4.1. Therapeutic indications

Non-Small Cell Lung Cancer (NSCLC)

IMFINZI as monotherapy is indicated for the treatment of locally advanced, unresectable non‑small cell lung cancer (NSCLC) in adults whose tumours express PD-L1 on ≥ 1% of tumour cells and whose disease has not progressed following platinum‑based chemoradiation therapy (see section 5.1).

IMFINZI in combination with platinum-based chemotherapy as neoadjuvant treatment, followed by IMFINZI as monotherapy after surgery, is indicated for the treatment of adults with resectable (tumours ≥ 4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements.

Small Cell Lung Cancer (SCLC)

IMFINZI as monotherapy is indicated for the treatment of adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following platinum-based chemoradiation therapy.

IMFINZI in combination with etoposide and either carboplatin or cisplatin is indicated for the first-line treatment of adults with extensive-stage small cell lung cancer (ES‑SCLC).

Biliary Tract Cancer (BTC)

IMFINZI in combination with gemcitabine and cisplatin is indicated for the first line treatment of adults with locally advanced, unresectable, or metastatic biliary tract cancer (BTC).

Hepatocellular Carcinoma (HCC)

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

Endometrial Cancer

IMFINZI in combination with carboplatin and paclitaxel is indicated for the first-line treatment of adults with primary advanced or recurrent endometrial cancer who are candidates for systemic therapy, followed by maintenance treatment with:

• IMFINZI as monotherapy in endometrial cancer that is mismatch repair deficient (dMMR)

• IMFINZI in combination with olaparib in endometrial cancer that is mismatch repair proficient (pMMR).

Muscle Invasive Bladder Cancer (MIBC)

IMFINZI in combination with gemcitabine and cisplatin as neoadjuvant treatment, followed by IMFINZI as monotherapy adjuvant treatment after radical cystectomy, is indicated for the treatment of adults with resectable muscle invasive bladder cancer (MIBC).

Gastric or Gastro-oesophageal Junction Adenocarcinoma (GC/GEJC)

IMFINZI in combination with FLOT chemotherapy as neoadjuvant and adjuvant treatment, followed by adjuvant IMFINZI monotherapy, is indicated for the treatment of adults with resectable gastric or gastro‑oesophageal junction adenocarcinoma.

4.2. Posology and method of administration

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

PD-L1 testing for patients with locally advanced NSCLC

Patients with locally advanced NSCLC should be evaluated for treatment based on the tumour expression of PD-L1 confirmed by a validated test (see section 5.1).

MMR testing for patients with endometrial cancer

Patients with endometrial cancer should be evaluated for treatment based on tumour MMR status confirmed by a validated test (see section 5.1).

Posology

The recommended dose for IMFINZI monotherapy and IMFINZI combination therapy is presented in Table 1. IMFINZI is administered as an intravenous infusion over 1 hour.

When IMFINZI 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 IMFINZI monotherapy and combination therapy

Indication

Recommended IMFINZI dose

Duration of therapy

Monotherapy

Locally Advanced NSCLC

10 mg/kg every 2 weeks or 1 500 mg every 4 weeksa

Until disease progression, unacceptable toxicity, or a maximum of 12 monthsb

LS-SCLC

1 500 mg every 4 weeksa

Until disease progression, unacceptable toxicity, or a maximum of 24 months

Combination therapy

Resectable NSCLC

1 500 mgf in combination with platinum-based chemotherapy every 3 weeks for up to 4 cycles prior to surgery,

followed by 1 500 mg monotherapy every 4 weeks for up to 12 cycles after surgery.

Until disease is deemed unresectable, recurrence, unacceptable toxicity, or a maximum of 12 cycles after surgery

ES‑SCLC

1 500 mgc in combination with chemotherapy every 3 weeks (21 days) for 4 cycles,

followed by 1 500 mg every 4 weeks as monotherapy

Until disease progression or unacceptable toxicity

BTC

1 500 mgd in combination with chemotherapy every 3 weeks (21 days), for up to 8 cycles,

followed by 1 500 mg every 4 weeks as monotherapy

Until disease progression or until unacceptable toxicity

HCC

IMFINZI 1500 mge administered in combination with 300 mge tremelimumab as a single dose at Cycle 1/Day 1,

followed by IMFINZI as monotherapy every 4 weeks

Until disease progression or unacceptable toxicity

Endometrial Cancer

1 120 mg in combination with carboplatin and paclitaxel every 3 weeks (21 days) for a minimum of 4 and up to 6 cycles,

followed by IMFINZI 1 500 mgg every 4 weeks as monotherapy (dMMR patients) or in combination with olaparib 300 mg twice daily (pMMR patients)

Until disease progression or unacceptable toxicity

MIBC

1 500 mgh in combination with chemotherapy every 3 weeks for 4 cycles prior to surgery,

followed by 1 500 mgh every 4 weeks as monotherapy for up to 8 cycles after surgery

Neoadjuvant phase: until disease progression that precludes definitive surgery or unacceptable toxicity

Adjuvant phase: until recurrence, unacceptable toxicity, or a maximum of 8 cycles after surgery

GC/GEJC

1 500 mgi in combination with FLOT chemotherapy every 4 weeks for up to 2 cycles prior to surgery,

followed by 1 500 mgi, with FLOT chemotherapy, every 4 weeks for up to 2 cycles and then as 1 500 mg monotherapy every 4 weeks for up to 10 cycles, for a total of up to 12 cycles after surgery

Neoadjuvant phase: until disease progression that precludes definitive surgery or unacceptable toxicity

Adjuvant phase: until progression or recurrence, unacceptable toxicity, or a maximum of 12 cycles after surgery

a Patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 30kg.

b It is recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed.

c Patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg. In combination with chemotherapy dose every 3 weeks (21 days), followed by 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 30 kg.

d BTC patients with a body weight of 36 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg. In combination with chemotherapy dose every 3 weeks (21 days), followed by 20 mg/kg every 4 weeks as monotherapy until weight increases to greater than 36 kg.

e HCC patients with a body weight of 30 kg or less must receive weight-based dosing, equivalent to IMFINZI 20 mg/kg until weight increases to greater than 30 kg. Patients with a body weight of 40 kg or less must receive weight-based dosing, equivalent to tremelimumab 4 mg/kg until weight increases to greater than 40 kg.

f Resectable NSCLC patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg. In combination with platinum-based chemotherapy dose at 20 mg/kg every 3 weeks (21 days) prior to surgery, followed by monotherapy at 20 mg/kg every 4 weeks after surgery until weight increases to greater than 30 kg.

g Endometrial cancer patients with a body weight of 30 kg or less during maintenance phase must receive weight-based dosing equivalent to IMFINZI at 20 mg/kg, until weight increases to greater than 30 kg.

h MIBC patients with a body weight of 30 kg or less must receive weight-based dosing of IMFINZI at 20 mg/kg.

i GC/GEJC patients with a body weight of 30 kg or less must receive weight‑based dosing of IMFINZI at 20 mg/kg.

Dose escalation or reduction is not recommended. Treatment withholding or discontinuation may be required based on individual safety and tolerability.

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

Table 2. Treatment modifications for IMFINZI or IMFINZI in combination with other products

Adverse reactions

Severity a

Treatment modification

Immune‑mediated pneumonitis/interstitial lung disease

Grade 2

Withhold dose

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 dose

ALT or AST > 5 - ≤ 10 x ULN

Withhold IMFINZI and permanently discontinue tremelimumab (where appropriate)

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

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)c

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

Withhold dose

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 ULNb

Withhold IMFINZI and permanently discontinue tremelimumab (where appropriate).

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

Permanently discontinue

Immune‑mediated colitis or diarrhoea

Grade 2

Withhold dose

Grade 3 for IMFINZI monotherapy

Withhold dose

Grade 3 for IMFINZI + tremelimumab

Permanently discontinue tremelimumabd

Grade 4

Permanently discontinue

Intestinal perforatione

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 or 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 dose

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

Withhold dose

Grade 3

Grade 4

Permanently discontinue

Immune-mediated myocarditis

Grade 2-4

Permanently discontinue

Immune-mediated myositis/polymyositis/rhabdomyolysis

Grade 2 or 3

Withhold dosef

Grade 4

Permanently discontinue

Infusion‑related reactions

Grade 1 or 2

Interrupt or slow the rate of infusion

Grade 3 or 4

Permanently discontinue

Infection

Grade 3 or 4

Withhold dose until clinically stable

Immune-mediated myasthenia gravis

Grade 2-4

Permanently discontinue

Immune-mediated Myelitis transverse

Any Grade

Permanently discontinue

Immune-mediated meningitis

Grade 2

Withhold dose

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 dose

Grade 4

Permanently discontinue

Pure red cell aplasia (PRCA)h

Any Grade

Permanently discontinue

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

c 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.

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

e Adverse drug reaction is only associated with IMFINZI in combination with tremelimumab.

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

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

h Adverse drug reaction is only associated when olaparib maintenance treatment is used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy.

Based on the severity of the adverse reaction, IMFINZI and/or tremelimumab should be withheld and corticosteroids administered (refer to section 4.4). After withhold, IMFINZI and/or tremelimumab 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. IMFINZI and tremelimumab should be permanently discontinued for recurrent Grade 3 (severe) immune-mediated adverse reactions and for any Grade 4 (life-threatening) immune-mediated adverse reactions, except for endocrinopathies that are controlled with replacement hormones.

For non-immune-mediated adverse reactions, withhold IMFINZI for Grade 2 and 3 adverse reactions until ≤ Grade 1 or baseline. IMFINZI should be discontinued for Grade 4 adverse reactions (with the exception of Grade 4 laboratory abnormalities, about which the decision to discontinue 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 5.1).

Renal impairment

No dose adjustment of IMFINZI 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

Data from patients with severe hepatic impairment are limited. Due to minor involvement of hepatic processes in the clearance of durvalumab no dose adjustment of IMFINZI is recommended for patients with hepatic impairment as no difference in exposure is expected (see section 5.2).

Paediatric population

The safety and efficacy of IMFINZI in children and adolescents aged below 18 years of age has not been established with regard to NSCLC, SCLC, BTC, HCC, endometrial cancer and GC/GEJC. No data are available. Outside its authorised indications, IMFINZI in combination with tremelimumab 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

IMFINZI is for intravenous use. It is to be administered as an intravenous infusion solution over 1 hour (see section 6.6).

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

IMFINZI in combination with chemotherapy

When IMFINZI is administered in combination with chemotherapy, administer IMFINZI prior to chemotherapy on the same day.

IMFINZI in combination with tremelimumab

When IMFINZI is administered in combination with tremelimumab, administer tremelimumab prior to IMFINZI on the same day. IMFINZI and tremelimumab are administered as separate intravenous infusions. Refer to the summary of product characteristics (SmPC) for tremelimumab dosing information.

4.3. Contraindications

Hypersensitivity to the active substance(s) 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 etiology or exclude alternate etiologies. Based on the severity of the adverse reaction, IMFINZI or IMFINZI in combination with tremelimumab should be withheld or permanently discontinued. Treatment with corticosteroids or endocrine therapy should be initiated. For events requiring corticosteroid therapy, and 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 IMFINZI, IMFINZI in combination with tremelimumab or IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib (see section 4.8). 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.

Pneumonitis and radiation pneumonitis

Radiation pneumonitis is frequently observed in patients receiving radiation therapy to the lung and the clinical presentation of pneumonitis and radiation pneumonitis is very similar. In the PACIFIC Study, in patients who had completed treatment with at least 2 cycles of concurrent chemoradiation within 1 to 42 days prior to initiation of study treatment, pneumonitis or radiation pneumonitis occurred in 161 (33.9%) patients in the IMFINZI‑treated group and 58 (24.8%) in the placebo group, including Grade 3 (3.4% vs. 3.0%) and Grade 5 (1.1% vs. 1.7%). In the AEGEAN study, in patients who have received post-operative radiotherapy (PORT), pneumonitis and radiation pneumonitis occurred in 10 (33.3%) patients in the IMFINZI-treated group and 3 (11.1%) patients in the placebo group, including Grade 3 in 2 patients (6.7%) in the IMFINZI-treated group and 0 patients in the placebo group.

In the ADRIATIC Study, in patients who had completed chemoradiation within 1 to 42 days prior to initiation of study treatment, pneumonitis or radiation pneumonitis occurred in 100 (38.2%) patients in the IMFINZI-treated group and 80 (30.2%) in the placebo group, including Grade 3 (3.1% vs. 2.3%), and Grade 5 (0.4% vs. 0.0).

Patients should be monitored for signs and symptoms of pneumonitis or radiation 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

Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (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 IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Adverse drug reactions of intestinal perforation and large intestine perforation were reported in patients receiving IMFINZI in combination with tremelimumab. 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 IMFINZI or IMFINZI in combination with tremelimumab, 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 IMFINZI or IMFINZI in combination with tremelimumab (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 a 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 IMFINZI or IMFINZI in combination with tremelimumab (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 IMFINZI or IMFINZI in combination with tremelimumab (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 a 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 IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Patients should be monitored for abnormal renal function tests prior to and periodically during treatment with IMFINZI or IMFINZI in combination with tremelimumab 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 a 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 IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Events of Stevens-Johnson Syndrome or toxic epidermal necrolysis have been reported in patients treated with PD-1 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 a 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 IMFINZI (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 IMFINZI or IMFINZI in combination with tremelimumab, other potential immune‑mediated adverse reactions may occur. The following immune-related adverse reactions have been observed in patients treated with IMFINZI monotherapy or IMFINZI in combination with tremelimumab: myasthenia gravis, myelitis transverse, myositis, polymyositis, rhabdomyolysis, meningitis, encephalitis, Guillain-Barré syndrome, immune thrombocytopenia, immune-mediated arthritis, uveitis, cystitis noninfective, polymyalgia rheumatica and pancreatitis (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 IMFINZI or IMFINZI in combination with tremelimumab (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 with pre-existing autoimmune disease

In patients with pre-existing autoimmune disease (AID), data from observational studies suggest an increased risk of immune-related adverse reactions following immune-checkpoint inhibitor therapy as compared with patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

Disease-specific precaution (BTC)

Cholangitis and biliary tract infections

Cholangitis and biliary tract infections are not uncommon in patients with advanced BTC. Cholangitis events were reported in TOPAZ-1 in both treatment groups (14.5% [IMFINZI + chemotherapy] vs. 8.2% [placebo + chemotherapy]); these were mostly in association with biliary stents and were not immune-mediated in aetiology. Patients with BTC (especially those with biliary stents) should be closely monitored for development of cholangitis or biliary tract infections before initiation of treatment and, regularly, thereafter.

Treatment-specific precaution (IMFINZI in combination with olaparib in endometrial cancer)

Haematological toxicity

Pure red cell aplasia (PRCA) (see section 4.8) was reported when olaparib maintenance treatment was used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy. If PRCA is confirmed, treatment with IMFINZI and olaparib should be discontinued.

Autoimmune haemolytic anemia (AIHA) was reported when olaparib maintenance treatment was used in combination with IMFINZI, following treatment with IMFINZI in combination with platinum-based chemotherapy. If AIHA is confirmed, treatment with IMFINZI and olaparib should be discontinued.

Patients excluded from clinical studies

Patients with the following were excluded from clinical studies: a baseline ECOG performance score ≥ 2; active or prior documented autoimmune disease within 2 years of initiation of the study; a history of immunodeficiency; a history of severe immune-mediated adverse reactions; medical conditions that required systemic immunosuppression, except physiological dose of systemic corticosteroids (≤ 10 mg/day prednisone or equivalent); uncontrolled intercurrent illnesses; 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 IMFINZI. In the absence of data, durvalumab should be used with caution in these populations after careful consideration of the potential benefit/risk on an individual basis. The safety of concurrent prophylactic cranial irradiation (PCI) with IMFINZI in patients with ES‑SCLC is unknown.

For more information on exclusion criteria for each specific study see section 5.1.

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

The use of systemic corticosteroids or immunosuppressants before starting durvalumab, 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 durvalumab. However, systemic corticosteroids or other immunosuppressants can be used after starting durvalumab to treat immune‑related adverse reactions (see section 4.4).

No formal pharmacokinetic (PK) drug‑drug interaction studies have been conducted with durvalumab. Since the primary elimination pathways of durvalumab are protein catabolism via reticuloendothelial system or target‑mediated disposition, no metabolic drug-drug interactions are expected. PK drug-drug interactions of durvalumab in combination with other therapeutic agents were compared with durvalumab in the CASPIAN, POSEIDON, HIMALAYA, and DUO-E studies; no clinically meaningful PK drug-drug interactions were identified.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

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

Pregnancy

There are no data on the use of durvalumab in pregnant women. Based on its mechanism of action, durvalumab has the potential to impact maintenance of pregnancy, and in a mouse allogeneic pregnancy model, disruption of PD-L1 signaling was shown to result in an increase in foetal loss. Animal studies with durvalumab are not indicative of reproductive toxicity (see section 5.3). Human IgG1 is known to cross the placental barrier and placental transfer of durvalumab was confirmed in animal studies. Durvalumab may cause foetal harm when administered to a pregnant woman and 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

It is unknown whether durvalumab is secreted in human breast milk. Available toxicological data in cynomolgus monkeys have shown low levels of durvalumab in breast milk on day 28 after birth (see section 5.3). In humans, antibodies may be transferred to breast milk, but the potential for absorption and harm to the newborn is unknown. However, a potential risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue or abstain from durvalumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the potential effects of durvalumab on fertility in humans or animals.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

IMFINZI as monotherapy

The safety of IMFINZI as monotherapy is based on pooled data in 4 642 patients across multiple tumour types. IMFINZI was administered at a dose of 10 mg/kg every 2 weeks or 20 mg/kg every 4 weeks. The most common (> 10%) adverse reactions were cough/productive cough (18.1%), diarrhoea (15.1%), rash (15.2%), pyrexia (12.5%), arthralgia (12.4%), upper respiratory tract infections (11.8%), abdominal pain (11.8%), hypothyroidism (11.6%) and pruritus (11.1%). The most common (> 2%) Grade ≥ 3 adverse reactions were pneumonia (3.9%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.5%).

IMFINZI was discontinued due to adverse reactions in 4.0% of patients. The most common adverse reaction leading to treatment discontinuation was pneumonitis (1.1%) and pneumonia (0.8%).

IMFINZI was delayed or interrupted due to adverse reactions in 13.1% of patients. The most common adverse reactions leading to dose delay or interruption were pneumonia (2.3%), aspartate aminotransferase increased/alanine aminotransferase increased (2.0%), pneumonitis (1.4%), diarrhoea (1.1%), pyrexia (1.0%) and hypothyroidism (1.0%).

The most frequent (>1%) serious adverse reactions were pneumonia (4.4%), pneumonitis (1.4%), abdominal pain (1.2%), and pyrexia (1.2%).

IMFINZI in combination with chemotherapy

The safety of IMFINZI in combination with chemotherapy is based on pooled data in 2 244 patients from 6 studies (AEGEAN, TOPAZ-1, CASPIAN, DUO-E, NIAGARA and MATTERHORN). The most common (> 10%) adverse reactions were neutropenia (44.6%), nausea (42.4%), fatigue (41.2%), anaemia (37.4%), diarrhoea (27.5%), constipation (26.7%), decreased appetite (24.0%), alopecia (22.0%), neuropathy peripheral (21.6%), rash (21.0%), thrombocytopenia (19.7%), vomiting (18.8%), abdominal pain (17.9%), pyrexia (15.2%), leukopenia (14.9%), pruritus (12.5%), hypothyroidism (11.1%), arthralgia (10.9%), cough/productive cough (10.8%) and aspartate aminotransferase increased/alanine aminotransferase increased (10.5%).

The most common (> 2%) Grade 3 or 4 adverse reactions were neutropenia (28.5%), anaemia (11.9%), thrombocytopenia (5.6%), leukopenia (4.9%), fatigue (3.3%), febrile neutropenia (2.4%), diarrhoea (2.3%) and pneumonia (2.2%).

IMFINZI was discontinued due to adverse reactions in 6.2% of patients. The most common adverse reactions leading to treatment discontinuation were pneumonitis (0.8%), rash (0.7%), fatigue (0.5%), hepatitis (0.5%), nephritis (0.4%), anaemia (0.3%), aspartate aminotransferase increased/alanine aminotransferase increased (0.3%), blood creatinine increased (0.3%), interstitial lung disease (0.2%), neuropathy peripheral (0.2%), myositis (0.2%), neutropenia (0.2%), diarrhoea (0.2%) and colitis (0.2%).

IMFINZI was delayed or interrupted due to adverse reactions in 32.4% of patients. The most common adverse reactions leading to dose delay or interruption were neutropenia (15.5%), thrombocytopenia (4.1%), anaemia (3.3%), leukopenia (2.0%), fatigue (2.0%), aspartate aminotransferase increased/alanine aminotransferase increased (2.0%), diarrhoea (1.5%) and rash (1.2%).

The most frequent (>1%) serious adverse reactions were pneumonia (2.9%), febrile neutropenia (1.8%), anaemia (1.6%), neutropenia (1.5%), pyrexia (1.3%), vomiting (1.2%) and thrombocytopenia (1.1%).

IMFINZI in combination with tremelimumab 300 mg

The safety of IMFINZI given in combination with a single dose of tremelimumab 300 mg is based on pooled data (HCC pool) in 462 HCC patients 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 4). 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.

IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily

The safety of IMFINZI given in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib 300 mg twice daily is based on data in 238 patients with endometrial cancer. The most common (> 20%) adverse reactions were anaemia (61.8%), nausea (54.6%), fatigue (54.2%), neuropathy peripheral (51.7%), alopecia (50.8%), neutropenia (39.5%), constipation (32.8%), thrombocytopenia (29.8%), diarrhoea (28.2%), vomiting (25.6%), arthralgia (24.4%), rash (23.9%), abdominal pain (23.5%), decreased appetite (23.1%) and leukopenia (20.2%).

The most common (> 2%) NCI CTCAE Grade ≥ 3 adverse reactions were neutropenia (25.2%), anaemia (23.5%), leukopenia (6.7%), thrombocytopenia (5.9%), fatigue (5.5%), febrile neutropenia (3.4%), nausea (2.9%), aspartate aminotransferase increased / alanine aminotransferase increased (2.9%) and neuropathy peripheral (2.5%).

IMFINZI was discontinued in 4.6% of patients. The most common adverse reaction leading to treatment discontinuation was pneumonitis (1.7%).

IMFINZI was interrupted in 38.2% of patients. The most common adverse reactions leading to dose interruption were anaemia (13.4%), thrombocytopenia (11.8%), neutropenia (10.1%), leukopenia (2.9%), hypothyroidism (2.1%) and upper respiratory tract infection (2.1%).

Tabulated list of adverse reactions

Table 3 lists the incidence of adverse reactions in the IMFINZI monotherapy pooled safety dataset (N=4 642), in patients treated with IMFINZI in combination with chemotherapy (N=2 244) and in patients treated with IMFINZI in combination with platinum-based chemotherapy followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib) (N=238). Table 4 lists the incidence of adverse reactions in patients treated with IMFINZI in combination with a single dose of tremelimumab 300 mg in the HCC pool (N=462). Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse reactions 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 < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.

Table 3. Adverse drug reactions in patients treated with IMFINZI

IMFINZI as monotherapy

IMFINZI in combination with chemotherapy

Platinum-based chemotherapy + IMFINZI + olaparib*

Infections and infestations

Very common

Upper respiratory tract infectionsa

Upper respiratory tract infectiona

Common

Pneumoniab,c, Influenza, Oral candidiasis, Dental and oral soft tissue infectionsd

Upper respiratory tract infectionsa, Pneumoniab,c, Dental and oral soft tissue infectionsd

Pneumonia, Oral candidiasis, Dental and oral soft tissue infectionsd

Uncommon

Influenza, Oral candidiasis

Influenza

Blood and lymphatic system disorders

Very Common

Neutropeniaf, Anaemia, Thrombocytopeniag Leukopeniae

Anaemiah, Leukopeniah Neutropeniah, Thrombocytopeniah

Common

Febrile neutropenia

Aplasia pure red cell, Febrile neutropeniah, Lymphopeniai

Uncommon

Immune thrombocytopeniac

Pancytopeniac

Pancytopeniah

Rare

Immune thrombocytopenia

Immune system disorders

Common

Hypersensitivityi,j

Endocrine disorders

Very common

Hypothyroidismk

Hypothyroidismk

Hypothyroidism

Common

Hyperthyroidisml

Hyperthyroidisml

Hyperthyroidism, Thyroiditis

Uncommon

Thyroiditism, Adrenal insufficiency, Hypophysitis/Hypopituitarism, Type 1 diabetes mellitus

Adrenal insufficiency,

Thyroiditism, Type 1 diabetes mellitus, Hypophysitis/Hypopituitarismpp

Rare

Diabetes insipidus

Eye disorders

Uncommon

Uveitis

Rare

Uveitis

Uveitis

Metabolism and nutrition disorders

Very common

Decreased appetite

Decreased appetiteh

Nervous System Disorders

Very common

Neuropathy peripheraln

Neuropathy peripheral, Dizzinessi, Headachei, Dysgeusiai,o

Uncommon

Myasthenia gravis, Encephalitisc,p

Myasthenia gravisqq

Rare

Meningitis

Encephalitisp,ff, Guillain-Barré syndrome

Not known

Guillain-Barré syndrome, Myelitis transverser

Vascular disorders

Common

Venous thromboembolic eventsi,s

Rare

Deep vein thrombosisv

Cardiac disorders

Uncommon

Myocarditis

Acute myocardial infarctionrr,ss, Myocarditisc,oo

Respiratory, thoracic and mediastinal disorders

Very common

Cough/Productive Cough

Cough/Productive Cough

Cough/Productive cough, Dyspnoeai,t

Common

Pneumonitisc,u Dysphonia

Pneumonitisc,u,

Dysphonia

Pneumonitis, Dysphonia

Uncommon

Interstitial lung disease

Pulmonary embolismv, Interstitial lung disease

Interstitial lung disease

Gastrointestinal disorders

Very common

Diarrhoea, Abdominal painw

Nausea, Diarrhoea, Constipation, Vomiting, Abdominal painw

Diarrhoea, Abdominal painw, Constipationh, Nauseah, Vomitingh, Stomatitisx

Common

Stomatitisx, Colitisy

Dyspepsiai, Colitisy

Uncommon

Colitisc,y, Pancreatitisz

Pancreatitisz, Pancreatic exocrine insufficiency

Rare

Coeliac diseaser, Pancreatic failure, Pancreatic exocrine insufficiency

Coeliac diseaser

Hepatobiliary disorders

Very common

Aspartate aminotransferase increased or Alanine aminotransferase increasedaa

Aspartate aminotransferase increased or Alanine aminotransferase increased

Common

Aspartate aminotransferase increased or Alanine aminotransferase increasedc,aa, Hepatitisc,bb

Hepatitisc,bb

Uncommon

Hepatitisbb

Skin and subcutaneous tissue disorders

Very common

Rashcc, Pruritus

Alopecia, Rashcc, Pruritus

Rashcc, Alopeciah, Pruritus

Common

Night sweats, Dermatitisdd

Dermatitisdd

Dermatitisdd

Uncommon

Psoriasis, Pemphigoidee

Night sweats, Psoriasis, Pemphigoidee

Night sweats

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Arthralgia

Arthralgiah, Myalgia

Common

Myalgia

Myalgia

Uncommon

Myositisgg, Immune-mediated arthritishh

Myositisgg, Immune-mediated arthritishh

Myositis

Rare

Polymyositisii, Polymyalgia rheumatica

Polymyalgia rheumaticajj

Polymyalgia rheumaticajj

Renal and urinary disorders

Very common

Blood creatinine increased

Common

Blood creatinine increased, Dysuria

Blood creatinine increased, Dysuria

Dysuria

Uncommon

Nephritiskk, Cystitis noninfective

Nephritiskk, Cystitis noninfective

Cystitis noninfectiveh

General disorders and administration site conditions

Very common

Pyrexia

Fatiguell, Pyrexia

Pyrexia, Fatigueh, Peripheral oedemamm

Common

Peripheral oedemamm

Peripheral oedemamm

Injury, poisoning and procedural complications

Common

Infusion-related reactionnn

Infusion-related reactionnn

Infusion-related reaction

Adverse reaction frequencies may not be fully attributed to durvalumab alone but may contain contributions from the underlying disease or from other medicinal products used in a combination.

* overall study of treatment with up to six 21-day cycles with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib.

a includes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection.

b includes candida pneumonia, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia legionella, pneumonia pneumococcal, pneumonia klebsiella and pneumonia streptococcal.

c including fatal outcome.

d includes gingivitis, oral infection, periodontitis, pulpitis dental, tooth abscess and tooth infection.

e includes leukopenia and white blood cell count decreased.

f includes neutropenia and neutrophil count decreased.

g includes thrombocytopenia and platelet count decreased.

h adverse reaction only applies to chemotherapy ADRs in the DUO-E study.

i adverse reaction only applies to olaparib ADRs in the DUO-E study.

j includes drug hypersensitivity and hypersensitivity.

k includes autoimmune hypothyroidism, blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.

l includes blood thyroid stimulating hormone decreased, Graves' disease, hyperthyroidism, immune-mediated hyperthyroidism.

m includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis, and thyroiditis subacute.

n includes neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.

o includes dysgeusia and taste disorder.

p includes encephalitis, encephalitis autoimmune, immune-mediated encephalitis and noninfective encephalitis.

q reported frequency from AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare, with no events at Grade > 2.

r events were reported from post-marketing data.

s includes deep vein thrombosis, embolism, embolism venous, pelvic venous thrombosis, superficial vein thrombosis and thrombosis.

t includes dyspnoea and dyspnoea exertional.

u includes immune‑mediated lung disease and pneumonitis.

v adverse reaction only applies to oxaliplatin ADRs in the MATTERHORN study.

w includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.

x includes mucosal inflammation and stomatitis.

y includes colitis, enteritis, enterocolitis, immune-mediated enterocolitis and proctitis.

z includes immune-mediated pancreatitis, pancreatitis, pancreatitis acute, and pancreatitis necrotising.

aa includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.

bb includes autoimmune hepatitis, hepatic cytolysis, hepatitis, hepatitis acute, hepatitis toxic, hepatotoxicity and immune-mediated hepatitis.

cc includes drug eruption, eczema, erythema, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, rash pustular, rash vesicular.

dd includes dermatitis, dermatitis acneiform and urticarial dermatitis.

ee includes dermatitis bullous, pemphigoid and pemphigus. Reported frequency from completed and ongoing studies is uncommon.

ff reported frequency from ongoing AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare and includes two events of encephalitis, one was Grade 5 fatal (immune-mediated encephalitis) and one was Grade 2 (autoimmune encephalitis).

gg. includes myositis and rhabdomyolysis.

hh includes autoimmune arthritis, immune-mediated arthritis, polyarthritis and rheumatoid arthritis.

ii polymyositis (fatal) was observed in a patient treated with IMFINZI from an ongoing sponsored clinical study outside of the pooled dataset: rare in any grade, rare in Grade 3 or 4 or 5.

jj not observed in the IMFINZI+Chemotherapy pool or the platinum-based chemotherapy+IMFINZI+olaparib dataset, but observed in other AstraZeneca-sponsored clinical studies.

kk includes autoimmune nephritis, glomerulonephritis, glomerulonephritis membranous, immune-mediated nephritis, nephritis and tubulointerstitial nephritis.

ll includes asthenia and fatigue.

mm includes oedema peripheral and peripheral swelling.

nn includes infusion-related reaction and urticaria with onset on the day of dosing or 1 day after dosing.

oo includes myocarditis.

pp includes hypophysitis and hypopituitarism.

qq includes myasthenia gravis.

rr adverse reaction only applies to 5-FU ADRs in the MATTERHORN study.

ss includes acute coronary syndrome, acute myocardial infarction, coronary artery disease, myocardial infarction, and myocardial ischaemia.

Table 4. Adverse drug reactions in patients treated with IMFINZI in combination with tremelimumab

IMFINZI in combination with tremelimumab 300 mg

Infections and infestations

Common

Upper respiratory tract infectionsa, Pneumoniab, Influenza, Dental and oral soft tissue infectionsc

Uncommon

Oral candidiasis

Blood and lymphatic system disorders

Not known

Immune thrombocytopeniad

Endocrine disorders

Very common

Hypothyroidisme

Common

Hyperthyroidismf, Thyroiditisg, Adrenal insufficiency

Uncommon

Hypopituitarism/Hypophysitis

Not known

Diabetes insipidusd, Type 1 diabetes mellitusd

Eye disorders

Rare

Uveitisd

Nervous system disorders

Uncommon

Myasthenia gravis, Meningitis

Not known

Guillain-Barré syndromed, Encephalitisd, Transverse myelitish

Cardiac disorders

Uncommon

Myocarditis

Respiratory, thoracic, and mediastinal disorders

Very common

Cough/Productive cough

Common

Pneumonitisi

Uncommon

Dysphonia, Intersitial lung disease

Gastrointestinal disorders

Very common

Diarrhoea, Abdominal painj

Common

Lipase increased, Amylase increased, Colitisk, Pancreatitisl,

Rare

Coeliac diseased

Not known

Intestinal perforationd, Large intestinal perforationd

Hepatobiliary disorders

Very common

Aspartate aminotransferase increased/Alanine aminotransferase increasedm

Common

Hepatitisn

Skin and subcutaneous tissue disorders

Very common

Rasho, Pruritus

Common

Dermatitisp, Night sweats,

Uncommon

Pemphigoid

Musculoskeletal and connective tissue disorders

Common

Myalgia

Uncommon

Myositisq, Polymyositisq, Immune-mediated arthritis, Polymyalgia rheumatica

Renal and urinary disorders

Common

Blood creatinine increased, Dysuria

Uncommon

Nephritisr

Not known

Cystitis noninfectived

General disorders and administration site conditions

Very common

Pyrexia, Oedema peripherals

Injury, poisoning and procedural complications

Common

Infusion-related reactiont

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 IMFINZI or IMFINZI+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 Reported in studies outside of the POSEIDON study and HCC pool.

i Includes immune-mediated pneumonitis and pneumonitis.

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

k Includes colitis, enteritis and enterocolitis.

l Includes pancreatitis and pancreatitis acute.

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

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

o Includes eczema, erythema, rash, rash macular, rash maculopapular, rash papular and rash pruritic.

p Includes dermatitis and immune-mediated dermatitis.

q Includes rhabdomyolysis, myositis, and polymyositis.

r Includes autoimmune nephritis and immune-mediated nephritis.

s Includes oedema peripheral and peripheral swelling.

t Includes infusion-related reaction and urticaria.

Description of selected adverse reactions

IMFINZI is associated with immune‑mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy and/or treatment modifications. The data for the following immune‑mediated adverse reactions reflect the IMFINZI monotherapy combined safety database of 4 642 patients which includes the PACIFIC, HIMALAYA and ADRIATIC studies and additional studies in patients with various solid tumours, in indications for which durvalumab is not approved. Across all studies, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks, or 1 500 mg every 3 or 4 weeks. Details for the significant adverse reactions for IMFINZI when given in combination with chemotherapy are presented if clinically relevant differences were noted in comparison to IMFINZI monotherapy.

The data for the following immune-mediated adverse reactions also reflect the IMFINZI in combination with tremelimumab 300 mg combined safety database of 462 patients with HCC (the HCC pool). In these two studies, IMFINZI was administered at a dose of 1500 mg in combination with tremelimumab 300 mg every 4 weeks.

The management guidelines for these adverse reactions are described in section 4.2 and 4.4.

Immune‑mediated pneumonitis

In the combined safety database with IMFINZI monotherapy, (n=4 642 multiple tumour types), immune‑mediated pneumonitis occurred in 147 (3.2%) patients, including Grade 3 in 37 (0.8%) patients, Grade 4 in 2 (< 0.1%) patients and Grade 5 in 10 (0.2%) patients. The median time to onset was 56 days (range: 1‑1308 days). One hundred and fourteen of the 147 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), and 4 patients also received other immunosuppressants including infliximab and cyclosporine. IMFINZI was discontinued in 60 patients. Resolution occurred in 85 patients.

Immune‑mediated pneumonitis occurred more frequently in patients in the PACIFIC Study who had completed treatment with concurrent chemoradiation within 1 to 42 days prior to initiation of study treatment (9.9%), than in the other patients in the combined safety database (1.8%).

In the PACIFIC Study, (n = 475 in the IMFINZI arm, and n = 234 in the placebo arm) immune‑mediated pneumonitis occurred in 47 (9.9%) patients in the IMFINZI‑treated group and 14 (6.0%) patients in the placebo group, including Grade 3 in 9 (1.9%) patients on IMFINZI vs. 6 (2.6%) patients on placebo and Grade 5 (fatal) in 4 (0.8%) patients on IMFINZI vs. 3 (1.3%) patients on placebo. The median time to onset in the IMFINZI‑treated group was 46 days (range: 2‑342 days) vs. 57 days (range: 26‑253 days) in the placebo group. In the IMFINZI‑treated group, all patients received systemic corticosteroids, including 30 patients who received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 2 patients also received infliximab. In the placebo group, all patients received systemic corticosteroids, including 12 patients who received high‑dose corticosteroid treatment and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29 patients in the IMFINZI treated group vs. 6 in placebo.

In the ADRIATIC Study, in patients with LS-SCLC (n=262 in the IMFINZI arm, and n=265 in the placebo arm), immune-mediated pneumonitis occurred in 31 (11.8%) patients in the IMFINZI‑treated group and 8 (3.0%) patients in the placebo group, including Grade 3 in 5 (1.9%) patients on IMFINZI vs. 1 (0.4%) patient on placebo and Grade 5 (fatal) in 1 (0.4%) patient on IMFINZI. The median time to onset in the IMFINZI-treated group was 55 days (range: 1-375 days) vs. 65.5 days (range: 24‑124 days) in the placebo group. In the IMFINZI‑treated group all patients received systemic corticosteroids, including 25 patients who received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received infliximab. In the placebo group all patients received systemic corticosteroids, including 7 patients who received high‑dose corticosteroid treatment. Resolution occurred for 18 patients in the IMFINZI treated group vs. 3 in placebo.

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 DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm) immune-mediated pneumonitis occurred in 5 (2.1%) patients, including Grade 3 in 3 (1.3%) patients. The median time to onset was 85 days (range: 65-321 days). Five patients received systemic corticosteroids, including 4 patients who received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in all 5 patients.

Immune‑mediated hepatitis

In the combined safety database with IMFINZI monotherapy, immune‑mediated hepatitis occurred in 120 (2.6%) patients, including Grade 3 in 70 (1.5%) patients, Grade 4 in 9 (0.2%) patients and Grade 5 (fatal) in 6 (0.1%) patients. The median time to onset was 36 days (range: 1‑644 days). Ninety-four of the 120 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Nine patients also received other immunosuppressants including mycophenolate treatment. IMFINZI was discontinued in 30 patients. Resolution occurred in 56 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.

Immune‑mediated colitis

In the combined safety database with IMFINZI monotherapy, immune‑mediated colitis or diarrhoea occurred in 79 (1.7%) patients, including Grade 3 in 15 (0.3%) patients and Grade 4 in 2 (<0.1%) patients. The median time to onset was 72 days (range: 1‑920 days). Fifty-five of the 79 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Five patients also received other immunosuppressants including infliximab treatment and mycophenolate. IMFINZI was discontinued in 15 patients. Resolution occurred in 54 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 IMFINZI in combination with tremelimumab (rare) in studies outside of the HCC pool.

Immune‑mediated endocrinopathies

Immune-mediated hypothyroidism

In the combined safety database with IMFINZI monotherapy, immune‑mediated hypothyroidism occurred in 384 (8.3%) patients, including Grade 3 in 7 (0.2%) patients. The median time to onset was 90.5 days (range: 1‑951 days). Of the 384 patients, 379 patients received hormone replacement therapy and 7 patients received high‑dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism. One patient discontinued IMFINZI due to immune-mediated hypothyroidism. Resolution occurred in 79 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.

Immune-mediated hyperthyroidism

In the combined safety database with IMFINZI monotherapy, immune‑mediated hyperthyroidism occurred in 76 (1.6%) patients. The median time to onset was 43 days (range: 1‑253 days). Seventy one of the 76 patients received medical therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta‑blocker), 15 patients received systemic corticosteroids and 8 of the 15 patients received high‑dose systemic corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated hyperthyroidism. Resolution occurred in 62 patients. Thirty-one patients experienced hypothyroidism following 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 corticosteroids, 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 combined safety database with IMFINZI monotherapy, immune-mediated thyroiditis occurred in 21 (0.5%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 57 days (range: 14-217 days). Of the 21 patients, 18 patients received hormone replacement therapy and 3 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated thyroiditis. Resolution occurred in 8 patients. Five patients experienced hypothyroidism following 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 combined safety database with IMFINZI monotherapy, immune‑mediated adrenal insufficiency occurred in 24 (0.5%) patients, including Grade 3 in 8 (0.2%) patients. The median time to onset was 157.5 days (range: 20‑547 days). All 24 patients received systemic corticosteroids; 8 of the 24 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in 6 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

In the combined safety database with IMFINZI monotherapy, immune‑mediated type 1 diabetes mellitus occurred in 5 ( 0.1%) patient, including Grade 3 in 3 (0.1%) patients and Grade 4 in 1 (<0.1%) patient. The time to onset was 43 days (range: 29-631 days). All five patients required insulin therapy, IMFINZI was permanently discontinued in one patient. One patient recovered and one patient recovered with sequelae.

Immune-mediated hypophysitis/hypopituitarism

In the combined safety database with IMFINZI monotherapy, immune‑mediated hypophysitis/hypopituitarism occurred in 6 ( 0.1%) patients, including Grade 3 in 5 (0.1%) patients. The time to onset for the events was 85 days (range: 44-225 days). Three patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), three patients discontinued IMFINZI due to immune-mediated hypophysitis/hypopituitarism and resolution occurred in 1 patient.

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 combined safety database with IMFINZI monotherapy, immune‑mediated nephritis occurred in 17 (0.4%) patients, including Grade 3 in 4 (0.1%) patients and Grade 4 in 1 (<0.1%). The median time to onset was 84 days (range: 4‑393 days). Twelve patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and 1 patient also received mycophenolate. IMFINZI was discontinued in 7 patients. Resolution occurred in 8 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 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 combined safety database with IMFINZI monotherapy, immune‑mediated rash or dermatitis (including pemphigoid) occurred in 74 (1.6%) patients, including Grade 3 in 20 (0.4%) patients. The median time to onset was 56 days (range: 4‑600 days). Thirty-seven of the 74 patients received high‑dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 5 patients. Resolution occurred in 46 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 DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm) immune‑mediated rash occurred in 8 (3.4%) patients, including Grade 3 in 2 (0.8%) patients. The median time to onset was 155 days (range: 2-308 days). All patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in all 8 patients.

Infusion related reactions

In the combined safety database with IMFINZI monotherapy, infusion-related reactions occurred in 70 (1.54%) patients, including Grade 3 in 6 (0.2%) patients. There were no Grade 4 or 5 events.

In the DUO-E Study, out of 238 patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), infusion-related reactions occurred in 13 (5.5%) patients, including Grade 3 in 1 (0.4%) patient. There were no Grade 4 or 5 events.

Pure Red Cell Aplasia

Pure Red Cell Aplasia (PRCA) has been reported when IMFINZI has been used in combination with olaparib. In a clinical study of patients with endometrial cancer treated with IMFINZI in combination with olaparib, the incidence of PRCA was 1.6%. All events were CTCAE Grade 3 or 4. Events were manageable following discontinuation of both IMFINZI and olaparib. The majority of events were managed with blood transfusion and immunosuppression and recovered; there were no fatal events. For management see section 4.4.

Laboratory abnormalities

In patients treated with IMFINZI monotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 3.7% for alanine aminotransferase increased, 5.7% for aspartate aminotransferase increased, 0.9% for blood creatinine increased, 5.8% for amylase increased and 8.24% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 20% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 18.2%.

In patients treated with IMFINZI in combination with chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 4.2% for alanine aminotransferase increased, 3.4% for aspartate aminotransferase increased, 4.0% for blood creatinine increased, 6.0% for amylase increased, and 12.1% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 22.8% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 22.6%.

In patients treated with IMFINZI in combination with tremelimumab, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 5.1% for alanine aminotransferase increased, 5.8% for aspartate aminotransferase, 1.0% for blood creatinine increased, 5.9% for amylase increased and 11.3% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was 4.2% and a TSH shift from baseline that was ≥ LLN to < LLN was 17.2%.

In patients treated with platinum-based chemotherapy in combination with IMFINZI, followed by IMFINZI in combination with olaparib (platinum-based chemotherapy + IMFINZI + olaparib arm), the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows : 3.8% for alanine aminotransferase increased, 3.4% for aspartate aminotransferase increased and 1.7% for blood creatinine increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was 28.6% and a TSH shift from baseline that was ≥ LLN to < LLN was 20.1% .

Immunogenicity

Immunogenicity of IMFINZI as monotherapy is based on pooled data in 2 280 patients who were treated with IMFINZI 10 mg/kg every 2 weeks, or 20 mg/kg every 4 weeks as a single-agent and evaluable for the presence of anti-drug antibodies (ADAs). Sixty-nine patients (3.0%) tested positive for treatment emergent ADAs. Neutralising antibodies (nAb) against durvalumab were detected in 0.5% (12/2 280) of patients. The presence of ADAs did not have a clinically relevant effect on safety. There are insufficient number of patients to determine ADA impact on efficacy. Based on population PK analysis, slightly lower exposure are expected in ADA-positive patients however, the reduction of PK exposure is less than 30% compared to a typical patient and is not considered clinically relevant.

Across multiple phase III studies, in patients treated with IMFINZI in combination with other therapeutic agents, 0% to 3.1% of patients developed treatment-emergent ADAs. Neutralizing antibodies against durvalumab were detected in 0% to 1.7% of patients treated with IMFINZI in combination with other therapeutic agents. The presence of ADAs did not have an apparent effect on pharmacokinetics or safety.

Elderly

In studies PACIFIC, ADRIATIC, CASPIAN, TOPAZ-1, AEGEAN, NIAGARA, and MATTERHORN data on safety for patients 75 years and older are too limited to draw a conclusion on this population.

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 durvalumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment instituted immediately.