Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Hypersensitivity to atezolizumab or to any of the excipients listed in section 6.1.
In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded in the patient file.
Most immune-related adverse reactions occurring during treatment with atezolizumab were reversible with interruptions of atezolizumab and initiation of corticosteroids and/or supportive care. Immune-related adverse reactions affecting more than one body system have been observed. Immune-related adverse reactions with atezolizumab may occur after the last dose of atezolizumab.
For suspected immune-related adverse reactions, thorough evaluation to confirm aetiology or exclude other causes should be performed. Based on the severity of the adverse reaction, atezolizumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤1, corticosteroid should be tapered over ≥1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with systemic corticosteroid use, administration of other systemic immunosuppressants may be considered.
Atezolizumab must be permanently discontinued for any Grade 3 immune-related adverse reaction that recurs and for any Grade 4 immune-related adverse reactions, except for endocrinopathies that are controlled with replacement hormones (see sections 4.2 and 4.8).
Cases of pneumonitis, including fatal cases, have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of pneumonitis.
Treatment with atezolizumab should be withheld for Grade 2 pneumonitis, and 1 to 2 mg/kg/day prednisone or equivalent should be started. If symptoms improve to ≤Grade 1, corticosteroids should be tapered over ≥1 month. Treatment with atezolizumab may be resumed if the event improves to ≤Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or 4 pneumonitis.
Cases of hepatitis, some leading to fatal outcomes have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of hepatitis.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin should be monitored prior to initiation of treatment, periodically during treatment with atezolizumab and as indicated based on clinical evaluation. Treatment with atezolizumab should be withheld if Grade 2 event (ALT or AST >3 to 5 x ULN or blood bilirubin >1.5 to 3 x ULN) persists for more than 5 to 7 days, and 1 to 2 mg/kg/day of prednisone or equivalent should be started. If the event improves to ≤Grade 1, corticosteroids should be tapered over ≥1 month.
Treatment with atezolizumab may be resumed if the event improves to ≤Grade 1 within 12 weeks and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day.
Treatment with atezolizumab must be permanently discontinued for Grade 3 or Grade 4 events (ALT or AST >5.0 x ULN or blood bilirubin >3 x ULN).
Cases of diarrhoea or colitis have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of colitis.
Treatment with atezolizumab should be withheld for Grade 2 or 3 diarrhoea (increase of ≥4 stools/day over baseline) or colitis (symptomatic). For Grade 2 diarrhoea or colitis, if symptoms persist >5 days or recur, treatment with 1 to 2 mg/kg/day prednisone or equivalent should be started. For Grade 3 diarrhoea or colitis, treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should be started. If symptoms improve to ≤Grade 1, corticosteroids should be tapered over ≥1 month. Treatment with atezolizumab may be resumed if the event improves to ≤Grade 1 within 12 weeks and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 4 (life threatening; urgent intervention indicated) diarrhoea or colitis.
Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab (see section 4.8).
Patients should be monitored for clinical signs and symptoms of endocrinopathies. Thyroid function should be monitored prior to and periodically during treatment with atezolizumab. Appropriate management of patients with abnormal thyroid function tests at baseline should be considered.
Asymptomatic patients with abnormal thyroid function tests can receive atezolizumab. For symptomatic hypothyroidism, atezolizumab should be withheld and thyroid hormone replacement should be initiated as needed. Isolated hypothyroidism may be managed with replacement therapy and without corticosteroids. For symptomatic hyperthyroidism, atezolizumab should be withheld and an anti-thyroid medicinal product should be initiated as needed. Treatment with atezolizumab may be resumed when symptoms are controlled and thyroid function is improving.
For symptomatic adrenal insufficiency, atezolizumab should be withheld and treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow. If symptoms improve to ≤Grade 1, corticosteroids should be tapered over ≥1 month. Treatment may be resumed if the event improves to ≤Grade 1 within 12 weeks and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day and the patient is stable on replacement therapy (if required).
For Grade 2 or Grade 3 hypophysitis, atezolizumab should be withheld and treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started, and hormone replacement should be initiated as needed. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow. If symptoms improve to ≤Grade 1, corticosteroids should be tapered over ≥1 month. Treatment may be resumed if the event improves to ≤Grade 1 within 12 weeks and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day and the patient is stable on replacement therapy (if required). Treatment with atezolizumab should be permanently discontinued for Grade 4 hypophysitis.
Treatment with insulin should be initiated for type 1 diabetes mellitus. For ≥Grade 3 hyperglycaemia (fasting glucose >250 mg/dL or 13.9 mmol/L), atezolizumab should be withheld. Treatment with atezolizumab may be resumed if metabolic control is achieved on insulin replacement therapy.
Meningoencephalitis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for clinical signs and symptoms of meningitis or encephalitis.
Treatment with atezolizumab must be permanently discontinued for any grade of meningitis or encephalitis. Treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow.
Myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome, which may be life threatening, were observed in patients receiving atezolizumab. Patients should be monitored for symptoms of motor and sensory neuropathy.
Treatment with atezolizumab must be permanently discontinued for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Initiation of systemic corticosteroids (at a dose of 1 to 2 mg/kg/day of prednisone or equivalent) should be considered.
Pancreatitis, including increases in serum amylase and lipase levels, has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be closely monitored for signs and symptoms that are suggestive of acute pancreatitis.
Treatment with atezolizumab should be withheld for ≥Grade 3 serum amylase or lipase levels increased (>2 x ULN), or Grade 2 or 3 pancreatitis, and treatment with intravenous corticosteroids (1 to 2 mg/kg/day methylprednisolone or equivalent) should be started. Once symptoms improve, treatment with 1 to 2 mg/kg/day of prednisone or equivalent should follow. Treatment with atezolizumab may be resumed when serum amylase and lipase levels improve to ≤Grade 1 within 12 weeks, or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinued for Grade 4, or any grade of recurrent pancreatitis.
Myocarditis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of myocarditis.
Treatment with atezolizumab should be withheld for Grade 2 myocarditis, and treatment with systemic corticosteroids at a dose of 1 to 2mg/kg/day of prednisone or equivalent should be started. Treatment with atezolizumab may be resumed if the event improves to ≤Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or 4 myocarditis.
Nephritis has been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for changes in renal function.
Treatment with atezolizumab should be withheld for Grade 2 nephritis, and treatment with systemic corticosteroids at a dose of 1 to 2mg/kg/day of prednisone or equivalent should be started. Treatment with atezolizumab may be resumed if the event improves to ≤Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10 mg prednisone or equivalent per day. Treatment with atezolizumab must be permanently discontinued for Grade 3 or 4 nephritis.
Cases of myositis, including fatal cases, have been observed in clinical trials with atezolizumab (see section 4.8). Patients should be monitored for signs and symptoms of myositis.
Treatment with atezolizumab should be withheld for Grade 2 or 3 myositis and corticosteroid therapy (1-2 mg/kg/day prednisone or equivalent) should be initiated. If symptoms improve to ≤Grade 1, taper corticosteroids as clinically indicated. Treatment with atezolizumab may be resumed if the event improves to ≤Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10 mg oral prednisone or equivalent per day. Treatment with atezolizumab should be permanently discontinued for Grade 4 or grade 3 recurrent myositis, or when unable to reduce the corticosteroid dose to the equivalent of ≤10 mg prednisone per day within 12 weeks after onset.
Infusion-related reactions have been observed with atezolizumab (see section 4.8).
The rate of infusion should be reduced or treatment should be interrupted in patients with Grade 1 or 2 infusion-related reactions. Atezolizumab should be permanently discontinued in patients with Grade 3 or 4 infusion-related reactions. Patients with Grade 1 or 2 infusion-related reactions may continue to receive atezolizumab with close monitoring; premedication with antipyretic and antihistamines may be considered.
Physicians should carefully consider the combined risks of the four-drug regimen of atezolizumab bevacizumab, paclitaxel, and carboplatin before initiating treatment (see section 4.8).
Neutropenia and peripheral neuropathies occurring during treatment with atezolizumab and nab- paclitaxel may be reversible with interruptions of atezolizumab and/or nab-paclitaxel. Physicians should consult the nab-paclitaxel summary of product characteristics (SmPC) for specific precautions and contraindications of this medicine.
Patients with the following conditions were excluded from clinical trials: a history of autoimmune disease, history of pneumonitis, active brain metastasis, HIV, hepatitis B or hepatitis C infection, significant cardiovascular disease and patients with inadequate hematologic and end-organ function. Patients who were administered a live, attenuated vaccine within 28 days prior to enrolment; systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior to study entry were excluded from clinical trials.
The baseline and prognostic disease characteristics of the IMvigor210 Cohort 1 study population were overall comparable to patients in the clinic who would be considered cisplatin ineligible but would be eligible for a carboplatin-based combination chemotherapy. There are insufficient data for the subgroup of patients that would be unfit for any chemotherapy; therefore atezolizumab should be used with caution in these patients, after careful consideration of the potential balance of risks and benefits on an individual basis.
Patients with NSCLC that had clear tumour infiltration into the thoracic great vessels or clear cavitation of pulmonary lesions, as seen on imaging, were excluded from the pivotal clinical study IMpower150 after several cases of fatal pulmonary haemorrhage were observed, which is a known risk factor of treatment with bevacizumab.
In the absence of data, atezolizumab should be used with caution in these populations after careful evaluation of the balance of benefits and risks for the patient.
In study IMpower150, there are no data on the efficacy of atezolizumab in combination with bevacizumab, paclitaxel and carboplatin in EGFR+ patients who have progressed previously on erlotinib+bevacizumab.
All prescribers of Tecentriq must be familiar with the Physician Information and Management Guidelines. The prescriber must discuss the risks of Tecentriq therapy with the patient. The patient will be provided with the patient alert card and instructed to carry the card at all times.
No formal pharmacokinetic drug interaction studies have been conducted with atezolizumab. Since atezolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.
The use of systemic corticosteroids or immunosuppressants before starting atezolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of atezolizumab. However, systemic corticosteroids or other immunosuppressants can be used to treat immune-related adverse reactions after starting atezolizumab (see section 4.4).
Women of childbearing potential have to use effective contraception during and for 5 months after treatment with atezolizumab.
There are no data from the use of atezolizumab in pregnant women. No developmental and reproductive studies were conducted with atezolizumab. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway in murine pregnancy models can lead to immune-related rejection of the developing foetus resulting in foetal death (see section 5.3). These results indicate a potential risk, based on its mechanism of action, that administration of atezolizumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.
Human immunoglobulins G1 (IgG1) are known to cross the placental barrier and atezolizumab is an IgG1; therefore, atezolizumab has the potential to be transmitted from the mother to the developing foetus.
Atezolizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with atezolizumab.
It is unknown whether atezolizumab is excreted in human milk. Atezolizumab is a monoclonal antibody and is expected to be present in the first milk and at low levels afterwards. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue Tecentriq therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
No clinical data are available on the possible effects of atezolizumab on fertility. No reproductive and development toxicity studies have been conducted with atezolizumab; however, based on the 26-week repeat dose toxicity study, atezolizumab had an effect on menstrual cycles at an estimated AUC approximately 6 times the AUC in patients receiving the recommended dose and was reversible (see section 5.3). There were no effects on the male reproductive organs.
Tecentriq has minor influence on the ability to drive and use machines. Patients experiencing fatigue should be advised not to drive and use machines until symptoms abate (see section 4.8).
The safety of atezolizumab as monotherapy is based on pooled data in 3,178 patients across multiple tumour types. The most common adverse reactions (>10%) were fatigue (35.9%), decreased appetite (25.5%), nausea (23.5%), cough (20.8%), dyspnoea (20.5%), pyrexia (20.1%), diarrhoea (19.7%), rash (19.5%), back pain (15.3%), vomiting (15.0%), asthenia (14.5%), arthralgia (13.9%), musculoskeletal pain (13.0%), pruritus (12.6%) and urinary tract infection (11.6%).
The safety of atezolizumab given in combination with other medicinal products, has been evaluated in 2,759 patients across multiple tumour types. The most common adverse reactions (≥20%) were nausea (37.4%), fatigue (36.4%), neutropenia (33.7%), anaemia (33.2%), diarrhoea (29.5%), rash (28.5%), constipation (27.0%), peripheral neuropathy (26.8%), decreased appetite (24.6%), thrombocytopenia (21.2%) and cough (20.1%).
Further details on serious adverse reactions are provided in Section 4.4 Warnings & Precautions.
The Adverse Drug Reactions (ADRs) are listed by MedDRA system organ class (SOC) and categories of frequency in Table 2 for atezolizumab given as monotherapy or as combination therapy. Adverse reactions known to occur with atezolizumab or chemotherapies given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy. The following categories of frequency have been used: 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). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 2. Summary of adverse reactions occurring in patients treated with atezolizumab:
Atezolizumab monotherapy:
Very common: urinary tract infectiona
Common: thrombocytopeniac
Common: infusion-related reactionf
Common: hypothyroidismg
Uncommon: hyperthyroidismh, diabetes mellitusi, adrenal insufficiencyj
Rare: hypophysitisk
Very common: decreased appetite
Common: hypokalaemia, hyponatraemia, hyperglycaemia
Uncommon: Guillain-Barré syndromem, meningoencephalitisn
Rare: myasthenic syndrome°
Rare: myocarditisp
Common: hypotension
Very common: cough, dyspnoea
Common: pneumonitisq, hypoxia, nasal congestion, nasopharyngitis
Very common: nausea, vomiting, diarrhoear
Common: abdominal pain, colitiss, dysphagia, oropharyngeal paint
Uncommon: pancreatitisu
Common: AST increased, ALT increased, hepatitisv
Very common: rashw, pruritus
Very common: arthralgia, back pain, musculoskeletal painx
Uncommon: myositisy
Rare: nephritisaa
Very common: pyrexia, fatigue, asthenia
Common: influenza like illness, chills
Atezolizumab in combination therapy:
Very common: lung infectionb
Very common: anaemia, thrombocytopeniac, neutropeniad, leukopeniae
Common: lymphocyte count decreased
Very common: hypothyroidismg
Very common: decreased appetite
Common: hypokalaemia, hyponatraemia, hypomagnesaemia
Very common: peripheral neuropathyl, dizziness, headache
Common: syncope
Very common: dyspnoea, cough
Common: dysphonia
Very common: nausea, diarrhoear, constipation, vomiting
Common: stomatitis, dysgeusia
Common: AST increased, ALT increased
Very common: rashw, pruritus
Very common: arthralgia, musculoskeletal painx, back pain
Common: proteinuriaz
Very common: pyrexia, fatigue, asthenia
a Includes reports of urinary tract infection, cystitis, pyelonephritis, escherichia urinary tract infection, urinary tract infection bacterial, kidney infection, pyelonephritis acute, urinary tract infection fungal, urinary tract infection pseudomonal.
b Includes reports of pneumonia, bronchitis, lung infection, lower respiratory tract infection, infective exacerbation of COPD, infectious pleural effusion, tracheobronchitis, atypical pneumonia, lung abscess, pyopneumothorax.
c Includes reports of thrombocytopenia and platelet count decreased.
d Includes reports of neutropenia, neutrophil count decreased, febrile neutropenia, neutropenic sepsis, granulocytopenia.
e Includes reports of white blood cell count decreased and leukopenia.
f Includes reports of cytokine release syndrome, hypersensitivity, anaphylaxis.
g Includes reports of autoimmune hypothyroidism, autoimmune thyroiditis, blood thyroid stimulating hormone abnormal, blood thyroid stimulating hormone decreased, blood thyroid stimulating hormone increased, euthyroid sick syndrome, goitre, hypothyroidism, myxoedema, thyroid disorder, thyroid function test abnormal, thyroiditis, thyroiditis acute, thyroxine decreased, thyroxine free decreased, thyroxine free increased, thyroxine increased, tri-iodothyronine decreased, tri-iodothyronine free abnormal, tri-iodothyronine free decreased, tri-iodothyronine free increased.
h Includes reports of hyperthyroidism, Basedow’s disease, endocrine ophthalmopathy, exophthalmos.
i Includes reports of diabetes mellitus, type 1 diabetes mellitus, diabetic ketoacidosis, ketoacidosis.
j Includes reports of adrenal insufficiency and primary adrenal insufficiency.
k Incudes reports of hypophysitis and temperature regulation disorder.
l Includes reports of neuropathy peripheral, autoimmune neuropathy, peripheral sensory neuropathy, polyneuropathy, herpes zoster, peripheral motor neuropathy, neuralgic amyotrophy, peripheral sensorimotor neuropathy, toxic neuropathy, axonal neuropathy, lumbosacral plexopathy, neuropathic arthropathy, peripheral nerve infection.
m Includes reports of Guillain-Barré syndrome and demyelinating polyneuropathy. n Includes reports of encephalitis, meningitis, photophobia.
° Incudes reports of myasthenia gravis.
p Reported in studies outside the pooled dataset. The frequency is based on the program wide exposure.
q Includes reports of pneumonitis, lung infiltration, bronchiolitis, interstitial lung disease, radiation pneumonitis.
r Includes reports of diarrhoea, defaecation urgency, frequent bowel movements, gastrointestinal hypermotility.
s Includes reports of colitis, autoimmune colitis, colitis ischaemic, colitis microscopic, colitis ulcerative.
t Includes reports of oropharyngeal pain, oropharyngeal discomfort, throat irritation.
u Includes reports of autoimmune pancreatitis, pancreatitis, pancreatitis acute, lipase increased, amylase increased.
v Includes reports of ascites, autoimmune hepatitis, hepatocellular injury, hepatitis, hepatitis acute, hepatotoxicity, liver disorder, drug-induced liver injury, hepatic failure, hepatic steatosis, hepatic lesion, oesophageal varices haemorrhage, varices oesophageal.
w Includes reports of acne, acne pustular, dermatitis, dermatitis acneiform, dermatitis allergic, dermatitis bullous, dermatitis exfoliative generalised, drug eruption, eczema, eczema infected, erythema, erythema multiforme, erythema of eyelid, exfoliative rash, eyelid rash, fixed eruption, folliculitis, furuncle, generalised erythema, palmar-plantar erythrodysaesthesia syndrome, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rash papular, rash papulosquamous, rash pruritic, rash pustular, rash vesicular, seborrhoeic dermatitis, skin exfoliation, skin toxicity, skin ulcer, toxic epidermal necrolysis, toxic skin eruption.
x Includes reports of musculoskeletal pain and myalgia.
y Includes reports of myositis, rhabdomyolysis, polymyalgia rheumatica, dermatomyositis, muscle abscess, myoglobin urine present.
z Includes reports of proteinuria, protein urine present, haemoglobinurea, nephrotic syndrome.
aa Includes report of nephritis, Henoch-Schonlein Purpura nephritis.
The data below reflect information for significant adverse reactions for atezolizumab as monotherapy in clinical studies (see section 5.1). Details for the significant adverse reactions for atezolizumab when given in combination are presented if clinically relevant differences were noted in comparison to atezolizumab monotherapy. The management guidelines for these adverse reactions are described in sections 4.2 and 4.4.
Pneumonitis occurred in 2.7% (87/3,178) of patients who received atezolizumab monotherapy. Of the 87 patients, one experienced a fatal event. The median time to onset was 3.4 months (range 3 days to 24.8 months). The median duration was 1.4 months (range 0 day to 21.2+ months; + denotes a censored value). Pneumonitis led to discontinuation of atezolizumab in 12 (0.4%) patients. Pneumonitis requiring the use of corticosteroids occurred in 1.6% (51/3,178) of patients receiving atezolizumab monotherapy.
Hepatitis occurred in 2.0% (62/3,178) of patients who received atezolizumab monotherapy. Of the 62 patients, two experienced a fatal event. The median time to onset was 1.5 months (range 6 days to 18.8 months). The median duration was 2.1 months (range 0 day to 22.0+ months; + denotes a censored value). Hepatitis led to discontinuation of atezolizumab in 6 (<0.2%) patients. Hepatitis requiring the use of corticosteroids occurred in 0.6% (18/3,178) of patients receiving atezolizumab monotherapy.
Colitis occurred in 1.1% (34/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 4.7 months (range 15 days to 17.2 months). The median duration was 1.2 months (range 3 days to 17.8+ months; + denotes a censored value). Colitis led to discontinuation of atezolizumab in 8 (0.3%) patients. Colitis requiring the use of corticosteroids occurred in 0.6% (19/3,178) of patients receiving atezolizumab monotherapy.
Hypothyroidism occurred in 5.2% (164/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 4.9 months (range: 0 day to 31.3 months). Hyperthyroidism occurred in 0.9% (30/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 2.1 months (range 21 days to 15.7 months).
Adrenal insufficiency occurred in 0.4% (12/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 5.5 months (range: 3 days to 19 months). The median duration was 16.8 months (range: 0 day to 16.8 months). Adrenal insufficiency led to discontinuation of atezolizumab in 1 (<0.1%) patient. Adrenal insufficiency requiring the use of corticosteroids occurred in 0.3% (9/3,178) of patients receiving atezolizumab monotherapy.
Hypophysitis occurred in <0.1% (2/3,178) of patients who received atezolizumab monotherapy. The median time to onset 7.2 months (range: 24 days to 13.7 months). One patient required the use of corticosteroids and treatment with atezolizumab was discontinued.
Hypophysitis occurred in 0.8% (3/393) of patients who received atezolizumab with bevacizumab, paclitaxel, and carboplatin. The median time to onset was 7.7 months (range: 5.0 to 8.8 months). Two patients required the use of corticosteroids.
Hypophysitis occurred in 0.4% (2/473) of patients who received atezolizumab in combination with nab-paclitaxel and carboplatin. The median time to onset was 5.2 months (range: 5.1 to 5.3 months). Both patients required the use of corticosteroids.
Diabetes mellitus occurred in 0.3% (11/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 3.6 months (range 3 days to 9.9 months). Diabetes mellitus led to the discontinuation of atezolizumab in <0.1% (3/3,178) patients.
Meningoencephalitis occurred in 0.4% (13/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 15 days (range: 0 day to 12.5 months). The median duration was 26 days (range 6 days to 14.5+ months; + denotes a censored value).
Meningoencephalitis requiring the use of corticosteroids occurred in 0.2% (6/3,178) of patients receiving atezolizumab and four patients discontinued atezolizumab.
Guillain-Barré syndrome and demyelinating polyneuropathy occurred in 0.2% (5/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 7 months (range: 18 days to 8.1 months). The median duration was 8.0 months (range 18 days to 8.3+ months; + denotes a censored value). Guillain-Barré syndrome led to discontinuation of atezolizumab in 1 patient (<0.1%). Guillain-Barré syndrome requiring the use of corticosteroids occurred in <0.1% (2/3,178) of patients receiving atezolizumab monotherapy.
Myasthenia gravis occurred in <0.1% (1/3,178) of patients who received atezolizumab monotherapy. The time to onset was 1.2 months.
Pancreatitis, including amylase increased and lipase increased, occurred in 0.6% (18/3,178) of patients who received atezolizumab monotherapy. The median time to onset was 5.0 months (range: 9 days to 16.9 months). The median duration was 24 days (range 3 days to 12.0+ months; + denotes a censored value). Pancreatitis led to the discontinuation of atezolizumab in 3 (<0.1%) patients. Pancreatitis requiring the use of corticosteroids occurred in 0.1% (4/3,178) of patients receiving atezolizumab monotherapy.
Myocarditis occurred in <0.1% (2/8,000) of patients across all atezolizumab clinical trials in multiple tumour types and treatment combinations. The time to onset was 18 and 33 days. Both patients required corticosteroids and discontinued atezolizumab.
Nephritis occurred in <0.1% (3/3,178) of patients who received atezolizumab. The median time to onset was 13.1 months (range: 9.0 to 17.5 months). The median duration was 2.8 months (range 15 days to 9.5+ months; + denotes a censored value). Nephritis led to discontinuation of atezolizumab in 2 (<0.1%) patients. One patient required corticosteroids and discontinued atezolizumab.
Myositis occurred in 0.4% (12/3178) of patients who received atezolizumab monotherapy. The median time to onset was 5.4 months (range: 0.7 to 11.0 months). The median duration was 3.5 months (range 0.1 to 22.6+ months; + denotes a censored value). Myositis led to discontinuation of atezolizumab in 1 (<0.1%) patient. Seven (0.2%) patients required the use of corticosteroids.
In the first-line NSCLC study (IMpower150), an overall higher frequency of adverse events was observed in the four-drug regimen of atezolizumab, bevacizumab, paclitaxel, and carboplatin compared to atezolizumab, paclitaxel and carboplatin, including Grade 3 and 4 events (63.6% compared to 57.5%), Grade 5 events (6.1% compared to 2.5%), adverse events of special interest to atezolizumab (52.4% compared to 48.0%), as well as adverse events leading to withdrawal of any study treatment (33.8% compared to 13.3%). Nausea, diarrhoea, stomatitis, fatigue, pyrexia, mucosal inflammation, decreased appetite, weight decreased, hypertension and proteinuria were reported higher (≥5% difference) in patients receiving atezolizumab in combination with bevacizumab, paclitaxel and carboplatin. Other clinically significant adverse events which were observed more frequently in the atezolizumab, bevacizumab, paclitaxel, and carboplatin arm were epistaxis, haemoptysis, cerebrovascular accident, including fatal events.
Across multiple phase III studies, 13.1% to 36.4% of patients developed treatment-emergent anti-drug antibodies (ADAs). Overall, ADA status appeared to have no clinically relevant impact on safety.
No data are available to allow conclusions to be drawn on possible effects of neutralising antibodies.
No overall differences in safety were observed between patients ≥ 65 years of age and younger patients receiving atezolizumab monotherapy. In study IMpower150, age ≥ 65 was associated with an increased risk of developing adverse events in patients receiving atezolizumab in combination with bevacizumab, carboplatin and paclitaxel.
In studies IMpower150 and IMpower133, data for patients ≥75 years of age are too limited to draw conclusions on this population.
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 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 except those mentioned in section 6.6.
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