Source: European Medicines Agency (EU) Revision Year: 2020 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.
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 etiology, occurred in patients receiving IMFINZI.
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 trial, 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%) (see section 4.8).
Patients should be monitored for signs and symptoms of pneumonitis or radiation pneumonitis. Patients with suspected pneumonitis should be evaluated with radiographic imaging and managed as recommended in section 4.2.
Immune-mediated hepatitis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI (see section 4.8). Patients should be monitored for abnormal liver tests prior to and periodically during treatment with IMFINZI, and as indicated based on clinical evaluation. Immune-mediated hepatitis should be managed as recommended in section 4.2.
Immune-mediated colitis or diarrhoea, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI (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 hypothyroidism and hyperthyroidism (including thyroiditis) occurred in patients receiving IMFINZI, 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 and hyperthyroidism (including thyroiditis) should be managed as recommended in section 4.2.
Immune-mediated adrenal insufficiency occurred in patients receiving IMFINZI (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 occurred in patients receiving IMFINZI (see section 4.8). Patients should be monitored for clinical signs and symptoms of type 1 diabetes mellitus. For symptomatic type 1 diabetes mellitus, patients should be managed as recommended in section 4.2.
Immune-mediated hypophysitis or hypopituitarism occurred in patients receiving IMFINZI (see section 4.8). Patients should be monitored for clinical signs and symptoms of hypophysitis or hypopituitarism. For symptomatic hypophysitis or hypopituitarism, patients should be managed as recommended in section 4.2.
Immune-mediated nephritis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI (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 or dermatitis, defined as requiring use of systemic corticosteroids and with no clear alternate etiology, occurred in patients receiving IMFINZI (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.
Given the mechanism of action of IMFINZI, other potential immune-mediated adverse reactions may occur. The following immune-related adverse reactions were reported in less than 1% of patients treated with IMFINZI monotherapy in clinical trials (n=1889): Myasthenia gravis, myocarditis, myositis, polymyositis. Patients should be monitored for signs and symptoms and managed as recommended in section 4.2. Events of pancreatitis have been reported in patients in the clinical study programme. Patients should be monitored for signs and symptoms and managed as recommended for other immune-mediated adverse reactions, in section 4.2.
Patients should be monitored for signs and symptoms of infusion related reactions. Severe infusion related reactions have been reported in patients receiving IMFINZI (see section 4.8). Infusion related reactions should be managed as recommended in section 4.2
Patients with the following were excluded from the PACIFIC Study: 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); 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 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.
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 (10 mg/kg) has been evaluated in the PACIFIC Study (n=475) in patients with locally advanced, unresectable NSCLC who had completed treatment with at least 2 cycles of concurrent chemoradiation within 1 to 42 days prior to initiation of the study. In this patient population, the most frequent adverse reactions were cough (40.2% vs 30.3% in placebo), upper respiratory tract infections (26.1% vs 11.5% in placebo) and rash (21.7% vs 12.0% in placebo). The most frequent Grade 3-4 adverse reaction was pneumonia (6.5% vs 5.6% in placebo). The overall incidence of Grade 3 or 4 adverse reactions was 12.8% in the IMFINZI arm vs 9.8% in placebo.
Table 2 lists the incidence of adverse reactions in patients with locally advanced, unresectable NSCLC in the PACIFIC Study, based on the frequency of that adverse reaction type regardless of investigator assessed causality. Adverse drug 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 for each ADR is defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.
Table 2. Adverse drug reactions in patients with locally advanced unresectable NSCLC treated with IMFINZI at 10 mg/kg:
| Any Grade (%) | Grade 3-4 (%) | ||
|---|---|---|---|
| Infections and infestations | |||
| Upper respiratory tract infectionsa | Very common | 26.1 | 0.4 |
| Pneumoniab,c | Very common | 17.1 | 6.5 |
| Dental and oral soft tissue infectiond | Common | 3.6 | 0 |
| Oral candidiasis | Common | 3.2 | 0 |
| Influenza | Common | 2.5 | 0 |
| Endocrine disorders | |||
| Hypothyroidisme | Very common | 11.6 | 0.2 |
| Hyperthyroidismf | Common | 8.2 | 0 |
| Adrenal insufficiency | Uncommon | 0.2 | 0 |
| Type 1 diabetes mellitus | Uncommon | 0.2 | 0.2 |
| Hypophysitis/Hypopituitarism | Rareg | <0.1 | <0.1 |
| Diabetes insipidus | Rareg | <0.1 | <0.1 |
| Nervous System Disorders | |||
| Myasthenia gravis | Rareh | <0.1 | <0.1 |
| Cardiac disorders | |||
| Myocarditis | Rareg | <0.1 | <0.1 |
| Respiratory, thoracic and mediastinal disorders | |||
| Cough/Productive Coughi | Very common | 40.2 | 0.6 |
| Pneumonitisb | Very common | 12.6 | 1.7 |
| Dysphonia | Common | 3.8 | 0 |
| Interstitial lung disease | Uncommon | 0.6 | 0 |
| Gastrointestinal disorders | |||
| Diarrhoea | Very common | 18.3 | 0.6 |
| Abdominal painj | Very common | 10.1 | 0.4 |
| Colitisk | Common | 1.1 | 0.2 |
| Hepatobiliary disorders | |||
| Aspartate aminotransferase increased or Alanine aminotransferase increasedl | Common | 6.1 | 1.9 |
| Hepatitisc,m | Uncommon | 0.6 | 0 |
| Skin and subcutaneous tissue disorders | |||
| Rashn | Very common | 21.7 | 0.6 |
| Pruritus° | Very common | 12.4 | 0 |
| Dermatitis | Common | 1.5 | 0 |
| Night sweats | Common | 2.3 | 0 |
| Musculoskeletal and connective tissue disorders | |||
| Myalgia | Common | 8.0 | 0.2 |
| Myositis | Uncommon | 0.4 | 0 |
| Polymyositisc | Rareg | <0.1 | <0.1 |
| Renal and urinary disorders | |||
| Blood creatinine increased | Common | 4.6 | 0.2 |
| Dysuria | Common | 2.3 | 0 |
| Nephritisp | Uncommon | 0.4 | 0 |
| General disorders and administration site conditions | |||
| Pyrexia | Very common | 14.7 | 0.2 |
| Peripheral oedema | Common | 7.8 | 0 |
| Injury, poisoning and procedural complications | |||
| Infusion related reactionq | Common | 1.9 | 0 |
a includes laryngitis, nasopharyngitis, peritonsillar abscess, pharyngitis, rhinitis, sinusitis, tonsillitis, tracheobronchitis and upper respiratory tract infection.
b includes lung infection, pneumocystis jirovecii pneumonia, pneumonia, pneumonia adenoviral, pneumonia bacterial, pneumonia cytomegaloviral, pneumonia haemophilus, pneumonia klebsiella, pneumonia necrotising, pneumonia pneumococcal and pneumonia streptococcal.
c fatal pneumonitis and fatal pneumonia were reported at similar rate between the IMFINZI-treated group and placebo group in the PACIFIC Study; fatal hepatitis and fatal polymyositis were reported in other clinical trials.
d includes gingivitis, oral infection, periodontitis, pulpitis dental, tooth abscess and tooth infection.
e includes autoimmune hypothyroidism and hypothyroidism.
f includes hyperthyroidism, autoimmune thyroiditis, thyroiditis, thyroiditis subacute and Basedow’s disease.
g frequency is based on events not observed in the PACIFIC Study but observed in other clinical trials (n=1889).
h frequency is based on events not observed in the PACIFIC Study but observed in AstraZeneca clinical trials (n=4067).
i includes cough and productive cough.
j includes abdominal pain, abdominal pain lower, abdominal pain upper and flank pain.
k includes colitis, enteritis, enterocolitis, and proctitis.
l includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased and transaminases increased.
m includes hepatitis, autoimmune hepatitis, hepatitis toxic, hepatocellular injury, hepatitis acute, and hepatotoxicity.
n includes rash erythematous, rash generalised, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, erythema, eczema and rash.
° includes pruritus generalised and pruritus.
p includes autoimmune nephritis, tubulointerstitial nephritis, nephritis, glomerulonephritis and glomerulonephritis membranous.
q ncludes infusion related reaction and urticaria with onset on the day of dosing or 1 day after dosing.
IMFINZI is most commonly associated with immune-mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of IMFINZI. The data for the following immune-mediated adverse reactions reflect the combined safety database of 1889 patients which includes the PACIFIC Study and two additional studies (a multi-cohort, open-label clinical trial in patients with advanced solid tumours, and an open-label study in patients with locally advanced or metastatic NSCLC). Across all studies, IMFINZI was administered at a dose of 10 mg/kg every 2 weeks. The management guidelines for these adverse reactions are described in section 4.4.
In the combined safety database with IMFINZI monotherapy, (n=1889 multiple tumour types), immune-mediated pneumonitis occurred in 79 (4.2%) patients, including Grade 3 in 12 (0.6%) patients, Grade 4 in 1 (<0.1%) patient, and Grade 5 in 5 (0.3%) patients. The median time to onset was 53 days (range: 1-341 days). Forty-five of the 79 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day), and 2 patients also received infliximab. IMFINZI was discontinued in 26 patients. Resolution occurred in 42 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 (2.0%).
In the PACIFIC Study, (n=475 in the IMFINZI arm, and n=234 in the placebo arm) immune-mediated pneumonitis occurred in 51 (10.7%) patients in the IMFINZI-treated group and 16 (6.8%) patients in the placebo group, including Grade 3 in 8 (1.7%) 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 53 days (range: 1-341 days) vs. 55.5 days (range: 0-231 days) in the placebo group. In the IMFINZI-treated group, 44 of the 51 patients received systemic corticosteroids, including 28 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, 11 of the 16 patients received systemic corticosteroids, including 9 patients who received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). Resolution occurred for 27 patients in the IMFINZI treated group vs 6 in placebo.
In the combined safety database with IMFINZI monotherapy, immune-mediated hepatitis occurred in 19 (1.0%) patients, including Grade 3 in 11 (0.6%) patients and Grade 5 (fatal) in 1 (<0.1%) patient. The median time to onset was 70 days (range: 15-312 days). Thirteen of the 19 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received mycophenolate treatment. IMFINZI was discontinued in 4 patients. Resolution occurred in 13 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated colitis or diarrhoea occurred in 31 (1.6%) patients, including Grade 3 in 6 (0.3%) patients and Grade 4 in 1 (<0.1%) patient. The median time to onset was 74 days (range: 1-365 days). Sixteen of the 31 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). One patient also received infliximab treatment. IMFINZI was discontinued in 8 patients. Resolution occurred in 23 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated hypothyroidism occurred in 137 (7.3%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 85 days (range: 9-378 days). Of the 137 patients, 134 patients received hormone replacement therapy and two patients received high-dose corticosteroids (at least 40 mg prednisone or equivalent per day) for hypothyroidism followed by hormone replacement. IMFINZI was not discontinued in any patient due to hypothyroidism.
In the combined safety database with IMFINZI monotherapy, immune-mediated hyperthyroidism occurred in 34 (1.8%) patients, there were no Grade 3 or 4 cases. The median time to onset was 41 days (range: 14-195 days). Twenty-six of the 34 patients received medical therapy (thiamazole, carbimazole, propylthiouracil or beta-blocker), 12 patients received thyroxine when hyperthyroidism transitioned to hypothyroidism, 12 patients received systemic corticosteroids and 3 of the 12 patients received high-dose systemic corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was not discontinued in any patient due to hyperthyroidism. Eight patients experienced hypothyroidism following hyperthyroidism.
In the combined safety database with IMFINZI monotherapy, immune-mediated adrenal insufficiency occurred in 7 (0.4%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 141 days (range: 70-265 days). All 7 patients received systemic corticosteroids; 2 of the 7 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was not discontinued in any patient due to adrenal insufficiency. Resolution occurred in 1 patient.
In the combined safety database with IMFINZI monotherapy, immune-mediated type 1 diabetes mellitus occurred in 1 (<0.1%) patient (Grade 3). IMFINZI was discontinued due to type 1 diabetes mellitus. The time to onset was 42 days. This 1 patient received insulin.
In the combined safety database with IMFINZI monotherapy, immune-mediated hypopituitarism occurred in 1 (<0.1%) patient (Grade 3). This 1 patient received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day) and IMFINZI was not discontinued.
In the combined safety database with IMFINZI monotherapy, immune-mediated nephritis occurred in 3 (0.2%) patients, including Grade 3 in 1 (<0.1%) patient. The median time to onset was 95 days (range: 28-239 days). Two (0.1%) patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in all 3 patients. Resolution occurred in 2 patients.
In the combined safety database with IMFINZI monotherapy, immune-mediated rash or dermatitis occurred in 30 (1.6%) patients, including Grade 3 in 7 (0.4%) patients. The median time to onset was 74 days (range: 1-365 days). Eleven of the 30 patients received high-dose corticosteroid treatment (at least 40 mg prednisone or equivalent per day). IMFINZI was discontinued in 2 patients. Resolution occurred in 18 patients.
In the combined safety database with IMFINZI monotherapy, infusion related reactions occurred in 35 (1.9%) patients, including Grade 3 in 5 (0.3%) patients.
In patients treated with durvalumab in the PACIFIC Study, the proportion of patients who experienced a laboratory abnormality worsening from baseline was as follows: 38.5% (all Grades), 2.3% (Grades 3-4) for alanine aminotransferase increased, 36.0% (all Grades), 2.8% (Grade 3-4) for aspartate aminotransferase increased, 16.3% (all Grades) for creatinine increased, 26.5% (all Grades) for TSH elevated > ULN and above baseline, 31.9% (all Grades) for TSH decreased < LLN and below baseline.
Of the 1570 patients who were treated with IMFINZI 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug antibodies (ADAs), 2.9% (45/1570) of patients tested positive for treatment-emergent ADAs. Neutralising antibodies (nAbs) against durvalumab were detected in 0.5% (8/1570) 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.
No overall differences in safety were reported between elderly (≥65 years) and younger patients. Data from NSCLC patients 75 years of age or older are limited.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
