4.1. Therapeutic indications

IMJUDO in combination with durvalumab is indicated for the first line treatment of adults with advanced or unresectable hepatocellular carcinoma (HCC).

4.2. Posology and method of administration

Treatment must be initiated and supervised by a physician experienced in the treatment of cancer.

Posology

The recommended dose of IMJUDO is presented in Table 1. IMJUDO is administered as an intravenous infusion over 1 hour.

When IMJUDO is administered in combination with other therapeutic agents, refer to the summary of product characteristics (SmPC) of the therapeutic agents for further information.

Table 1. Recommended dose of IMJUDO

Indication

Recommended IMJUDO dosage

Duration of Therapy

Advanced or unresectable HCC

IMJUDO 300 mga as a single dose administered in combination with durvalumab 1500 mga at Cycle 1/Day 1, followed by durvalumab monotherapy every 4 weeks.

Until disease progression or unacceptable toxicity.

a For IMJUDO, HCC patients with a body weight of 40 kg or less must receive weight-based dosing, equivalent to IMJUDO 4 mg/kg until weight is greater than 40 kg. For durvalumab, patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to durvalumab 20 mg/kg until weight is greater than 30 kg.

Dose escalation or reduction is not recommended during treatment with IMJUDO in combination with durvalumab. Treatment withholding or discontinuation may be required based on individual safety and tolerability.

Guidelines for management of immune-mediated adverse reactions are described in Table 2 (refer to section 4.4 for further management recommendations, monitoring, and evaluation information). Refer also to the SmPC for durvalumab.

Table 2. Treatment modifications for IMJUDO in combination with durvalumab

Adverse reactions

Severitya

Treatment modification

Immune-mediated pneumonitis/interstitial lung disease

Grade 2

Withhold doseb

Grade 3 or 4

Permanently discontinue

Immune-mediated hepatitis

ALT or AST > 3 - ≤ 5 x ULN or total bilirubin > 1.5 - ≤ 3 x ULN

Withhold doseb

ALT or AST > 5 - ≤ 10 x ULN

Withhold durvalumab and permanently discontinue IMJUDO (where appropriate)

Concurrent ALT or AST > 3 x ULN and total bilirubin > 2 x ULNc

Permanently discontinue

ALT or AST > 10 x ULN or total bilirubin > 3 x ULN

Immune-mediated hepatitis in HCC (or secondary tumour involvement of the liver with abnormal baseline values)d

ALT or AST > 2.5 - ≤ 5 x BLV and ≤ 20 x ULN

Withhold doseb

ALT or AST > 5 - 7 x BLV and ≤ 20 x ULN or concurrent ALT or AST 2.5 - 5 x BLV and ≤ 20 x ULN and total bilirubin > 1.5 - < 2 x ULNc

Withhold durvalumab and permanently discontinue IMJUDO (where appropriate)

ALT or AST > 7 x BLV or > 20 x ULN whichever occurs first or bilirubin > 3 x ULN

Permanently discontinue

Immune-mediated colitis or diarrhoea

Grade 2

Withhold doseb

Grade 3 or 4

Permanently discontinuee

Intestinal perforation

ANY grade

Permanently discontinue

Immune-mediated hyperthyroidism, thyroiditis

Grade 2-4

Withhold dose until clinically stable

Immune-mediated hypothyroidism

Grade 2-4

No changes

Immune-mediated adrenal insufficiency, hypophysitis/hypopituitarism

Grade 2-4

Withhold dose until clinically stable

Immune-mediated Type 1 diabetes mellitus

Grade 2-4

No changes

Immune-mediated nephritis

Grade 2 with serum creatinine > 1.5-3 x (ULN or baseline)

Withhold doseb

Grade 3 with serum creatinine > 3 x baseline or > 3-6 x ULN; Grade 4 with serum creatinine > 6 x ULN

Permanently discontinue

Immune-mediated rash or dermatitis (including pemphigoid)

Grade 2 for > 1 week or Grade 3

Withhold doseb

Grade 4

Permanently discontinue

Immune-mediated myocarditis

Grade 2-4

Permanently discontinue

Immune-mediated myositis/polymyositis/rhabdomyolysis

Grade 2 or 3

Withhold doseb,f

Grade 4

Permanently discontinue

Infusion-related reactions

Grade 1 or 2

Interrupt or slow the rate of infusion

Grade 3 or 4

Permanently discontinue

Immune-mediated myasthenia gravis

Grade 2-4

Permanently discontinue

Immune-mediated myelitis transverse

Any grade

Permanently discontinue

Immune-mediated meningitis

Grade 2

Withhold doseb

Grade 3 or 4

Permanently discontinue

Immune-mediated encephalitis

Grade 2-4

Permanently discontinue

Immune-mediated Guillain-Barré syndrome

Grade 2-4

Permanently discontinue

Other immune-mediated adverse reactionsg

Grade 2 or 3

Withhold doseb

Grade 4

Permanently discontinue

Non-immune-mediated adverse reactions

Grade 2 and 3

Withhold dose until ≤ Grade 1 or return to baseline

Grade 4

Permanently discontinueh

a Common Terminology Criteria for Adverse Events, version 4.03. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal; BLV: baseline value.

b After withholding, IMJUDO and/or durvalumab can be resumed within 12 weeks if the adverse reactions improved to ≤ Grade 1 and the corticosteroid dose has been reduced to ≤ 10 mg prednisone or equivalent per day. IMJUDO and durvalumab should be permanently discontinued for recurrent Grade 3 adverse reactions, as applicable.

c For patients with alternative cause follow the recommendations for AST or ALT increases without concurrent bilirubin elevations.

d If AST and ALT are less than or equal to ULN at baseline in patients with liver involvement, withhold or permanently discontinue durvalumab based on recommendations for hepatitis with no liver involvement.

e Permanently discontinue IMJUDO for Grade 3; however, treatment with durvalumab can be resumed once event has resolved.

f Permanently discontinue IMJUDO and durvalumab if the adverse reaction does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory insufficiency.

g Includes immune thrombocytopenia, pancreatitis, cystitis noninfective, immune-mediated arthritis, uveitis and polymyalgia rheumatica.

h With the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue treatment should be based on accompanying clinical signs/symptoms and clinical judgment.

Special populations

Elderly

No dose adjustment is required for elderly patients (≥ 65 years of age) (see section 5.2).

Renal impairment

No dose adjustment of IMJUDO is recommended in patients with mild or moderate renal impairment. Data from patients with severe renal impairment are too limited to draw conclusions on this population (see section 5.2).

Hepatic impairment

No dose adjustment of IMJUDO is recommended for patients with mild or moderate hepatic impairment. IMJUDO has not been studied in patients with severe hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of IMJUDO in children and adolescents aged below 18 years of age has not been established with regard to HCC. No data are available. Outside its authorised indications, IMJUDO in combination with durvalumab has been studied in children aged 1 to 17 years with neuroblastoma, solid tumour and sarcoma, however the results of the study did not allow to conclude that the benefits of such use outweigh the risks. Currently available data are described in sections 5.1 and 5.2.

Method of administration

IMJUDO is for intravenous use, it is administered as an intravenous infusion after dilution, over 1 hour (see section 6.6).

For instructions on dilution of the medicinal product before administration, see section 6.6.

IMJUDO in combination with durvalumab

For advanced or uHCC, when IMJUDO is given in combination with durvalumab, administer IMJUDO as a separate intravenous infusion prior to durvalumab on the same day. Refer to the SmPC for durvalumab administration information.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Refer to section 4.2, Table 2 for recommended treatment modifications. For suspected immune-mediated adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude alternate aetiologies. Based on the severity of the adverse reaction, 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.

Traceability

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

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. 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

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.

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

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. 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 endocrinopathies

Immune-mediated hypothyroidism, hyperthyroidism and thyroiditis

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. 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

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. 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

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. Treatment with insulin can be initiated as clinically indicated for Grades 2-4.

Immune-mediated hypophysitis/hypopituitarism

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. 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 nephritis

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. 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

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. 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

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. 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.

Other immune-mediated adverse reactions

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, myelitis transverse, myositis, polymyositis, rhabdomyolysis, meningitis, encephalitis, Guillain‑Barré syndrome, immune thrombocytopenia, cystitis noninfective, immune-mediated arthritis, uveitis and polymyalgia rheumatica (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.

Infusion-related reactions

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 institutional standard, appropriate clinical practice guidelines and/or society guidelines.

Patients excluded from clinical studies

Advanced or unresectable HCC

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.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

Women of childbearing potential should use effective contraception during treatment with tremelimumab and for at least 3 months after the last dose of tremelimumab.

Pregnancy

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.

Breast-feeding

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.

Fertility

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.

4.7. Effects on ability to drive and use machines

Tremelimumab has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

IMJUDO in combination with durvalumab

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%).

Tabulated list of adverse reactions

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 treated with tremelimumab in combination with durvalumab

Tremelimumab 300 mg in combination with durvalumab

Any Grade (%)

Grade 3-4 (%)

Infections and infestations

Upper respiratory tract infectionsa

Common

8.4

0

Pneumoniab

Common

4.3

1.3

Influenza

Common

2.2

0

Oral candidiasis

Uncommon

0.6

0

Dental and oral soft tissue infectionsc

Common

1.3

0

Blood and lymphatic system disorders

Immune thrombocytopenia

Uncommond

0.3

0

Endocrine disorders

Hypothyroidisme

Very common

13.0

0

Hyperthyroidismf

Common

9.5

0.2

Adrenal insufficiency

Common

1.3

0.2

Hypopituitarism/Hypophysitis

Uncommon

0.9

0

Thyroiditisg

Common

1.7

0

Diabetes insipidus

Rareh

<0.1

0

Type 1 diabetes mellitus

Uncommonh

0.3

<0.1

Eye disorders

Uveitis

Rareh

<0.1

0

Nervous system disorders

Encephalitis

Rareh

<0.1

0

Myasthenia gravis

Uncommon

0.4

0

Guillain-Barré syndrome

Rarei

<0.1

0

Meningitis

Uncommon

0.2

0.2

Myelitis transversej

Not known

-

-

Cardiac disorders

Myocarditisk

Uncommon

0.4

0

Respiratory, thoracic and mediastinal disorders

Cough/Productive cough

Very common

10.8

0.2

Pneumonitisl

Common

2.4

0.2

Dysphonia

Uncommon

0.9

0

Interstitial lung disease

Uncommon

0.2

0

Gastrointestinal disorders

Diarrhoea

Very common

25.3

3.9

Amylase increased

Common

8.9

4.3

Abdominal painm

Very common

19.7

2.2

Lipase increased

Common

10.0

7.1

Colitisn

Common

3.5

2.6

Pancreatitiso

Common

1.3

0.6

Intestinal perforation

Rarei

<0.1

<0.1

Large intestine perforation

Uncommoni

0.1

<0.1

Coeliac disease

Rarei

0.03

0.03

Hepatobiliary disorders

Aspartate aminotransferase increased/Alanine aminotransferase increasedp

Very common

18.0

8.9

Hepatitisq

Common

5.0

1.7

Skin and subcutaneous tissue disorders

Rashr

Very common

32.5

3.0

Pruritus

Very common

25.5

0

Dermatitiss

Common

1.3

0

Night sweats

Common

1.3

0

Pemphigoid

Uncommon

0.2

0

Musculoskeletal and connective tissue disorders

Myalgia

Common

3.5

0.2

Myositist

Uncommon

0.6

0.2

Polymyositist

Uncommon

0.2

0.2

Immune-mediated arthritis

Uncommon

0.6

0

Polymyalgia rheumatica

Uncommon

0.6

0.2

Renal and urinary disorders

Blood creatinine increased

Common

4.5

0.4

Dysuria

Common

1.5

0

Nephritisu

Uncommon

0.6

0.4

Cystitis noninfective

Rareh

<0.1

0

General disorders and administration site conditions

Pyrexia

Very common

13.9

0.2

Oedema peripheralv

Very common

10.4

0.4

Injury, poisoning and procedural complications

Infusion-related reactionw

Common

1.3

0

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 Reported in studies outside of the HCC pool. Frequency is based on the POSEIDON study.

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 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.

i 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.

j Reported in studies outside of the POSEIDON study and HCC pool.

k Includes autoimmune myocarditis.

l Includes immune-mediated pneumonitis and pneumonitis.

m Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.

n Includes colitis, enteritis and enterocolitis

o Includes pancreatitis and pancreatitis acute.

p Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.

q Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity and immune-mediated hepatitis.

r Includes eczema, erythema, rash, rash macular, rash maculopapular, rash popular and rash pruritic.

s Includes dermatitis and immune-mediated dermatitis.

t Includes rhabdomyolysis, myositis, and polymyositis.

u Includes autoimmune nephritis and immune-mediated nephritis.

v Includes oedema peripheral and peripheral swelling.

w Includes infusion-related reaction and urticaria.

Description of selected adverse reactions

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.

Immune‑mediated pneumonitis

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.

Immune‑mediated hepatitis

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.

Immune‑mediated colitis

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.

Immune‑mediated endocrinopathies

Immune-mediated hypothyroidism

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.

Immune-mediated hyperthyroidism

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.

Immune-mediated thyroiditis

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.

Immune-mediated adrenal insufficiency

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

Immune-mediated type 1 diabetes mellitus was observed in patients receiving tremelimumab in combination with durvalumab (uncommon) in studies outside of the HCC pool.

Immune-mediated hypophysitis/hypopituitarism

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.

Immune‑mediated nephritis

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.

Immune‑mediated rash

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.

Immune checkpoint inhibitor class effects

There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with tremelimumab: pancreatic exocrine insufficiency.

Immunogenicity

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.

Elderly

Data from HCC patients 75 years of age or older are limited.

Reporting of suspected adverse reactions

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no information on overdose with tremelimumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.