Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden
Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
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.
In order to improve the traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded.
Immune-mediated pneumonitis or interstitial lung disease, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving 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.
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 the study, 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%).
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, 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 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 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 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 taper and a hormone replacement as clinically indicated for Grades 2-4.
Immune-mediated type 1 diabetes mellitus, which can first present as diabetic ketoacidosis that can be fatal if not detected early, occurred in patients receiving 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 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 taper and a hormone replacement as clinically indicated for Grades 2-4.
Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving 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 taper for Grades 2-4.
Immune-mediated rash or dermatitis (including pemphigoid), defined as requiring use of systemic corticosteroids and with no clear alternate aetiology, occurred in patients receiving 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 taper for Grade 2 >1 week or Grade 3 and 4.
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. Corticosteroids should be administered with an initial dose of 2-4 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4. If no improvement within 2 to 3 days despite corticosteroids, promptly start additional immunosuppressive therapy. Upon resolution (Grade 0), corticosteroid taper should be initiated and continued over at least 1 month.
Immune-mediated pancreatitis, occurred in patients receiving IMFINZI in combination with tremelimumab and chemotherapy (see section 4.8). Patients should be monitored for signs and symptoms of immune-mediated pancreatitis and managed as recommended in section 4.2.
Given the mechanism of action of 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 and cystitis noninfective (see section 4.8). Patients should be monitored for signs and symptoms and managed as recommended in section 4.2. Corticosteroids should be administered with an initial dose of 1-2 mg/kg/day prednisone or equivalent followed by taper for Grades 2-4.
Patients should be monitored for signs and symptoms of infusion-related reactions. Severe infusionrelated 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 insititutional standard, appropriate clinical practice guidelines and/or society guidelines.
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.
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.
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.
Limited data are available in elderly patients (≥75 years) treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy (see sections 4.8 and 5.1). Careful consideration of the potential benefit/risk of this regimen on an individual basis is recommended.
Patients with the following were excluded from clinical studies: 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.
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 interaction between durvalumab and chemotherapy was assessed in the CASPIAN study and showed concomitant treatment with durvalumab did not impact the PK of etoposide, carboplatin or cisplatin. Additionally, based on population PK analysis, concomitant chemotherapy treatment did not meaningfully impact the PK of durvalumab. PK drug-drug interactions between durvalumab in combination with tremelimumab and platinum-based chemotherapy were assessed in the POSEIDON study and showed no clinically meaningful PK interactions between tremelimumab, durvalumab, nab-paclitaxel, gemcitabine, pemetrexed, carboplatin or cisplatin in the concomitant treatment. Furthermore, in the DUO-E study, the exposure to durvalumab was similar in both treatment arms which indicates that there were no clinically meaningful PK drug-drug interactions between durvalumab and olaparib, although exposure to olaparib was not measured throughout the study.
Women of childbearing potential should use effective contraception during treatment with durvalumab and for at least 3 months after the last dose of durvalumab.
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.
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.
There are no data on the potential effects of durvalumab on fertility in humans or animals.
Durvalumab has no or negligible influence on the ability to drive and use machines.
The safety of IMFINZI as monotherapy is based on pooled data in 4 045 patients across multiple tumour types. IMFINZI was administered at a dose of 10 mg/kg every 2 weeks, 20 mg/kg every 4 weeks or 1 500 mg every 4 weeks. The most common (>10%) adverse reactions were cough/productive cough (18.7%), diarrhoea (16.1%), rash (15.5%), arthralgia (13.8%), pyrexia (13.0%), abdominal pain (13.0%), upper respiratory tract infections (12.1%), pruritus (11.4%), and hypothyroidism (10.9%). The most common (>2%) NCI CTCAE Grade ≥3 adverse reactions were pneumonia (3.6%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.9%).
IMFINZI was discontinued due to adverse reactions in 3.7% of patients. The most common adverse reaction leading to treatment discontinuation was pneumonitis (0.9%) and pneumonia (0.7%).
IMFINZI was delayed or interrupted due to adverse reactions in 13.0% of patients. The most common adverse reactions leading to dose delay or interruption were pneumonia (2.2%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.2%).
The safety of IMFINZI as monotherapy in patients treated for HCC is based on data in 492 patients and was consistent with the overall safety profile in the IMFINZI monotherapy pool (N=4 045). The most common (>10%) adverse reactions were AST increased/ALT increased (20.3%), abdominal pain (17.9%), diarrhoea (15.9%), pruritus (15.4%), and rash (15.2%). The most common (>2%) Grade ≥3 adverse reactions were AST increased/ALT increased (8.1%) and abdominal pain (2.2%).
IMFINZI was discontinued due to adverse reactions in 3.7% of patients. The most common adverse reactions leading to treatment discontinuation were AST increased/ALT increased (0.8%) and hepatitis (0.6%).
IMFINZI was delayed or interrupted due to adverse reactions in 11.6% of patients. The most common adverse reaction leading to dose delay or interruption was AST increased/ALT increased (5.9%).
The safety of IMFINZI in combination with chemotherapy is based on pooled data in 838 patients from 3 studies (TOPAZ-1, CASPIAN and DUO-E). The most common (>10%) adverse reactions were neutropenia (47.3%), anaemia (44.9%), fatigue (38.8%), nausea (38.4%), thrombocytopenia (28.0%), alopecia (27.4%), constipation (25.9%), decreased appetite (21.2%), neuropathy peripheral (21.2%), abdominal pain (20.3%), diarrhoea (19.1%), rash (18.5%), vomiting (18.0%), leukopenia (17.2%), pyrexia (13.4%), arthralgia (12.4%), cough/productive cough (12.4%), pruritus (11.8%), hypothyroidism (11.0%), aspartate aminotransferase increased/alanine aminotransferase increased (10.7%) and oedema peripheral (10.1%). The most common (>2%) NCI CTCAE Grade ≥3 adverse reactions were neutropenia (30.7%), anaemia (17.1%), thrombocytopenia (9.9%), leukopenia (6.4%), fatigue (4.5%), febrile neutropenia (2.9%), aspartate aminotransferase increased/alanine aminotransferase increased (2.1%) and pneumonia (2.0%).
IMFINZI was discontinued due to adverse reactions in 3.6% of patients. The most common adverse reactions leading to treatment discontinuation were anaemia (0.5%), rash (0.5%) and fatigue (0.5%).
IMFINZI was delayed or interrupted due to adverse reactions in 31.0% of patients. The most common adverse reactions leading to dose delay or interruption were neutropenia (15.0%), thrombocytopenia (6.8%), anaemia (5.1%) and leukopenia (2.9%).
The safety of IMFINZI given in combination with tremelimumab 75 mg and chemotherapy is based on data in 330 patients with metastatic NSCLC. The most common (>20%) adverse reactions were anaemia (49.7%), nausea (41.5%), neutropenia (41.2%), fatigue (36.1%), rash (25.8%), thrombocytopenia (24.5%) and diarrhoea (21.5%). The most common (>2%) NCI CTCAE Grade ≥3 adverse reactions were neutropenia (23.9%), anaemia (20.6%), pneumonia (9.4%), thrombocytopenia (8.2%), leukopenia (5.5%), fatigue (5.2%), lipase increased (3.9%), amylase increased (3.6%), febrile neutropenia (2.4%), colitis (2.1%) and aspartate aminotransferase increased/alanine aminotransferase increased (2.1%).
IMFINZI was discontinued due to adverse reactions in 8.5% of patients. The most common adverse reactions leading to treatment discontinuation were pneumonia (2.1%) and colitis (1.2%).
IMFINZI was interrupted due to adverse reactions in 49.4% of patients. The most common adverse reactions leading to dose interruption were neutropenia (16.1%), anaemia (10.3%), thrombocytopenia (7.3%), leukopenia (5.8%), pneumonia (5.2%), aspartate aminotransferase increased/alanine aminotransferase increased (4.8%), colitis (3.3%) and pneumonitis (3.3%).
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) were 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 were colitis (2.6%), diarrhoea (2.4%), pneumonia (2.2%), and hepatitis (1.7%).
The frequency of treatment discontinuation due to adverse reactions was 6.5%. The most common adverse reactions leading to treatment discontinuation were hepatitis (1.5%) and aspartate aminotransferase increased/alanine aminotransferase increased (1.3%).
The 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.
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 (23.5%), 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%).
Table 3 lists the incidence of adverse reactions in the IMFINZI monotherapy pooled safety dataset (N=4 045), in patients treated with IMFINZI in combination with chemotherapy (N=838) 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). Unless otherwise stated, Table 4 lists the incidence of adverse reactions in patients treated with IMFINZI in combination with tremelimumab 75 mg and platinum-based chemotherapy in the POSEIDON study (N=330) and 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 | Pneumoniab,c, Upper respiratory tract infectionsa, Dental and oral soft tissue infectionsd | Pneumonia, Oral candidiasis, Dental and oral soft tissue infectionsd |
| Uncommon | Oral candidiasis, Influenza | Influenza | |
| Blood and lymphatic system disorders | |||
| Very Common | Anaemia, Leukopeniae, Neutropeniaf, Thrombocytopeniag | Anaemiah, Leukopeniah Neutropeniah, Thrombocytopeniah | |
| Common | Febrile neutropenia, Pancytopeniac | Aplasia pure red cell, Febrile neutropeniah, Lymphopeniai | |
| Uncommon | Immune thrombocytopenia | Pancytopeniah | |
| Rare | Immune thrombocytopeniac | ||
| Immune system disorders | |||
| Common | Hypersensitivityi,j | ||
| Endocrine disorders | |||
| Very common | Hypothyroidismk | Hypothyroidismk | Hypothyroidism |
| Common | Hyperthyroidisml | Hyperthyroidisml, Thyroiditism | Hyperthyroidism, Thyroiditis |
| Uncommon | Thyroiditism, Adrenal insufficiency | Adrenal insufficiency, Type 1 diabetes mellitus | |
| Rare | Type 1 diabetes mellitus, Hypophysitis/Hypopituitarism, Diabetes insipidus | ||
| Eye disorders | |||
| Uncommon | Uveitis | Uveitis | |
| Rare | 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 | ||
| Rare | Myasthenia gravis, Meningitisp | ||
| Not known | Noninfective encephalitisq, Guillain- Barré syndrome, Myelitis transverser | ||
| Vascular disorders | |||
| Common | Venous thromboembolic eventsi,s | ||
| Cardiac disorders | |||
| Uncommon | Myocarditis | ||
| Respiratory, thoracic and mediastinal disorders | |||
| Very common | Cough/Productive Cough | Cough/Productive Cough | Cough/Productive cough, Dyspnoeai,t |
| Common | Pneumonitisc, Dysphonia | Pneumonitis | Pneumonitis, Dysphonia |
| Uncommon | Interstitial lung disease | Interstitial lung disease, Dysphonia | Interstitial lung disease |
| Gastrointestinal disorders | |||
| Very common | Diarrhoea, Abdominal painu | Diarrhoea, Abdominal painu, Constipation, Nausea, Vomiting | Diarrhoea, Abdominal painu, Constipationh, Nauseah, Vomitingh, Stomatitish |
| Common | Stomatitisv | Dyspepsiai, Colitisw | |
| Uncommon | Colitisw, Pancreatitisx | Colitisw, Pancreatitisx | |
| Rare | Coeliac diseaser | Coeliac diseaser | |
| Hepatobiliary disorders | |||
| Very common | Aspartate aminotransferase increased or Alanine aminotransferase increasedy | Aspartate aminotransferase increased or Alanine aminotransferase increased | |
| Common | Hepatitisc,z, Aspartate aminotransferase increased or Alanine aminotransferase increasedc,y | Hepatitisc,z | |
| Uncommon | Hepatitisz | ||
| Skin and subcutaneous tissue disorders | |||
| Very common | Rashaa, Pruritus | Rashaa, Alopecia, Pruritus | Rashaa, Alopeciah, Pruritus |
| Common | Night sweats | Dermatitis | Dermatitisbb |
| Uncommon | Dermatitis, Psoriasis, Pemphigoidcc | Pemphigoidcc, Night sweats, Psoriasis | Night sweats |
| Musculoskeletal and connective tissue disorders | |||
| Very common | Arthralgia | Arthralgia | Arthralgiah, Myalgia |
| Common | Myalgia | Myalgia | |
| Uncommon | Myositisdd | Immune-mediated arthritis, Myositis | Myositis |
| Rare | Polymyositisee, Immune- mediated arthritis | ||
| Renal and urinary disorders | |||
| Very common | Blood creatinine | ||
| Common | Blood creatinine increased, Dysuria | Blood creatinine increased, Dysuria | Dysuria |
| Uncommon | Nephritisff | Cystitis noninfective | Cystitis noninfectiveh |
| Rare | Cystitis noninfective | ||
| General disorders and administration site conditions | |||
| Very common | Pyrexia | Pyrexia, Fatiguegg, Peripheral oedemahh | Pyrexia, Fatigueh, Peripheral oedemahh |
| Common | Peripheral oedemahh | ||
| Injury, poisoning and procedural complications | |||
| Common | Infusion-related reactionii | Infusion-related reactionii | 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 pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia pneumococcal, pneumonia streptococcal, candida pneumonia and pneumonia legionella.
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, hypothyroidism, immune-mediated hypothyroidism, blood thyroid stimulating hormone increased.
l includes hyperthyroidism, Basedow’s disease, immune-mediated hyperthyroidism and blood thyroid stimulating hormone decreased.
m includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis, and thyroiditis subacute.
n includes neuropathy peripheral, paraesthesia and peripheral sensory neuropathy.
° includes dysgeusia and taste disorder.
p includes meningitis and noninfective meningitis.
q reported frequency from ongoing AstraZeneca-sponsored clinical studies outside of the pooled dataset is rare and includes fatal outcome.
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 abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
v includes stomatitis and mucosal inflammation.
w includes colitis, enteritis, enterocolitis, and proctitis.
x includes pancreatitis and pancreatitis acute.
y includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.
z includes hepatitis, autoimmune hepatitis, hepatitis toxic, hepatocellular injury, hepatitis acute, hepatotoxicity and immune-mediated hepatitis.
aa includes rash erythematous, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema and rash.
bb includes dermatitis and immune-mediated dermatitis.
cc includes pemphigoid, dermatitis bullous and pemphigus. Reported frequency from completed and ongoing studies is uncommon.
dd includes rhabdomyolysis, myositis, and polymyositis.
ee polymyositis (fatal) was observed in a patient treated with IMFINZI from an ongoing sponsored clinical study outside of the pooled dataset.
ff includes autoimmune nephritis, tubulointerstitial nephritis, nephritis, glomerulonephritis and glomerulonephritis membranous.
gg includes fatigue and asthenia.
hh includes oedema peripheral and peripheral swelling.
ii includes infusion-related reaction and urticaria with onset on the day of dosing or 1 day after dosing.
Table 4. Adverse drug reactions in patients treated with IMFINZI in combination with tremelimumab:
| IMFINZI in combination with tremelimumab 75 mg and platinum-based chemotherapy | IMFINZI in combination with tremelimumab 300 mg | |
|---|---|---|
| Infections and infestations | ||
| Very common | Upper respiratory tract infectionsa, Pneumoniab | |
| Common | Influenza, Oral candidiasis | Upper respiratory tract infectionsa, Pneumoniab, Influenza, Dental and oral soft tissue infectionsc |
| Uncommon | Dental and oral soft tissue infectionsc | Oral candidiasis |
| Blood and lymphatic system disorders | ||
| Very Common | Anaemiad, Neutropeniad,e, Thrombocytopeniad,f, Leukopeniad,g | |
| Common | Febrile neutropeniad, Pancytopeniad | |
| Uncommon | Immune thrombocytopenia | |
| Not known | Immune thrombocytopeniah | |
| Endocrine disorders | ||
| Very common | Hypothyroidismi | Hypothyroidismi |
| Common | Hyperthyroidismj, Adrenal insufficiency, Hypopituitarism/ Hypophysitis, Thyroiditisk | Hyperthyroidismj, Thyroiditisk, Adrenal insufficiency |
| Uncommon | Diabetes insipidus, Type 1 diabetes mellitus | Hypopituitarism/Hypophysitis |
| Not known | Diabetes insipidush, Type 1 diabetes mellitush | |
| Eye disorders | ||
| Uncommon | Uveitis | |
| Rare | Uveitish | |
| Metabolism and nutrition disorders | ||
| Very common | Decreased appetited | |
| Nervous system disorders | ||
| Common | Neuropathy peripherald,l | |
| Uncommon | Encephalitism | Myasthenia gravis, Meningitis |
| Not known | Myasthenia gravisn, Guillain-Barre syndromen, Meningitisn | Guillain-Barré syndromeh, Encephalitish |
| Cardiac disorders | ||
| Uncommon | Myocarditis° | Myocarditis |
| Respiratory, thoracic, and mediastinal disorders | ||
| Very common | Cough/Productive Cough | Cough/Productive cough |
| Common | Pneumonitisp, Dysphonia | Pneumonitisp |
| Uncommon | Interstitial lung disease | Dysphonia, Intersitial lung disease |
| Gastrointestinal disorders | ||
| Very common | Nausead, Diarrhoea, Constipationd, Vomitingd | Diarrhoea, Abdominal painq |
| Common | Stomatitisd,r, Amylase increased, Abdominal painq, Lipase increased, Colitiss, Pancreatitist | Lipase increased, Amylase increased, Colitiss, Pancreatitist |
| Rare | Coeliac diseasen | Coeliac diseaseh |
| Not known | Intestinal perforationn, Large intestine perforationn | Intestinal perforationh, Large intestinal perforationh |
| Hepatobiliary disorders | ||
| Very common | Aspartate aminotransferase increased/Alanine aminotransferase increasedu | Aspartate aminotransferase increased/Alanine aminotransferase increasedu |
| Common | Hepatitisv | Hepatitisv |
| Skin and subcutaneous tissue disorders | ||
| Very common | Alopeciad, Rashw, Pruritus | Rashw, Pruritus |
| Common | Dermatitisx, Night sweats | |
| Uncommon | Dermatitis, Night sweats, Pemphigoid | Pemphigoid |
| Musculoskeletal and connective tissue disorders | ||
| Very common | Arthralgia | |
| Common | Myalgia | Myalgia |
| Uncommon | Myositisy, Polymyositisy, Immune- mediated arthritisn | Myositisy, Polymyositisy, Immune- mediated arthritis |
| Renal and urinary disorders | ||
| Common | Blood creatinine increased, Dysuria | Blood creatinine increased, Dysuria |
| Uncommon | Nephritis, Cystitis noninfective | Nephritisz |
| Not known | Cystitis noninfectiveh | |
| General disorders and administration site conditions | ||
| Very common | Fatigued, Pyrexia | Pyrexia, Oedema peripheralaa |
| Common | Oedema peripheralaa | |
| Injury, poisoning and procedural complications | ||
| Common | Infusion-related reactionbb | Infusion-related reactionbb |
a Includes laryngitis, nasopharyngitis, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection.
b Includes pneumocystis jirovecii pneumonia, pneumonia and pneumonia bacterial.
c Includes periodontitis, pulpitis dental, tooth abscess and tooth infection.
d Adverse reaction only applies to chemotherapy ADRs in the Poseidon study.
e Includes neutropenia and neutrophil count decreased.
f Includes platelet count decreased and thrombocytopenia.
g Includes leukopenia and white blood cell count decreased.
h 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.
i Includes blood thyroid stimulating hormone increased, hypothyroidism and immune-mediated hypothyroidism.
j Includes blood thyroid stimulating hormone decreased and hyperthyroidism.
k Includes autoimmune thyroiditis, immune-mediated thyroiditis, thyroiditis and thyroiditis subacute.
l Includes neuropathy peripheral, parasthesia and peripheral sensory neuropathy.
m Includes encephalitis and encephalitis autoimmune.
n Adverse reaction was not observed in the POSEIDON study but was reported in patients treated with IMFINZI or IMFINZI+tremelimumab in clinical studies outside of the POSEIDON dataset.
° Includes autoimmune myocarditis.
p Includes immune-mediated pneumonitis and pneumonitis.
q Includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
r Includes mucosal inflammation and stomatitis.
s Includes colitis, enteritis and enterocolitis.
t Includes autoimmune pancreatitis, pancreatitis and pancreatitis acute.
u Includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.
v Includes autoimmune hepatitis, hepatitis, hepatocellular injury, hepatotoxicity, hepatitis acute and immune- mediated hepatitis.
w Includes eczema, erythema, rash, rash macular, rash maculopapular, rash papular, rash pruritic and rash pustular.
x Includes dermatitis and immune-mediated dermatitis.
y Includes rhabdomyolysis, myositis, and polymyositis.
z Includes autoimmune nephritis and immune-mediated nephritis.
aa Includes oedema peripheral and peripheral swelling.
bb Includes infusion-related reaction and urticaria.
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 4 045 patients which includes the PACIFIC Study 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 are also based on 2 280 patients who received IMFINZI 20 mg/kg every 4 weeks in combination with tremelimumab 1 mg/kg or IMFINZI 1 500 mg in combination with tremelimumab 75 mg every 4 weeks. Details for the significant adverse reactions for IMFINZI when given in combination with tremelimumab and platinum-based chemotherapy are presented if clinically relevant differences were noted in comparison to IMFINZI in combination with tremelimumab.
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 1 500 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.
In the combined safety database with IMFINZI monotherapy, (n=4 045 multiple tumour types), immune-mediated pneumonitis occurred in 103 (2.5%) patients, including Grade 3 in 27 (0.7%) patients, Grade 4 in 2 (<0.1%) patients and Grade 5 in 7 (0.2%) patients. The median time to onset was 56 days (range: 2-814 days). Seventy-five of the 103 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), 2 patients also received infliximab and 1 patient also received cyclosporine. IMFINZI was discontinued in 40 patients. Resolution occurred in 61 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 the study (10.7%), than in the other patients in the combined safety database (1.0%).
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 (at least 40 mg prednisone or equivalent per day) and 1 patient also received cyclophosphamide and tacrolimus. Resolution occurred for 29 patients in the IMFINZI treated group vs. 6 in placebo.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated pneumonitis occurred in 86 (3.8%) patients, including Grade 3 in 30 (1.3%) patients, Grade 4 in 1 (<0.1%) patient, and Grade 5 (fatal) in 7 (0.3%) patients. The median time to onset was 57 days (range: 8-912 days). All patients received systemic corticosteroids and 79 of the 86 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seven patients also received other immunosuppressants. Treatment was discontinued in 39 patients. Resolution occurred in 51 patients.
In the HCC pool (n=462), immune-mediated pneumonitis occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient and Grade 5 (fatal) in 1 (0.2%) patient. The median time to onset was 29 days (range: 5-774 days). 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.
In the combined safety database with IMFINZI monotherapy, immune-mediated hepatitis occurred in 112 (2.8%) patients, including Grade 3 in 65 (1.6%) patients, Grade 4 in 8 (0.2%) patients and Grade 5 (fatal) in 6 (0.1%) patients. The median time to onset was 31 days (range: 1-644 days). Eighty-six of the 112 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Seven patients also received mycophenolate treatment. IMFINZI was discontinued in 26 patients. Resolution occurred in 54 patients.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hepatitis occurred in 80 (3.5%) patients, including Grade 3 in 48 (2.1%) patients, Grade 4 in 8 (0.4%) patients and Grade 5 (fatal) in 2 (<0.1%) patients. The median time to onset was 36 days (range: 1-533 days). All patients received systemic corticosteroids and 68 of the 80 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Eight patients also received other immunosuppressants. Treatment was discontinued in 27 patients. Resolution occurred in 47 patients.
In the HCC pool (n=462), immune-mediated hepatitis occurred in 34 (7.4%) patients, including Grade 3 in 20 (4.3%) patients, Grade 4 in 1 (0.2%) patient and Grade 5 (fatal) in 3 (0.6%) patients. The median time to onset was 29 days (range: 13-313 days). All patients received systemic corticosteroids, and 32 of the 34 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Nine patients also received other immunosuppressants. Treatment was discontinued in 10 patients. Resolution occurred in 13 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated colitis or diarrhoea occurred in 77 (1.9%) patients, including Grade 3 in 15 (0.4%) patients and Grade 4 in 2 (<0.1%) patients. The median time to onset was 71 days (range: 1-920 days). Fifty-five of the 77 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Two patient also received infliximab treatment and 1 patient also received mycophenolate. IMFINZI was discontinued in 13 patients. Resolution occurred in 54 patients.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated colitis or diarrhoea occurred in 167 (7.3%) patients, including Grade 3 in 76 (3.3%) patients and Grade 4 in 3 (0.1%) patients. The median time to onset was 57 days (range: 3-906 days). All patients received systemic corticosteroids and 151 of the 167 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty-two patients also received other immunosuppressants. Treatment was discontinued in 54 patients. Resolution occurred in 141 patients. Intestinal perforation and large intestine perforation were uncommonly reported in patients receiving IMFINZI in combination with tremelimumab.
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.
In the combined safety database with IMFINZI monotherapy, immune-mediated hypothyroidism occurred in 307 (7.6%) patients, including Grade 3 in 3 (<0.1%) patients. The median time to onset was 86 days (range: 1-951 days). Of the 307 patients, 303 patients received hormone replacement therapy and 5 patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for immune-mediated hypothyroidism. No patients discontinued IMFINZI due to immune-mediated hypothyroidism. Resolution occurred in 61 patients.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hypothyroidism occurred in 209 (9.2%) patients, including Grade 3 in 6 (0.3%) patients. The median time to onset was 85 days (range: 1-624 days). Thirteen patients received systemic corticosteroids and 8 of the 13 received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment discontinued in 3 patients. Resolution occurred in 52 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 25 patients or immune-mediated thyroiditis in 2 patients.
In the HCC pool (n=462), immune-mediated hypothyroidism occurred in 46 (10.0%) patients. The median time to onset was 85 days (range: 26-763 days). One patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy. Resolution occurred in 6 patients. Immune-mediated hypothyroidism was preceded by immune-mediated hyperthyroidism in 4 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated hyperthyroidism occurred in 64 (1.6%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 43 days (range: 1-253 days). Fifty-nine of the 64 patients received medical therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker), 13 patients received systemic corticosteroids and 5 of the 13 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 47 patients. Twenty-two patients experienced hypothyroidism following hyperthyroidism.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hyperthyroidism occurred in 62 (2.7%) patients, including Grade 3 in 5 (0.2%) patients. The median time to onset was 33 days (range: 4-176 days). Eighteen patients received systemic coticosteroids, and 11 of the 18 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Fifty-three patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker or beta-blocker), One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 47 patients.
In the HCC pool (n=462), immune-mediated hyperthyroidism occurred in 21 (4.5%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 30 days (range: 13-60 days). Four patients received systemic corticosteriods, and all of the four patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Twenty patients required other therapy (thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker). One patient discontinued treatment due to hyperthyroidism. Resolution occurred in 17 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated thyroiditis occurred in 16 (0.4%) patients, including Grade 3 in 2 (<0.1%) patients. The median time to onset was 49 days (range: 14-217 days). Of the 16 patients, 13 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 5 patients. Three patients experienced hypothyroidism following thyroiditis.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated thyroiditis occurred in 15 (0.7%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 57 days (range: 22-141 days). Five patients received systemic corticosteroids and 2 of the 5 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Thirteen patients required other therapy including, hormone replacement therapy, thiamazole, carbimazole, propylthiouracil, perchlorate, calcium channel blocker, or beta-blocker. No patients discontinued treatment due to immune-mediated thyroiditis. Resolution occurred in 5 patients.
In the HCC pool (n=462), immune-mediated thyroiditis occurred in 6 (1.3%) patients. The median time to onset was 56 days (range: 7-84 days). Two patients received systemic corticosteroids, and 1 of the 2 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). All patients required other therapy including hormone replacement therapy. Resolution occurred in 2 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated adrenal insufficiency occurred in 20 (0.5%) patients, including Grade 3 in 6 (0.1%) patients. The median time to onset was 157.5 days (range: 20-547 days). All 20 patients received systemic corticosteroids; 7 of the 20 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). No patients discontinued IMFINZI due to immune-mediated adrenal insufficiency. Resolution occurred in 6 patients.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated adrenal insufficiency occurred in 33 (1.4%) patients, including Grade 3 in 16 (0.7%) patients and Grade 4 in 1 (<0.1%) patient. The median time to onset was 105 days (range: 20-428 days). Thirty-two patients received systemic corticosteroids, and 10 of the 32 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in one patient. Resolution occurred in 11 patients.
In the HCC pool (n=462), immune-mediated adrenal insufficiency occurred in 6 (1.3%) patients, including Grade 3 in 1 (0.2%) patient. The median time to onset was 64 days (range: 43-504 days). All patients received systemic corticosteroids, and 1 of the 6 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred in 2 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated type 1 diabetes mellitus occurred in 3 (<0.1%) patients, including Grade 3 in 2 (<0.1%) patients and Grade 4 in 1 (<0.1%) patient. The time to onset was 43 days (range: 42-518 days). All three patients required long-term insulin therapy. IMFINZI was permanently discontinued in one patient. One patient recovered and one patient recovered with sequelae.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated type 1 diabetes mellitus occurred in 6 (0.3%) patients, including Grade 3 in 1 (<0.1%) patient and Grade 4 in 2 (<0.1%) patients. The median time to onset was 58 days (range: 7- 220 days). All patients required insulin. Treatment was discontinued for 1 patient. Resolution occurred in 1 patient.
In the combined safety database with IMFINZI monotherapy, immune-mediated hypophysitis/hypopituitarism occurred in 4 (<0.1%) patients, including Grade 3 in 3 (<0.1%) patients. The time to onset for the events was 74 days (range: 44-225 days). Two patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), two patients discontinued IMFINZI due to immune-mediated hypophysitis/hypopituitarism and resolution occurred in 1 patient.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated hypophysitis/hypopituitarism occurred in 16 (0.7%) patients, including Grade 3 in 8 (0.4%) patients. The median time to onset for the events was 123 days (range: 63-388 days). All patients received systemic corticosteroids and 8 of the 16 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Four patients also required endocrine therapy. Treatment was discontinued in 2 patients. Resolution occurred in 7 patients.
In the HCC pool (n=462), immune-mediated hypophysitis/hypopituitarism occurred in 5 (1.1%) patients. The median time to onset for the events was 149 days (range: 27-242 days). Four patients received systemic corticosteroids, and 1 of the 4 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Three patients also required endocrine therapy. Resolution occurred in 2 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated nephritis occurred in 18 (0.4%) patients, including Grade 3 in 4 (<0.1%) patients and Grade 4 in 1 (<0.1%) patient. The median time to onset was 77.5 days (range: 4-393 days). Thirteen 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 9 patients.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated nephritis occurred in 9 (0.4%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 79 days (range: 39-183 days). All patients received systemic corticosteroids and 7 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 3 patients. Resolution occurred in 5 patients.
In the HCC pool (n=462), immune-mediated nephritis occurred in 4 (0.9%) patients, including Grade 3 in 2 (0.4%) patients. The median time to onset was 53 days (range: 26-242 days). All patients received systemic corticosteroids, and 3 of the 4 received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 2 patients. Resolution occurred in 3 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated rash or dermatitis (including pemphigoid) occurred in 65 (1.6%) patients, including Grade 3 in 17 (0.4%) patients. The median time to onset was 54 days (range: 4-576 days). Thirty-three of the 65 patients received high- dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 5 patients. Resolution occurred in 43 patients.
In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), immune-mediated rash or dermatitis (including pemphigoid) occurred in 112 (4.9%) patients, including Grade 3 in 17 (0.7%) patients. The median time to onset was 35 days (range: 1-778 days). All patients received systemic corticosteroids, and 57 of the 112 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Treatment was discontinued in 10 patients. Resolution occurred in 65 patients.
In the HCC pool (n=462), immune-mediated rash or dermatitis (including pemphigoid) occurred in 26 (5.6%) patients, including Grade 3 in 9 (1.9%) patients and Grade 4 in 1 (0.2%) patient. The median time to onset was 25 days (range: 2-933 days). All patients received systemic corticosteroids and 14 of the 26 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient received other immunosuppressants. Treatment was discontinued in 3 patients. Resolution occurred in 19 patients.
In the 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.
In the combined safety database with IMFINZI monotherapy, infusion-related reactions occurred in 55 (1.4%) patients, including Grade 3 in 5 (0.1%) patients. There were no Grade 4 or 5 events. In the combined safety database with IMFINZI in combination with tremelimumab (n=2 280), infusion-related reactions occurred in 45 (2.0%) patients, including Grade 3 in 2 (<0.1%) patients. There were no Grade 4 or 5 events.
In 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 (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.
In patients treated with durvalumab monotherapy, 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, 6.1% for aspartate aminotransferase increased, 0.9% for blood creatinine increased, 5.4% for amylase increased and 8.4% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 19.3% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 17.5%.
In patients treated with durvalumab 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: 6.4% for alanine aminotransferase increased, 6.5% for aspartate aminotransferase increased, 4.2% for blood creatinine increased, 6.4% for amylase increased, and 11.7% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to any grade > ULN was 20.3% and a TSH shift from baseline that was ≥ LLN to any grade < LLN was 24.1%.
In patients treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy, the proportion of patients who experienced a shift from baseline to a Grade 3 or 4 laboratory abnormality was as follows: 6.2% for alanine aminotransferase increased, 5.2% for aspartate aminotransferase increased, 4.0% for blood creatinine increased, 9.4% for amylase increased and 13.6% for lipase increased. The proportion of patients who experienced a TSH shift from baseline that was ≤ ULN to > ULN was 24.8% and a TSH shift from baseline that was ≥ LLN to < LLN was 32.9%.
n 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 either as monotherapy (platinum-based chemotherapy + IMFINZI arm) or 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 in the platinum-based chemotherapy + IMFINZI arm: 3.5% for alanine aminotransferase increased, 3.0% for aspartate aminotransferase increased and 0.4% for blood creatinine increased, and as follows in the platinum-based chemotherapy + IMFINZI + olaparib arm: 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 27.2% and a TSH shift from baseline that was ≥ LLN to < LLN was 24.3% in the platinum-based chemotherapy + IMFINZI arm and 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% in the platinum-based chemotherapy + IMFINZI + olaparib arm.
There have been cases of the following adverse reactions reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with durvalumab: pancreatic exocrine insufficiency.
Immunogenicity of IMFINZI as monotherapy is based on pooled data in 3 069 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). Eighty-four patients (2.7%) tested positive for treatment emergent ADAs. Neutralising antibodies (nAb) against durvalumab were detected in 0.5% (16/3 069) of patients. The presence of ADAs did not have a clinically relevant effect on pharmacokinetics or safety. There are insufficient number of patients to determine ADA impact on efficacy.
Across multiple phase III studies, in patients treated with IMFINZI in combination with other therapeutic agents, 0% to 10.1% 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.
No overall differences in safety were reported between elderly (≥65 years) and younger patients.
In studies PACIFIC, CASPIAN, TOPAZ-1 and HIMALAYA data on safety for patients 75 years and older are too limited to draw a conclusion on this population.
In first line metastatic NSCLC patients in the POSEIDON study, some differences in safety were reported between elderly (≥65 years) and younger patients. The safety data from patients 75 years of age or older are limited to a total of 74 patients. There was a higher frequency of serious adverse reactions and discontinuation rate of any study treatment due to adverse reactions in 35 patients aged 75 years of age or older treated with IMFINZI in combination with tremelimumab and platinum-based chemotherapy (45.7% and 28.6%, respectively) relative to 39 patients aged 75 years of age or older who received platinum-based chemotherapy only (35.9% and 20.5%, respectively).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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