Atezolizumab

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.

Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab.

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.

Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab.

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).

Cases of diarrhoea or colitis have been observed in clinical trials with atezolizumab. 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.

Cases of hepatitis, some leading to fatal outcomes have been observed in clinical trials with atezolizumab. 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).

Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab.

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.

Cases of myositis, including fatal cases, have been observed in clinical trials with atezolizumab. 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.

Cases of pneumonitis, including fatal cases, have been observed in clinical trials with atezolizumab. 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.

Pancreatitis, including increases in serum amylase and lipase levels, has been observed in clinical trials with atezolizumab. 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.

Hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis and type 1 diabetes mellitus, including diabetic ketoacidosis have been observed in clinical trials with atezolizumab.

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.

Nephritis has been observed in clinical trials with atezolizumab. 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.

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.

Meningoencephalitis has been observed in clinical trials with atezolizumab. 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.

Myocarditis has been observed in clinical trials with atezolizumab. 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.

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. 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 atezolizumab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Women of childbearing potential

Women of childbearing potential have to use effective contraception during and for 5 months after treatment with atezolizumab.

Fertility

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. There were no effects on the male reproductive organs.

Atezolizumab 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.