Osimertinib

Registered South African indications:

• Locally advanced or metastatic non-small cell lung cancer (NSCLC)
• Locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation positive NSCLC

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Coadministration with St. John's wort

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with St. John's wort

Cautions

South African manufacturer recommendations

• Severe renal impairment
  - CrCl <15ml/min (ESRD)
  - On dialysis
• Severe hepatic impairment
• Congenital long QT syndrome
• Congestive heart failure
• Electrolyte abnormalities
• Torsades de pointes
• Polymorphic ventricular tachycardia
• Serious dysrhythmias
• Cardiac risk factors
• Conditions that can affect left ventricular ejection fraction
• Coadministration with agents that are known to prolong the QTc interval

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment
  - CrCl <15ml/min (ESRD)
  - On dialysis
• Severe hepatic impairment
• Elderly
• Past medical history of, drug-induced or any evidence of clinically active interstitial lung disease
• Radiation pneumonitis that required steroid treatment
• Clinically important abnormalities in rhythm and conduction
  - QTc interval >470msec
• Torsades de pointes
• Polymorphic ventricular tachycardia
• Serious arrhythmias
• Congenital long QT syndrome
• Congestive heart failure
• Electrolyte abnormalities
• Cardiac risk factors
• Conditions that can affect left ventricular ejection fraction
• Coadministration with agents that are known to prolong the QTc interval

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

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Used for the treatment of

• Locally advanced or metastatic non-small cell lung cancer (NSCLC)
  - First line treatment in those whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations
• Locally advanced or metastatic epidermal growth factor receptor (EGFR) T790M mutation positive NSCLC
  - Predominantly bronchial adenocarcinoma whose disease has progressed on or after EGFR TKI therapy

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International manufacturer recommendations

Used for the treatment of

• Stage IB-IIIA non-small cell lung cancer (NSCLC)
  - Adjuvant treatment after complete tumour resection in those whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations
• Locally advanced or metastatic NSCLC with activating epidermal growth factor receptor (EGFR) mutations
  - First line treatment
• Locally advanced or metastatic EGFR T790M mutation-positive NSCLC

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

South African manufacturer recommendations

• Contraindicated
• Osimertinib is contraindicated during pregnancy and in women of childbearing potential not using contraception
• Based on its mechanism of action and preclinical data, osimertinib may cause foetal harm when administered to a pregnant woman. Administration of osimertinib to pregnant rats was associated with embryolethality, reduced foetal growth and neonatal death at exposures similar to what is expected in humans
• Women of childbearing potential must avoid becoming pregnant while receiving osimertinib. Patients should be instructed to use effective contraception for the following periods after completion of treatment with osimertinib: at least 6 weeks for females and 4 months for males

International manufacturer recommendations

• Caution; positive evidence of risk in animal studies
• There are no or limited amount of data from the use of osimertinib in pregnant women. Studies in animals have shown reproductive toxicity (embryolethality, reduced foetal growth, and neonatal death). Based on its mechanism of action and preclinical data, osimertinib may cause foetal harm when administered to a pregnant woman. Osimertinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with osimertinib
• Women of childbearing potential should be advised to avoid becoming pregnant while receiving osimertinib. Patients should be advised to use effective contraception for the following periods after completion of treatment with this medicinal product: at least 2 months for females and 4 months for males. A risk for decreased exposure of hormonal contraceptives cannot be excluded

Breastfeeding

South African manufacturer recommendations

• Contraindicated 
• Breastfeeding is contraindicated when taking osimertinib. It is not known whether osimertinib or its metabolites are excreted in human milk
• Administration to rats during early lactation was associated with adverse effects, including reduced growth rates and neonatal death

International manufacturer recommendations

• Caution; not recommended
• It is not known whether osimertinib or its metabolites are excreted in human milk. There is insufficient information on the excretion of osimertinib or its metabolites in animal milk. However, osimertinib and its metabolites were detected in the suckling pups and there were adverse effects on pup growth and survival. A risk to the breastfeeding child cannot be excluded. Breastfeeding should be discontinued during treatment with osimertinib

Fertility

South African manufacturer recommendations

• Results from animal studies have shown that osimertinib has effects on male and female reproductive organs and could impair fertility

International manufacturer recommendations

• There are no data on the effect of osimertinib on human fertility. Results from animal studies have shown that osimertinib has effects on male and female reproductive organs and could impair fertility

Renal Impairment

• CrCl ≥15ml/min: No dose adjustment recommended
• CrCl <15ml/min/ESRD/On dialysis: Caution; no information available

Hepatic Impairment

South African manufacturer recommendations

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended
• Severe (Child-Pugh class C): Caution; no information available

International manufacturer recommendations

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended
• Severe (Child-Pugh class C): Caution; no information available
  - Use in patients with severe hepatic impairment is not recommended

Elderly

South African manufacturer recommendations

• No dose adjustment recommended 

International manufacturer recommendations

• Caution; no dose adjustment recommended
  - Elderly patients (>65 years) or patients with low body weight (<50kg) may be at increased risk of developing adverse events of Grade 3 or higher
  - Close monitoring is recommended in these patients

Drugs in Sport

• Permitted - No warnings 

Cardiovascular Disorders

• Prolonged QTc interval 

Respiratory Disorders

• Interstitial lung disease
  - Pneumonitis
• Epistaxis

Gastrointestinal Disorders

• Diarrhoea
• Stomatitis
  - Mouth ulceration

Skin and Subcutaneous Tissue Disorders

• Rash
  - Generalised rash
  - Erythematous rash
  - Macular rash
  - Maculopapular rash
  - Papular rash
  - Pustular rash
  - Pruritic rash
  - Vesicular rash
  - Follicular rash
  - Erythema
  - Folliculitis
  - Acne
  - Dermatitis
  - Acneiform dermatitis
  - Drug eruption
  - Skin erosion
  - Pustule
• Dry skin
  - Skin fissures
  - Xerosis
  - Eczema
  - Xeroderma
• Paronychia
  - Nail bed disorder
  - Nail bed inflammation
  - Nail bed infection
  - Nail discolouration
  - Nail pigmentation
  - Nail disorder
  - Nail toxicity
  - Nail dystrophy
  - Nail infection
  - Nail ridging
  - Onychalgia
  - Onychoclasis
  - Onycholysis
  - Onychomadesis
  - Onychomalacia
• Pruritus
  - Generalised pruritus
  - Eyelid pruritus
• Palmar-plantar erythrodysaesthesia syndrome
• Alopecia
• Erythema multiforme
• Stevens-Johnson syndrome
• Cutaneous Vasculitis
• Urticaria

Immune, Blood and Lymphatic System Disorders

• Decreased platelet count
• Decreased leucocytes
• Decreased lymphocytes
• Decreased neutrophils
• Increased blood creatinine

Sensory Disorders

• Keratitis
  - Punctate keratitis
  - Corneal erosion
  - Corneal epithelium defect

• Strong CYP3A4 inducers
• Phenytoin
• Rifampicin
• Carbamazepine
• Breast cancer resistant protein (BCRP) substrates
• P-glycoprotein (P-gp) substrates
• Moderate CYP3A4 inducers 
• Bosentan
• Efavirenz
• Etravirine
• Modafinil
• Rosuvastatin
• Hormonal contraceptives
• Digoxin
• Dabigatran
• Aliskiren

Others

• St. John's wort

• Epidermal growth factor receptor (EGFR) mutation status
• T790M EGFR mutation status

Specific cases may require

• Pregnancy test
• Electrocardiogram
• Electrolytes
• Left ventricular ejection fraction
• Cardiac function
• Hepatitis B screening
  - Hepatitis B surface antigen (HBsAg)
  - Hepatitis B core antibody (anti-HBc)
  -  Total Ig or IgG
  - Antibody to hepatitis B surface antigen (anti-HBs)

Additional observations

• Cardiac monitoring
• Signs/ symptoms of:
  - Interstitial lung disease
  - Pneumonitis
  - Dermatologic toxicity
  - Ocular toxicity
  - Gastrointestinal toxicity
• Monitor adherence

Assessment of EGFR mutation status

• When considering the use of osimertinib as adjuvant treatment after complete tumour resection in patients with NSCLC, it is important that the EGFR mutation positive status (exon 19 deletions (Ex19del) or exon 21 L858R substitution mutations (L858R)) indicates treatment eligibility. A validated test should be performed in a clinical laboratory using tumour tissue DNA from biopsy or surgical specimen
• When considering the use of osimertinib as a treatment for locally advanced or metastatic NSCLC, it is important that the EGFR mutation positive status is determined. A validated test should be performed using either tumour DNA derived from a tissue sample or circulating tumour DNA (ctDNA) obtained from a plasma sample
• Only robust, reliable and sensitive tests with demonstrated utility for the determination of EGFR mutation status should be used
• Positive determination of EGFR mutation status (activating EGFR mutations for first-line treatment or T790M mutations following progression on or after EGFR TKI therapy) using either a tissue-based or plasma-based test indicates eligibility for treatment with osimertinib. However, if a plasma-based ctDNA test is used and the result is negative, it is advisable to follow-up with a tissue test wherever possible due to the potential for false negative results using a plasma-based test

Interstitial Lung Disease (ILD)

• Severe, life-threatening or fatal Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) have been observed in patients treated with osimertinib in clinical studies. Most cases improved or resolved with interruption of treatment
• Careful assessment of all patients with an acute onset and/or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD
• Treatment with this medicinal product should be interrupted pending investigation of these symptoms. If ILD is diagnosed, osimertinib should be discontinued and appropriate treatment initiated as necessary
• Reintroduction of osimertinib should be considered only after careful consideration of the individual patient's benefits and risk

QTc interval prolongation

• QTc interval prolongation occurs in patients treated with osimertinib. QTc interval prolongation may lead to an increased risk for ventricular tachyarrhythmias (e.g. torsade de pointes) or sudden death. No arrhythmic events were reported in FLAURA or AURA studies. Patients with clinically important abnormalities in rhythm and conduction as measured by resting electrocardiogram (ECG) (e.g. QTc interval >470ms) were excluded from these studies
• When possible, the use of osimertinib in patients with congenital long QT syndrome should be avoided. Periodic monitoring with electrocardiograms (ECGs) and electrolytes should be considered in patients with congestive heart failure, electrolyte abnormalities, or those who are taking medicinal products that are known to prolong the QTc interval
• Treatment should be withheld in patients who develop a QTc interval >500msec on at least 2 separate ECGs until the QTc interval is <481msec or recovery to baseline if the QTc interval is ≥481 msec, then resume osimertinib at a reduced dose
• Osimertinib should be permanently discontinued in patients who develop QTc interval prolongation in combination with any of the following: Torsade de pointes, polymorphic ventricular tachycardia, signs/symptoms of serious arrhythmia

Osimertinib, a tyrosine kinase inhibitor (TKI), is an irreversible inhibitor of epidermal growth factor receptors (EGFRs) harboring sensitising-mutations (EGFRm) and TKI-resistance mutation T790M.

Tablet 40mg

• Tagrisso (AstraZeneca) originator

Tablet 80mg

• Tagrisso (AstraZeneca) originator