pneumoniab | Common | 20 (4.3%) | Common | 6 (1.3%) |
| Influenza | Common | 10 (2.2%) | ||
| Dental and oral soft tissue infectionsc | Common | 6 (1.3%) | ||
| Oral candidiasis | Uncommon | 3 (0.6%) | ||
| Blood and lymphatic system disorders | ||||
| Immune thrombocytopeniad | Not known | |||
| Endocrine disorders | ||||
| Hypothyroidisme | Very common | 60 (13.0%) | ||
| Hyperthyroidismf | Common | 44 (9.5%) | Uncommon | 1 (0.2%) |
| Thyroiditisg | Common | 8 (1.7%) | ||
| Adrenal insufficiency | Common | 6 (1.3%) | Uncommon | 1 (0.2%) |
| Hypopituitarism/Hypophysitis | Uncommon | 4 (0.9%) | ||
| Diabetes insipidusd | Not known | |||
| Type 1 diabetes mellitusd | Not known | |||
| Nervous system disorders | ||||
| Myasthenia gravis | Uncommon | 2 (0.4%) | ||
| Meningitis | Uncommon | 1 (0.2%) | Uncommon | 1 (0.2%) |
| Guillain-Barré syndromed | Not known | |||
| Encephalitisd | Not known | |||
| Cardiac disorders | ||||
| Myocarditis | Uncommon | 2 (0.4%) | ||
| Respiratory, thoracic and mediastinal disorders | ||||
| Cough/Productive cough | Very common | 50 (10.8%) | Uncommon | 1 (0.2%) |
| Pneumonitish | Common | 11 (2.4%) | Uncommon | 1 (0.2%) |
| Dysphonia | Uncommon | 4 (0.9%) | ||
| Interstitial lung disease | Uncommon | 1 (0.2%) | ||
| Gastrointestinal disorders | ||||
| Diarrhoea | Very common | 117 (25.3%) | Common | 18 (3.9%) |
| Abdominal paini | Very common | 91 (19.7%) | Common | 10 (2.2%) |
| Lipase increased | Common | 46 (10.0%) | Common | 33 (7.1%) |
| Amylase increased | Common | 41 (8.9%) | Common | 20 (4.3%) |
| Colitisj | Common | 16 (3.5%) | Common | 12 (2.6%) |
| Pancreatitisk | Common | 6 (1.3%) | Uncommon | 3 (0.6%) |
| Intestinal perforationd | Not known | |||
| Large intestine perforationd | Not known | |||
| Hepatobiliary disorders | ||||
| Aspartate aminotransferase increased/Alanine aminotransferase increasedl | Very common | 83 (18.0%) | Common | 41 (8.9%) |
| Hepatitism | Common | 23 (5.0%) | Common | 8 (1.7%) |
| Skin and subcutaneous tissue disorders | ||||
| Rashn | Very common | 150 (32.5%) | Common | 14 (3.0%) |
| Pruritus | Very common | 118 (25.5%) | ||
| Dermatitis° | Common | 6 (1.3%) | ||
| Night sweats | Common | 6 (1.3%) | ||
| Pemphigoid | Uncommon | 1 (0.2%) | ||
| Musculoskeletal and connective tissue disorders | ||||
| Myalgia | Common | 16 (3.5%) | Uncommon | 1 (0.2%) |
| Myositis | Uncommon | 3 (0.6%) | Uncommon | 1 (0.2%) |
| Polymyositis | Uncommon | 1 (0.2%) | Uncommon | 1 (0.2%) |
| Renal and urinary disorders | ||||
| Blood creatinine increased | Common | 21 (4.5%) | Uncommon | 2 (0.4%) |
| Dysuria | Common | 7 (1.5%) | ||
| Nephritisp | Uncommon | 3 (0.6%) | Uncommon | 2 (0.4%) |
| Cystitis noninfectived | Not known | |||
| General disorders and administration site conditions | ||||
| Pyrexia | Very common | 64 (13.9%) | Uncommon | 1 (0.2%) |
| Oedema peripheralq | Very common | 48 (10.4%) | Uncommon | 2 (0.4%) |
| Injury, poisoning and procedural complications | ||||
| Infusion-related reactionr | Common | 6 (1.3%) | ||
a Includes nasopharyngitis, pharyngitis, rhinitis, tracheobronchitis and upper respiratory tract infection.
b Includes pneumocystis jirovecii pneumonia and pneumonia.
c Includes periodontitis, pulpitis dental, tooth abscess and tooth infection.
d Adverse reaction was not observed in the HCC pool, but was reported in patients treated with durvalumab or durvalumab + tremelimumab in AstraZeneca-sponsored clinical studies.
e Includes blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.
f Includes blood thyroid stimulating hormone decreased and hyperthyroidism.
g Includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis and thyroiditis subacute.
h Includes immune-mediated pneumonitis and pneumonitis.
i Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
j Includes colitis, enteritis and enterocolitis.
k Includes pancreatitis and pancreatitis acute.
l Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.
m Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity and immune-mediated hepatitis.
n Includes eczema, erythema, rash, rash macular, rash maculo-papular, rash papular and rash pruritic.
° Includes dermatitis and immune-mediated dermatitis.
p Includes autoimmune nephritis and immune-mediated nephritis.
q Includes oedema peripheral and peripheral swelling.
r Includes infusion-related reaction and urticaria.
The data below reflects information for significant adverse reactions for tremelimumab 300 mg in combination with durvalumab in the HCC pool (n=462).
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). Six 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 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 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 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 therapyincluding hormone replacement therapy . Resolution occurred in 6 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 4 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 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 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.
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 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 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 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.
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 efficacy and 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.
Data from HCC patients 75 years of age or older are limited.
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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