Atezolizumab

Registered South African indications:

• Locally advanced or metastatic urothelial carcinoma (UC)
• Locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC)
• Small cell lung cancer
• Triple-negative breast cancer

Contraindications

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Coadministration with live vaccines

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
  - HCC patients with Child-Pugh C liver disease
• Elderly
• Females of reproductive potential
• Asian patients
• Previously severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents
• Urothelial carcinoma for previously untreated patients who are considered cisplatin-ineligible
• Monotherapy for first-line treatment in metastatic NSCLC
• History of autoimmune disease
• History of pneumonitis
• Active brain metastasis
• Human immunodeficiency virus
• Hepatitis B or hepatitis C infection (for non-HCC patients)
• Significant cardiovascular disease
• Inadequate haematologic and end-organ function
• Administration of live, attenuated vaccines within 28 days prior to therapy
• Administration of systemic immunostimulatory agents within 4 weeks prior to therapy
• Administration of systemic immunosuppressive medicinal products within 2 weeks prior to therapy
• Administration of therapeutic oral or IV antibiotics within 2 weeks prior to therapy
• Eastern Cooperative Oncology Group (ECOG) performance status ≥2
• Combination therapy
  -  Coadministration with bevacizumab, paclitaxel and carboplatin in metastatic non-squamous non-small cell lung cancer (4-drug regimen)
  - Coadministration with nab-paclitaxel in metastatic TNBC
  - Coadministration with bevacizumab, paclitaxel and carboplatin
  - Coadministration with bevacizumab, paclitaxel and carboplatin in EGFR+ patients with NSCLC who have progressed on erlotinib+bevacizumab
  - Coadministration with bevacizumab in hepatocellular carcinoma
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Severe renal impairment
• Moderate to severe hepatic impairment
• Females of reproductive potential
• Autoimmune diseases
• Diabetes mellitus
• Fructose intolerance
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

 Forms avail. in SA and covered in this monograph: inf

Dosages below include:

• International manufacturer recommendations
• South African manufacturer recommendations

International manufacturer recommendations

Used for the treatment of

Locally advanced or metastatic urothelial carcinoma (UC)
- After prior platinum-containing chemotherapy
- In those who are considered cisplatin ineligible, and whose tumours have a PD-L1 expression ≥5%
Metastatic non-squamous non-small cell lung cancer (NSCLC) - (Additional agents required)
- First line treatment of metastatic NSCLC
- In patients with EGFR mutant or ALK-positive NSCLC, after failure of appropriate targeted therapies
- First-line treatment in patients who do not have EGFR mutant or ALK-positive NSCLC
Metastatic non-small cell lung cancer (NSCLC) - (Monotherapy)
- First-line treatment of patients whose tumours have a PD-L1 expression ≥50% tumour cells (TC) or ≥10% tumour-infiltrating immune cells (IC) and who do not have EGFR mutant or ALK-positive NSCLC
Locally advanced or metastatic NSCLC
- After prior chemotherapy
Small cell lung cancer - (Additional agents required)
- First-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC)
Hepatocellular carcinoma - (Additional agent required)
- Advanced or unresectable hepatocellular carcinoma (HCC) who have not received prior systemic therapy
Unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) (Additional agent required)
- In patients with tumours that have PD-L1 expression ≥1% and who have not received prior chemotherapy for metastatic disease

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Consult specialist for dosages and regimens

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South African manufacturer recommendations

Used for the treatment of

Locally advanced or metastatic urothelial carcinoma (UC)
- After platinum-containing chemotherapy
- In those who are considered cisplatin ineligible, and whose tumours have a PD-L1 expression ≥5%
Metastatic non-squamous non-small cell lung cancer (NSCLC) - (Additional agents required)
- First line treatment of metastatic NSCLC
- In patients with EGFR mutant or ALK genomic tumour aberrations, after receiving targeted therapy, if clinically indicated, before receiving atezolizumab
- First-line treatment in patients who do not have EGFR mutant or ALK genomic tumour aberrations
Locally advanced or metastatic NSCLC
- After prior chemotherapy
Small cell lung cancer - (Additional agents required)
- First-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC)
Triple-negative breast cancer (TNBC) - (Additional agent required)
- In patients with unresectable locally advanced or metastatic TNBC whose tumours express PD-L1 ≥1%, and who have not been given chemotherapy for metastasis

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• 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
• Women of childbearing potential have to use effective contraception during and for 5 months after treatment with atezolizumab

South African manufacturer recommendations

• Contraindicated
• Atezolizumab is contraindicated for use during pregnancy
• Based on the mechanism of action, the use of atezolizumab may cause foetal harm. Animal studies have demonstrated that inhibition of the PD-L1/PD-1 pathway can lead to increased immune-related rejection of the developing foetus resulting in foetal death
• Female patients of childbearing potential should use highly effective contraception and take active measures to avoid pregnancy while undergoing atezolizumab treatment and for at least 5 months after the last dose

Breastfeeding

International manufacturer recommendations

• Caution; not recommended
• 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 breastfeeding or to discontinue atezolizumab therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

South African manufacturer recommendations

• Contraindicated
• Women receiving atezolizumab must not breastfeed their infants, or for 5 months after the last dose. Monoclonal antibodies, such as atezolizumab, are secreted in milk and may harm the infant

Fertility

International manufacturer recommendations

• 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

South African manufacturer recommendations

• Based on animal studies, atezolizumab may impair fertility in females of reproductive potential while receiving treatment

Renal Impairment

International manufacturer recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  Data from patients with severe renal impairment are too limited to draw conclusions on this population

South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no dose adjustment recommended
  Only a few patients in the population pharmacokinetic analysis had severe renal impairment

Hepatic Impairment

International manufacturer recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; no information available
  Atezolizumab has not been studied in patients with severe hepatic impairment 

South African manufacturer recommendations

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; no information available
  There are no data in patients with moderate or severe hepatic impairment

Elderly

International manufacturer recommendations

• Caution; no dose adjustment recommended
  ≥65 years was associated with an increased risk of developing adverse events in patients receiving atezolizumab in combination with bevacizumab, carboplatin and paclitaxel ⁷
  ≥75 years: Data are too limited to draw conclusions on this population

South African manufacturer recommendations

• No dose adjustment recommended
• Based on a population pharmacokinetic analysis, no dose adjustment of atezolizumab is required in patients ≥65 years of age

Drugs in Sport

• Permitted - No warnings

Asian Patients

International manufacturer recommendations

• Caution; dose adjustment recommended
  Due to increased haematologic toxicities observed in Asian patients in IMpower150, it is recommended that the starting dose of paclitaxel should be 175mg/m² every 3 weeks

Monotherapy

Central Nervous System Disorders

• Headache
• Guillain-Barré syndrome
  - Demyelinating polyneuropathy
• Meningoencephalitis
  - Encephalitis
  - Meningitis
  - Photophobia
• Myasthenic syndrome
  - Myasthenia gravis
• Fatigue

Cardiovascular Disorders

• Myocarditis
  - Autoimmune myocarditis
• Hypotension

Respiratory Disorders

• Cough
• Dyspnoea
• Pneumonitis
  - Lung infiltration
  - Bronchiolitis
  - Immune-related pneumonitis
  - Interstitial lung disease
  - Lung opacity
  - Pulmonary toxicity
  - Radiation pneumonitis
• Hypoxia
  - Decreased oxygen saturation
  - Decreased pO2
• Nasal congestion
• Nasopharyngitis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
  - Defaecation urgency
  - Frequent bowel movements
  - Haemorrhagic diarrhoea
  - Gastrointestinal hypermotility
• Abdominal pain
• Colitis
  - Autoimmune colitis
  - Ischaemic colitis
  - Ulcerative colitis
  - Microscopic colitis
  - Immune-related enterocolitis
• Dysphagia
• Oropharyngeal pain
  - Oropharyngeal discomfort
  - Throat irritation
• Pancreatitis
  - Autoimmune pancreatitis
  - Acute pancreatitis
  - Increased lipase
  - Increased amylase

Hepatobiliary Disorders

• Increased aspartate aminotransferase
• Increased alanine aminotransferase
• Hepatitis
  - Ascites
  - Autoimmune hepatitis
  - Hepatocellular injury
  - Acute hepatitis
  - Hepatotoxicity
  - Hepatic disorders
  - Drug-induced liver injury
  - Hepatic failure
  - Hepatic steatosis
  - Hepatic lesion
  - Oesophageal varices haemorrhage

Genitourinary Disorders

• Urinary tract infection
  - Cystitis
  - Pyelonephritis
  - Escherichia urinary tract infection
  - Bacterial urinary tract infection
  - Kidney infection
  - Acute pyelonephritis
  - Chronic pyelonephritis
  - Pyelitis
  - Renal abscess
  - Streptococcal urinary tract infection
  - Urethritis
  - Fungal urinary tract infection
  - Pseudomonal urinary tract infection
• Increased blood creatinine
  - Hypercreatininaemia
• Nephritis
  - Autoimmune nephritis
  - Henoch-Schonlein Purpura nephritis
  - Paraneoplastic glomerulonephritis
  - Tubulointerstitial nephritis
• Non-infective cystitis
  - Immune-mediated cystitis

Endocrine and Metabolic Disorders

• Hypothyroidism
  - Autoimmune thyroiditis
  - Abnormal blood thyroid-stimulating hormone
  - Decreased blood thyroid-stimulating hormone
  - Increased blood thyroid-stimulating hormone
  - Euthyroid sick syndrome
  - Goitre
  - Immune-related hypothyroidism
  - Myxedema
  - Myxedema coma
  - Thyroid disorder
  - Abnormal thyroid function test
  - Thyroiditis
  - Acute thyroiditis
  - Decreased thyroxine
  - Decreased thyroxine free
  - Increased thyroxine free
  - Increased thyroxine
  - Decreased tri-iodothyronine
  - Abnormal tri-iodothyronine free
  - Decreased tri-iodothyronine free
  - Increased tri-iodothyronine free
  - Silent thyroiditis
  - Chronic thyroiditis
• Hyperthyroidism
  - Basedow's disease
  - Endocrine ophthalmopathy
  - Exophthalmos
• Diabetes mellitus
  - Type 1 diabetes mellitus
  - Diabetic ketoacidosis
  - Ketoacidosis
• Adrenal insufficiency
  - Glucocorticoid deficiency
  - Primary adrenal insufficiency
• Hypophysitis
  - Temperature regulation disorders
• Decreased appetite
• Hypokalaemia
• Hyponatraemia
• Hyperglycaemia

Musculoskeletal Disorders

• Arthralgia
• Back pain
• Musculoskeletal pain
  - Myalgia
  - Bone pain
• Myositis
  - Rhabdomyolysis
  - Polymyalgia rheumatica
  - Dermatomyositis
  - Muscle abscess
  - Myoglobin urine present

Skin and Subcutaneous Tissue Disorders

• Rash
  - Acne
  - Pustular acne
  - Blister
  - Blood blister
  - Dermatitis
  - Acneiform dermatitis
  - Allergic dermatitis
  - Exfoliative dermatitis
  - Drug eruption
  - Eczema
  - Infected eczema
  - Erythema
  - Erythema of eyelid
  - Eyelid rash
  - Fixed eruption
  - Folliculitis
  - Furuncle
  - Hand dermatitis
  - Lip blister
  - Oral blood blister
  - Palmar-plantar erythrodysaesthesia syndrome
  - Erythematous rash
  - Follicular rash
  - Generalised rash
  - Macular rash
  - Macular-papular rash
  - Papular rash
  - Papulosquamous rash
  - Pruritic rash
  - Pustular rash
  - Vesicular rash
  - Scrotal dermatitis
  - Seborrhoeic dermatitis
  - Skin exfoliation
  - Skin toxicity
  - Skin ulcer
• Pruritus
• Dry skin
• Psoriasis
• Severe cutaneous adverse reactions
  - Bullous dermatitis
  - Exfoliative rash
  - Erythema multiforme
  - Generalised exfoliative dermatitis
  - Toxic skin eruption
  - Stevens-Johnson syndrome
  - Drug reaction with eosinophilia and systemic symptoms
  - Toxic epidermal necrolysis
  - Cutaneous vasculitis
• Pemphigoid

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
  - Decreased platelet count
• Infusion-related reaction
  - Cytokine release syndrome
  - Hypersensitivity
  - Anaphylaxis
• Fever
• Chills
• Influenza-like illness

Sensory Disorders

• Uveitis

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Combination therapy

Central Nervous System Disorders

• Headache
• Peripheral neuropathy
  - Autoimmune neuropathy
  - Peripheral sensory neuropathy
  - Polyneuropathy
  - Herpes zoster
  - Peripheral motor neuropathy
  - Neuralgic amyotrophy
  - Peripheral sensor
  - Axonal neuropathy
  - Lumbosacral plexopathy
  - Neuropathic arthropathy
  - Peripheral nerve infection
• Syncope
• Dizziness
• Fatigue

Cardiovascular Disorders

• Hypertension
  - Increased blood pressure
  - Hypertensive crisis
  - Increased systolic blood pressure
  - Diastolic hypertension
  - Inadequately controlled blood pressure
  - Hypertensive retinopathy
  - Hypertensive nephropathy
  - Essential hypertension

Respiratory Disorders

• Lung infection
  - Pneumonia
  - Bronchitis
  - Lung infection
  - Lower respiratory tract infection
  - Infective exacerbation of chronic obstructive pulmonary disease
  - Infectious pleural effusion
  - Tracheobronchitis
  - Atypical pneumonia
  - Lung abscess
  - Paracancerous pneumonia
  - Pyopneumothorax
  - Pleural infection
• Cough
• Dyspnoea
• Dysphonia

Gastrointestinal Disorders

• Constipation
• Stomatitis
• Nausea and vomiting
• Diarrhoea
  - Defaecation urgency
  - Frequent bowel movements
  - Haemorrhagic diarrhoea
  - Gastrointestinal hypermotility

Hepatobiliary Disorders

• Increased blood alkaline phosphatase
• Increased aspartate aminotransferase
• Increased alanine aminotransferase

Genitourinary Disorders

• Urinary tract infection
  - Cystitis
  - Pyelonephritis
  - Escherichia urinary tract infection
  - Bacterial urinary tract infection
  - Kidney infection
  - Acute pyelonephritis
  - Chronic pyelonephritis
  - Pyelitis
  - Renal abscess
  - Streptococcal urinary tract infection
  - Urethritis
  - Fungal urinary tract infection
  - Pseudomonal urinary tract infection
• Proteinuria
  - Protein urine present
  - Haemoglobinurea
  - Urine abnormality
  - Nephrotic syndrome
  - Albuminuria
• Increased blood creatinine
  - Hypercreatininaemia

Endocrine and Metabolic Disorders

• Hypothyroidism
  - Autoimmune thyroiditis
  - Abnormal blood thyroid-stimulating hormone
  - Decreased blood thyroid-stimulating hormone
  - Increased blood thyroid-stimulating hormone
  - Euthyroid sick syndrome
  - Goitre
  - Immune-related hypothyroidism
  - Myxedema
  - Myxedema coma
  - Thyroid disorders
  - Abnormal thyroid function test
  - Thyroiditis
  - Acute thyroiditis
  - Decreased thyroxine
  - Decreased thyroxine free
  - Increased thyroxine free
  - Increased thyroxine
  - Decreased tri-iodothyronine
  - Abnormal tri-iodothyronine free
  - Decreased tri-iodothyronine free
  - Increased tri-iodothyronine free
  - Silent thyroiditis
  - Chronic thyroiditis
• Hyperthyroidism
  - Basedow's disease
  - Endocrine ophthalmopathy
  - Exophthalmos
• Decreased appetite
• Hypokalaemia
• Hyponatraemia
• Hypomagnesaemia

Musculoskeletal Disorders

• Arthralgia
• Back pain
• Musculoskeletal pain
  - Myalgia
  - Bone pain

Skin and Subcutaneous Tissue Disorders

• Rash
  - Acne
  - Pustular acne
  - Blister
  - Blood blister
  - Dermatitis
  - Acneiform dermatitis
  - Allergic dermatitis
  - Exfoliative dermatitis
  - Drug eruption
  - Eczema
  - Infected eczema
  - Erythema
  - Erythema of eyelid
  - Eyelid rash
  - Fixed eruption
  - Folliculitis
  - Furuncle
  - Hand dermatitis
  - Lip blister
  - Oral blood blister
  - Palmar-plantar erythrodysaesthesia syndrome
  - Erythematous rash
  - Follicular rash
  - Generalised rash
  - Macular rash
  - Macular-papular rash
  - Papular rash
  - Papulosquamous rash
  - Pruritic rash
  - Pustular rash
  - Vesicular rash
  - Scrotal dermatitis
  - Seborrhoeic dermatitis
  - Skin exfoliation
  - Skin toxicity
  - Skin ulcer
• Pruritus
• Alopecia
  - Madarosis
  - Alopecia areata
  - Alopecia totalis
  - Hypotrichosis
• Psoriasis
• Severe cutaneous adverse reactions
  - Bullous dermatitis
  - Exfoliative rash
  - Erythema multiforme
  - Generalised exfoliative dermatitis
  - Toxic skin eruption
  - Stevens-Johnson syndrome
  - Drug reaction with eosinophilia and systemic symptoms
  - Toxic epidermal necrolysis
  - Cutaneous vasculitis
• Pemphigoid

Immune, Blood and Lymphatic System Disorders

• Sepsis
  - Septic shock
  - Urosepsis
  - Neutropenic sepsis
  - Pulmonary sepsis
  - Bacterial sepsis
  - Klebsiella sepsis
  - Abdominal sepsis
  - Candida sepsis
  - Escherichia sepsis
  - Pseudomonal sepsis
  - Staphylococcal sepsis
• Anaemia
• Thrombocytopenia
  - Decreased platelet count
• Neutropenia
  - Decreased neutrophil count
  - Febrile neutropenia
  - Neutropenic sepsis
  - Granulocytopenia
• Leukopenia
  - Decreased white blood cell count
• Lymphopenia
  - Decreased lymphocyte count
• Infusion-related reaction
  - Cytokine release syndrome
  - Hypersensitivity
  - Anaphylaxis
• Fever
• Peripheral oedema

Sensory Disorders

• Dysgeusia

• Systemic corticosteroids (before initiation of atezolizumab)
• Immunosuppressants (before initiation of atezolizumab)
  See additional prescribing points

• Hepatic function
  - Bilirubin
• Renal function
  - Serum creatinine
• Thyroid function
• Hepatitis B virus (HBV) screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Specific cases may require

• PD-L1 expression status
• BRAF V600 mutation status
• Serum glucose
• Pregnancy status

Additional observations

• Signs and symptoms of immune-mediated adverse reactions
  - Colitis
  - Diarrhoea
  - Endocrinopathies (adrenal insufficiency, diabetes, hypophysitis, thyroid disorders)
  - Hepatitis
  - Cardiovascular toxicity (myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis)
  - Myositis
  - Pneumonitis
  - Dermatologic toxicity
  - Ocular toxicity
• Signs and symptoms of infusion-related reactions
• Signs and symptoms of transplant-related complications

Traceability

• 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

Administration directions

• Atezolizumab is for intravenous use. The infusions must not be administered as an intravenous push or bolus
• The initial dose of atezolizumab must be administered over 60mins. If the first infusion is well tolerated, all subsequent infusions may be administered over 30mins
• Atezolizumab does not contain any antimicrobial preservative or bacteriostatic agents and should be prepared by a healthcare professional using aseptic technique to ensure the sterility of prepared solutions. Use a sterile needle and syringe to prepare atezolizumab

Aseptic preparation, handling and storage

- Aseptic handling must be ensured when preparing the infusion. Preparation should be:

• Performed under aseptic conditions by trained personnel in accordance with good practice rules especially with respect to the aseptic preparation of parenteral products
• Prepared in a laminar flow hood or biological safety cabinet using standard precautions for the safe handling of intravenous agents
• Followed by adequate storage of the prepared solution for intravenous infusion to ensure maintenance of the aseptic conditions
• Do not shake

Instructions for dilution

- 840mg concentrate for solution for infusion

• For the recommended dose of 840mg: 14ml of atezolizumab concentrate should be withdrawn from the vial and diluted into a polyvinyl chloride (PVC), polyolefin (PO), polyethylene (PE), or polypropylene (PP) infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection
• For the recommended dose of 1680mg: 28ml of atezolizumab concentrate should be withdrawn from two vials of atezolizumab 840mg and diluted into a polyvinyl chloride (PVC), polyolefin (PO), polyethylene (PE), or polypropylene (PP) infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection

-1200mg concentrate for solution for infusion

• 20ml of atezolizumab concentrate should be withdrawn from the vial and diluted into a polyvinyl chloride (PVC), polyolefin (PO), polyethylene (PE) or polypropylene (PP) infusion bag containing sodium chloride 9mg/ml (0.9%) solution for injection

- For all formulations

• After dilution, the final concentration of the diluted solution should be between 3.2 and 16.8mg/ml
• The bag should be gently inverted to mix the solution in order to avoid foaming. Once the infusion is prepared it should be administered immediately
• Parenteral medicinal products should be inspected visually for particulates and discolouration prior to administration. If particulates or discoloration are observed, the solution should not be used
• No incompatibilities have been observed between atezolizumab and intravenous bags with product-contacting surfaces of polyvinyl chloride (PVC), polyolefin (PO), polyethylene (PE), or polypropylene (PP)
• In addition, no incompatibilities have been observed with in-line filter membranes composed of polyethersulfone or polysulfone, and infusion sets and other infusion aids composed of PVC, PE, polybutadiene, or polyetherurethane. The use of in-line filter membranes is optional
• Do not coadminister other medicinal products through the same infusion line

Use of atezolizumab with systemic corticosteroids and immunosuppressants

• 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

Delayed or missed doses

• If a planned dose of atezolizumab is missed, it should be administered as soon as possible. The schedule of administration must be adjusted to maintain a 3 week interval between doses

Dose modifications during treatment

• Dose reductions of atezolizumab are not recommended

Dose modification advice for atezolizumab

Immune-related adverse reaction	Severity	Treatment modification
Pneumonitis	Grade 2	Withhold atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 3 or 4	Permanently discontinue atezolizumab
Hepatitis in patients without HCC	Grade 2: (ALT or AST >3 to 5 x upper limit of normal [ULN] or blood bilirubin >1.5 to 3 x ULN)	Withhold atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 3 or 4: (ALT or AST >5 x ULN or blood bilirubin >3 x ULN)	Permanently discontinue atezolizumab
Hepatitis in patients with HCC	If AST/ALT is within normal limits at baseline and increases to >3x to ≤10x ULN or If AST/ALT is >1 to ≤3x ULN at baseline and increases to >5x to ≤10x ULN or If AST/ALT is >3x to ≤5x ULN at baseline and increases to >8x to ≤10x ULN	Withhold atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	If AST/ALT increases to >10x ULN or total bilirubin increases to >3x ULN	Permanently discontinue atezolizumab
Colitis	Grade 2 or 3: Diarrhoea (increase of ≥4 stools/day over baseline) or Symptomatic colitis	Withhold atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 4: Diarrhoea or Colitis (life-threatening; urgent intervention indicated)	Permanently discontinue atezolizumab
Hypothyroidism or hyperthyroidism	Symptomatic	Withhold atezolizumab Hypothyroidism: Treatment may be resumed when symptoms are controlled by thyroid replacement therapy and TSH levels are decreasing Hyperthyroidism: Treatment may be resumed when symptoms are controlled by anti-thyroid medicinal product and thyroid function is improving
Adrenal insufficiency	Symptomatic	Withhold atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day and patient is stable on replacement therapy
Hypophysitis	Grade 2 or 3	Withhold atezolizumab Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day and patient is stable on replacement therapy
	Grade 4	Permanently discontinue atezolizumab
Type 1 diabetes mellitus	Grade 3 or 4 hyperglycaemia (fasting glucose >250 mg/dL or 13.9 mmol/L)	Withhold atezolizumab Treatment may be resumed when metabolic control is achieved on insulin replacement therapy
Infusion-related reactions	Grade 1 or 2	Reduce infusion rate or interrupt Treatment may be resumed when the event is resolved
	Grade 3 or 4	Permanently discontinue atezolizumab
Rash/Severe cutaneous adverse reactions	Grade 3 or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (Regardless of severity)	Withhold atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 4 or suspected Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (Regardless of severity)	Permanently discontinue atezolizumab
Myasthenic syndrome/myasthenia gravis, Guillain-Barré syndrome and Meningoencephalitis	All Grades	Permanently discontinue atezolizumab
Pancreatitis	Grade 3 or 4 serum amylase or lipase levels increased (>2 x ULN) or Grade 2 or 3 pancreatitis	Withhold atezolizumab Treatment may be resumed when serum amylase and lipase levels improve to Grade 0 or Grade 1 within 12 weeks, or symptoms of pancreatitis have resolved, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 4 or any grade of recurrent pancreatitis	Permanently discontinue atezolizumab
Myocarditis	Grade 2	Withhold atezolizumab Treatment may be resumed when the symptoms improve to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 3 or 4	Permanently discontinue atezolizumab
Nephritis	Grade 2: (creatinine level >1.5 to 3.0 x baseline or >1.5 to 3.0 x ULN)	Withhold atezolizumab Treatment may be resumed when the event improves to Grade 0 or Grade 1 within 12 weeks and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 3 or 4: (creatinine level >3.0 x baseline or >3.0 x ULN)	Permanently discontinue atezolizumab
Myositis	Grade 2 or 3	Withhold atezolizumab
	Grade 4 or grade 3 recurrent myositis	Permanently discontinue atezolizumab
Other immune-related adverse reactions	Grade 2 or Grade 3	Withhold until adverse reactions recovers to Grade 0-1 within 12 weeks, and corticosteroids have been reduced to ≤10mg prednisone or equivalent per day
	Grade 4 or recurrent Grade 3	Permanently discontinue atezolizumab (except endocrinopathies controlled with replacement hormones)

Note: Toxicity grades are in accordance with National Cancer Institute Common Terminology Criteria for Adverse Event Version 4.0 (NCI-CTCAE v.4.)

Atezolizumab is an Fc-engineered, humanised immunoglobulin G1 (IgG1) monoclonal antibody that directly binds to programmed death-ligand 1 (PD-L1) and provides a dual blockade of the PD-1 and B7.1 receptors, releasing PD-L1/PD-1 mediated inhibition of the immune response, including reactivating the antitumour immune response without inducing antibody-dependent cellular cytotoxicity. PD-L1 may be expressed on tumour cells and/or tumour-infiltrating immune cells, and can contribute to the inhibition of the antitumour immune response in the tumour microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production. Atezolizumab spares the PD-L2/PD-1 interaction allowing PD-L2/PD-1 mediated inhibitory signals to persist.

Injection (per vial) 840mg

• Tecentriq (Roche Products) originator

Injection (per vial) 1200mg

• Tecentriq (Roche Products) originator