Imfinzi 120 mg/2,4 ml/500 mg/10 ml Solution

Urothelial Carcinoma
IMFINZI in combination with cisplatin-based chemotherapy as neoadjuvant treatment, followed by IMFINZI as monotherapy adjuvant treatment after radical cystectomy, is indicated for the treatment of patients with muscle invasive bladder cancer (MIBC).

Non-Small Cell Lung Cancer (NSCLC)
IMFINZI is indicated for the treatment of patients with locally advanced, unresectable NSCLC whose disease has not progressed following platinum-based chemoradiation therapy (CRT). IMFINZI in combination with tremelimumab and platinum-based chemotherapy is indicated for the first-line treatment of patients with metastatic NSCLC with no sensitising epidermal growth factor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumour aberrations. IMFINZI in combination with chemotherapy as neoadjuvant treatment, followed by IMFINZI as monotherapy after surgery, is indicated for the treatment of patients with resectable (tumours u2265 4 cm and/or node positive) NSCLC and no known EGFR mutations or ALK rearrangements.

Small Cell Lung Cancer (SCLC)
IMFINZI is indicated for the treatment of patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following platinum-based chemoradiation therapy (CRT). IMFINZI in combination with etoposide and either carboplatin or cisplatin is indicated for the first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

Hepatocellular Carcinoma (HCC)
IMFINZI in combination with tremelimumab is indicated for the treatment of patients with unresectable hepatocellular carcinoma (uHCC).

Biliary Tract Cancer (BTC)
IMFINZI in combination with chemotherapy is indicated for the treatment of patients with locally advanced or metastatic biliary tract cancer (BTC).

Gastric or Gastroesophageal Junction Adenocarcinoma (GC/GEJC)
IMFINZI in combination with FLOT (Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel) chemotherapy as neoadjuvant and adjuvant treatment, followed by adjuvant IMFINZI monotherapy, is indicated for the treatment of patients with resectable gastric or gastroesophageal junction adenocarcinoma.

Posology
The recommended dose of IMFINZI depends on the indication as presented in Table 1. IMFINZI is administered as an intravenous infusion over 60 minutes.

Table 1. Recommended dosage of IMFINZI
Indication
Recommended IMFINZI dosage
Duration of Therapy
LS-SCLC
1500 mg b every 4 weeks
Until disease progression, unacceptable toxicity or a maximum of 24 months.
Locally Advanced NSCLC
10 mg/kg every 2 weeks or 1500 mg every 4 weeks a,b
Until disease progression or unacceptable toxicity
Metastatic NSCLC
During chemotherapy: 1500 mg f,g in combination with tremelimumab 75 mg h and platinum-based chemotherapy i every 3 weeks (21 days) for 4 cycles
Post-platinum chemotherapy: 1500 mg g,h every 4 weeks as monotherapy and histology-based pemetrexed maintenance i,j therapy every 4 weeks and, a fifth dose of tremelimumab k,l alongside IMFINZI dose 6 at week 16
Until disease progression or unacceptable toxicity
Resectable NSCLC
1500 mg o in combination with chemotherapy d,i every 3 weeks for up to 4 cycles prior to surgery, followed by 1500 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
1500 mg c in combination with chemotherapy d,e every 3 weeks (21 days) for 4 cycles, followed by 1500 mg every 4 weeks as monotherapy
Until disease progression or unacceptable toxicity

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

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 or IMFINZI in combination with tremelimumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis. Patients with suspected pneumonitis should be evaluated and the diagnosis should be confirmed with radiographic imaging and other infections and disease-related aetiologies (example tuberculosis) excluded and managed as recommended in section 4.2.

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 concurrent chemoradiation within 1 to 42 days prior to initiation of study treatment, pneumonitis including both immune-mediated pneumonitis and radiation pneumonitis, occurred in patients receiving IMFINZI 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 in 16 (3,4 %) patients on IMFINZI vs. 7 (3,0 %) patients on placebo and Grade 5 in 5 (1,1 %) patients on IMFINZI vs. 4 (1,7 %) patients on placebo. The median time to onset in the IMFINZI treated group was 55 days (range: 1-406 days) vs. 55 days (range: 1-255 days) in the placebo group.

In the ADRIATIC Study, in patients who had completed treatment with 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 in 8 (3,1 %) patients on IMFINZI vs 6 (2,3 %) patients on placebo, and Grade 5 in 1 (0,4 %) patient on IMFINZI vs 0 patients on placebo.

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). Patients should be monitored for abnormal liver tests prior to and periodically during treatment with IMFINZI. Immune-mediated hepatitis should be managed as recommended in section 4.2.

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). Patients should be monitored for signs and symptoms of colitis or diarrhoea and managed as recommended in section 4.2.

Immune-mediated endocrinopathies: Immune-mediated hypothyroidism hyperthyroidism/thyroiditis Immune-mediated hypothyroidism occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Patients should be monitored for abnormal thyroid function tests prior to and periodically during treatment and managed as recommended in section 4.2.

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.

Immune-mediated Type 1 diabetes mellitus Immune-mediated type 1 diabetes mellitus, which can present with diabetic ketoacidosis 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.

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.

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 and managed as recommended in section 4.2.

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). Patients should be monitored for signs and symptoms of rash or dermatitis and managed as recommended in section 4.2.

Immune-mediated myocarditis Immune-mediated myocarditis, which can be fatal, occurred in patients receiving IMFINZI or IMFINZI in combination with tremelimumab (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated myocarditis and managed as recommended in section 4.2.

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. Patients should be monitored for signs and symptoms and managed as recommended in section 4.2. Other immune-mediated adverse reactions are myasthenia gravis, myositis, polymyositis, Guillain-Barru00c8 syndrome, immune thrombocytopenia, pancreatitis, immune-mediated arthritis, uveitis and encephalitis (see section 4.8).

Human Immunodeficiency Virus (HIV): Safety and efficacy in patients with HIV have not been established.

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 (see section 4.8).

IMFINZI is an immunoglobulin, therefore no formal pharmacokinetic (PK) medicine-medicine interaction studies have been conducted with IMFINZI. PK drug-drug interaction between durvalumab in combination with tremelimumab was assessed in the HIMALAYA study and no clinically meaningful PK drug-drug interaction was identified.

Pregnancy
In animal reproduction studies, administration of IMFINZI to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery at exposure levels approximately 22 times higher than those observed at the clinical dose of 10 mg/kg of IMFINZI (based on AUC) was not associated with maternal toxicity or effects on embryofoetal development, pregnancy outcome or postnatal development. There are no data on the use of IMFINZI in pregnant women. Based on its mechanism of action, IMFINZI has the potential to impact maintenance of pregnancy and may cause foetal harm when administered to a pregnant woman. Human IgG1 is known to cross the placental barrier. IMFINZI 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.

Lactation
There is no information regarding the presence of IMFINZI in human milk, the absorption and effects on the breastfed infant, or the effects on milk production. Human IgG is excreted in human milk. In animal reproduction studies, administration of IMFINZI to pregnant cynomolgus monkeys was associated with dose-related low level excretion of IMFINZI in breast milk. Because of the potential for adverse reactions in breastfed infants from IMFINZI, advise a lactating woman not to breastfeed during treatment and for at least 3 months after the last dose.

Fertility
There are no data on the potential effects of IMFINZI on fertility in humans. In repeat-dose toxicology studies with IMFINZI in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs.

Based on its pharmacodynamic properties, IMFINZI is unlikely to affect the ability to drive and use machines. However, if patients experience adverse reactions affecting their ability to concentrate and react, they should be advised to use caution when driving or operating machinery.

Summary of the safety profile
The safety of IMFINZI as monotherapy is based on pooled data in 3006 patients from 9 studies across multiple tumour types the most frequent adverse reaction were cough, diarrhoea and rash. The safety of IMFINZI in combination with chemotherapy in patients with ES-SCLC is based on data in 265 patients from the CASPIAN study and was consistent with IMFINZI monotherapy and known chemotherapy safety profile. The safety of IMFINZI in combination with chemotherapy as neoadjuvant treatment in patients with resectable NSCLC, is based on data in 401 patients from the AEGEAN study and was consistent with known IMFINZI monotherapy and known chemotherapy safety profiles. The safety of IMFINZI in combination with chemotherapy in patients with BTC is based on data in 338 patients from the TOPAZ-1 study and was consistent with IMFINZI monotherapy and known chemotherapy safety profiles. The safety of IMFINZI in combination with tremelimumab and platinum-based chemotherapy treatment in patients with unresectable NSCLC is based on data in 330 patients from the POSEIDON study and was consistent with known IMFINZI + tremelimumab and known chemotherapy safety profiles. The safety of STRIDE treatment in patients with uHCC is based on data in 462 patients from the HCC pool and was consistent with known IMFINZI + tremelimumab safety profile. The safety of IMFINZI monotherapy in patients with LS-SCLC is based on data in 262 patients from the ADRIATIC study. The safety profile was consistent with IMFINZI monotherapy. The safety of IMFINZI in combination with chemotherapy in patients with MIBC is based on data in 530 patients from the NIAGARA study and was consistent with IMFINZI monotherapy and known chemotherapy safety profiles. The safety of IMFINZI in combination with FLOT chemotherapy as neoadjuvant and adjuvant treatment, followed by adjuvant IMFINZI monotherapy, in patients with GC/GEJC is based on data in 475 patients from the MATTERHORN study and was consistent with IMFINZI monotherapy and known FLOT chemotherapy safety profiles.

Tabulated list of adverse reactions
Adverse reactions are listed according to system organ class in MedDRA. Within each system organ class, the adverse drug reactions are presented in decreasing frequency. The corresponding frequency category is based on the CIOMS III convention and is defined as: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1,000 to < 1/100); rare (u2265 1/10,000 to < 1/1000); very rare (< 1/10,000); not determined (cannot be estimated from available data).

There is no specific treatment in the event of IMFINZI overdose, and symptoms of overdose are not established. In the event of an overdose, medical practitioners should follow general supportive measures and should treat symptomatically.