Afatinib Dimaleate

Registered South African indications:

• Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) of adenocarcinoma histology of the lungs (stage IIIB or IV) with Epidermal Growth Factor Receptor mutations(s) Del19 or L858R

Efficacy in EGFR-negative tumours has not been established

• Locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy

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
• Severe hepatic impairment (Child-Pugh Class C)
• Ocular/eye conditions/diseases/disorders with severe impairment of vision/eye sight

Cautions

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment (eGFR <59ml/min/1.73m²)
• Hepatic impairment
  - Severe hepatic impairment (Child-Pugh Class C)
  - Pre-existing liver disease and/or comorbidities associated with progression of underlying malignancy
• Dehydration
• Sun exposure
• EGFR-negative tumours
• Exposure to sunlight
• Female patients
  - Including women of childbearing potential
• Lower body weight 
• History of interstitial lung disease
• History of keratitis, ulcerative keratitis or severe dry eye
• Abnormal left ventricular ejection fraction (LVEF) or those with significant cardiac history thereof
• Cardiac risk factors and those with conditions that can affect LVEF
• Ejection fraction below the institution's lower limit of normal
• Concomitant use of contact lenses
• Risk factors for gastrointestinal perforation:
  - Underlying history of gastrointestinal ulceration
  - Underlying diverticular disease
  - Age
  - Bowel metastases at sites of perforation
  - Coadministration with corticosteroids, nonsteroidal anti-inflammatory drugs, or anti-angiogenic agents
• Coadministration with strong inducers or inhibitors of P-glycoprotein (P-gp) (See additional prescribing points)
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

South African manufacturer recommendations

• Moderate to severe renal impairment (eGFR <59ml/min/1.73m²)
• Mild to moderate hepatic impairment
  - Pre-existing liver disease and/or comorbidities associated with progression of underlying malignancy
• Elderly
• Dehydration
• Sun exposure
• EGFR-negative tumours
• Female patients
  - Including women of childbearing potential
• Lower body weight 
• History of interstitial lung disease
• History of keratitis, ulcerative keratitis or severe dry eye
• Concomitant use of contact lenses
• Abnormal left ventricular ejection fraction (LVEF) or those with significant cardiac history thereof
• Cardiac risk factors and those with conditions that can affect LVEF
• Ejection fraction below the institution's lower limit of normal
• Risk factors for gastrointestinal perforation:
  - Underlying history of gastrointestinal ulceration
  - Underlying diverticular disease
  - Age
  - Bowel metastases at sites of perforation
  - Coadministration with corticosteroids, nonsteroidal anti-inflammatory drugs, or anti-angiogenic agents
• Coadministration with strong inducers or inhibitors of P-glycoprotein (P-gp) (See additional prescribing points)
• Galactose intolerance (e.g. galactosaemia)
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

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

International manufacturer recommendations

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation(s)
Locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy

• Oral (tab): 40mg, dly; Max: 50mg/24hrs

Treatment should be initiated and supervised by a physician experienced in the use of anticancer therapies

A dose escalation to a maximum of 50mg/24hrs may be considered in patients who tolerate a 40mg starting dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE Grade >1) in the first cycle of treatment (21 days for EGFR mutation-positive NSCLC and 28 days for squamous NSCLC). The dose should not be escalated in any patients with a prior dose reduction

See additional prescribing points for recommended dose adjustments for adverse reactions

EGFR mutation status should be established prior to initiation of therapy

Tablets should be swallowed whole with water. If swallowing of whole tablets is not possible, see additional prescribing points for administration instructions

This medicinal product should be taken without food. Food should not be consumed for at least 3hrs before and at least 1hr after taking this medicinal product

Treatment should be continued until disease progression or until no longer tolerated by the patient

South African manufacturer recommendations

Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) of adenocarcinoma histology of the lungs (stage IIIB or IV) with Epidermal Growth Factor Receptor mutations(s) Del19 or L858R
Locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy

• Oral (tab): 40mg, dly; Max: 50mg/24hrs

Efficacy in EGFR-negative tumours has not been established

Treatment with afatinib should be initiated and supervised by a doctor experienced in the use of anticancer therapies

EGFR mutation status should be established prior to initiation of afatinib therapy

Afatinib should be taken without food. Food should not be consumed for at least 3hrs before and at least 1hr after taking afatinib

Afatinib treatment should be continued until disease progression or until no longer tolerated by the patient

A dose escalation to a maximum of 50mg/24hrs may be considered in patients who tolerate a 40mg starting dose (i.e. absence of diarrhoea, skin rash, stomatitis, and other adverse reactions with CTCAE Grade >1) in the first cycle of treatment (21 days for EGFR mutation-positive NSCLC and 28 days for squamous NSCLC). The dose should not be escalated in any patients with a prior dose reduction

Not indicated for use in children

Pregnancy

International manufacturer recommendations

• Caution; not recommended
• Mechanistically, all EGFR targeting medicinal products have the potential to cause foetal harm
• Animal studies with afatinib did not indicate direct or indirect harmful effects with respect to reproductive toxicity. Studies in animals have shown no signs of teratogenicity up to and including maternally lethal dose levels. Adverse changes were restricted to toxic dose levels. However, systemic exposures achieved in animals were either in a similar range or below the levels observed in patients
• There are no or limited amount of data from the use of this medicinal product in pregnant women. The risk for humans is thus unknown. If used during pregnancy or if the patient becomes pregnant while or after receiving afatinib, she should be informed of the potential hazard to the foetus
• As a precautionary measure, women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with afatinib. Adequate contraceptive methods should be used during therapy and for at least 1 month after the last dose

South African manufacturer recommendations

• Contraindicated
• Afatinib should not be used by women who are pregnant or who are planning to become pregnant. Mechanistically, all EGFR targeting medicines, such as afatinib, have the potential to cause foetal harm
• If a patient becomes pregnant while or after receiving afatinib, she should be informed of the potential harm to the foetus
• Afatinib should not be used by women who are pregnant or who are planning to become pregnant. Mechanistically, all EGFR targeting medicines, such as afatinib, have the potential to cause foetal harm
• If a patient becomes pregnant while or after receiving afatinib, she should be informed of the potential harm to the foetus

Breastfeeding

International manufacturer recommendations

• Caution; not recommended
• Available pharmacokinetic data in animals have shown excretion of afatinib in milk. Based on this, it is likely that afatinib is excreted in human milk. A risk to the breastfeeding child cannot be excluded. Mothers should be advised against breastfeeding while receiving this medicinal product

South African manufacturer recommendations

• Contraindicated
• Women on treatment with afatinib should not breastfeed their infants. Afatanib is excreted in milk of animals and it is likely that afatinib is excreted in human milk and harm to the baby cannot be excluded

Fertility

International manufacturer recommendations

• Fertility studies in humans have not been performed with afatinib. Available non-clinical toxicology data have shown effects on reproductive organs at higher doses. Therefore, an adverse effect of this medicinal product on human fertility cannot be excluded

South African manufacturer recommendations

• Non-clinical toxicology data have shown effects on reproductive organs at higher doses. Therefore, an adverse effect of afatinib on human fertility cannot be excluded

Renal Impairment

• Mild (eGFR 60-89ml/min/1.73m²): No dose adjustment recommended
• Moderate to severe (eGFR 15-59ml/min/1.73m²): Caution; no dose adjustment recommended
  Exposure to afatinib was found to be increased in patients with moderate or severe renal impairment
  Although adjustments to the starting dose are not necessary in patients with mild to severe impairment, monitor patients with severe renal impairment (eGFR 15-29 mL/min/1.73m²) and adjust dose if afatinib is not tolerated
• Severe (eGFR <15ml/min/1.73m²) or on dialysis: Use is not recommended

Hepatic Impairment

International manufacturer recommendations

• Mild to moderate (Child-Pugh Classes A & B): Caution; no dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; no information available 
  Afatinib has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); thus treatment in this population is not recommended 

South African manufacturer recommendations

• Mild to moderate (Child-Pugh Classes A & B): Caution; no dose adjustment recommended
• Severe (Child-Pugh Class C): Contraindicated 
  Afatinib has not been studied in patients with severe hepatic impairment (Child-Pugh Class C); thus treatment in this population is not recommended

Elderly

International manufacturer recommendations

• No dose adjustment recommended

South African manufacturer recommendations

• Caution; no information available

Drugs in Sport

• Permitted - No warnings

Respiratory Disorders

• Epistaxis
• Rhinorrhoea
  - Nasal inflammation
• Interstitial lung disease

Gastrointestinal Disorders

• Diarrhoea
• Stomatitis
  - Aphthous stomatitis
  - Mucosal inflammation
  - Mouth ulceration
  - Oral mucosa erosion
  - Mucosal erosion
  - Mucosal ulceration
• Nausea and vomiting
• Dyspepsia
• Cheilitis
• Pancreatitis
• Gastrointestinal perforation

Hepatobiliary Disorders

• Increased alanine aminotransferase
• Increased aspartate aminotransferase

Genitourinary Disorders

• Cystitis
  - Urinary tract infection
• Renal impairment/ renal failure

Endocrine and Metabolic Disorders

• Decreased appetite
• Dehydration
• Hypokalaemia
• Decreased weight

Musculoskeletal Disorders

• Muscle spasms

Skin and Subcutaneous Tissue Disorders

• Paronychia
  - Nail infection
  - Nail bed infection
• Rash
• Dermatitis acneiform
  - Acne
  - Pustular acne
• Pruritus, including generalised pruritus  
• Dry skin
  - Chapped skin
• Palmar-plantar erythrodysaesthesia syndrome
• Nail disorders
  - Onycholysis
  - Nail toxicity
  - Onychoclasis
  - Ingrowing nail
  - Nail pitting
  - Onychomadesis
  - Nail discolouration
  - Nail dystrophy
  - Nail ridging
  - Onychogryphosis
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis

Immune, Blood and Lymphatic System Disorders

• Fever

Sensory Disorders

• Dysgeusia
• Conjunctivitis
• Dry eye
• Keratitis

• Strong P-glycoprotein inhibitors
• Ritonavir
• Ciclosporin A
• Ketoconazole
• Itraconazole
• Erythromycin
• Verapamil
• Quinidine
• Tacrolimus
• Nelfinavir
• Saquinavir
• Amiodarone
• Strong P-glycoprotein inducers
• Rifampicin
• Carbamazepine
• Phenytoin
• Phenobarbital
• Breast cancer resistance protein substrates
• Rosuvastatin
• Sulfasalazine

Other interactions

• St. John's wort 
• Food with a high-fat content

• EGFR mutation status
• Renal function
• Hepatic function
• Hepatitis B virus screening
  - Hepatitis B surface antigen (HBsAg)
  - Hepatitis B core antibody (anti-HBc)
  - Total Ig or IgG and antibody to hepatitis B surface antigen (anti-HBs)  

Specific cases may require

• Left ventricular ejection fraction

Additional observations

• Skin toxicity
• Diarrhoea
• Signs and symptoms of:
  - Dehydration
  - Interstitial lung disease (eg, acute respiratory distress syndrome, allergic alveolitis, lung infiltration, pneumonitis)
  - Keratitis (eg, acute or worsening eye inflammation, blurred vision, eye pain, lacrimation, light sensitivity, red eye)

Dose adjustment for adverse reactions

• Symptomatic adverse reactions (e.g. severe/ persistent diarrhoea or skin related adverse reactions) may be successfully managed by treatment interruption and dose reductions or treatment discontinuation  as outlined below:

*The above adverse events are graded as per the Common Terminology Criteria for Adverse Events (CTCAE)

Method of administration

• This medicinal product is for oral use. The tablets should be swallowed whole with water
• If swallowing of whole tablets is not possible, these can be dispersed in approximately 100ml of non-carbonated drinking water. No other liquids should be used. The tablet should be dropped into the water without crushing it, and stirred occasionally for up to 15min until it is broken up into very small particles. The dispersion should be consumed immediately. The glass should be rinsed with approximately 100ml of water which should also be consumed
• The dispersion can also be administered through a gastric tube

Missed dose

• If a dose is missed, it should be taken within the same day as soon as the patient remembers. However, if the next scheduled dose is due within 8 hours then the missed dose must be skipped

Coadministration with P-glycoprotein (P-gp) inhibitors

• If P-gp inhibitors need to be taken, they should be administered using staggered dosing, i.e. the P-gp inhibitor dose should be taken as far apart in time as possible from the afatinib dose. This means preferably 6 hours (for P-gp inhibitors dosed twice daily) or 12 hours (for P-gp inhibitors dosed once daily) apart from afatinib

Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4.

Tablet 20mg

• Giotrif (Ingelheim Pharmaceuticals) originator

Tablet 30mg

• Giotrif (Ingelheim Pharmaceuticals) originator

Tablet 40mg

• Giotrif (Ingelheim Pharmaceuticals) originator