Erlotinib

Registered South African indications:

• Locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor type 1 (EGFR) activating mutation after failure of at least one prior chemotherapy regimen
• Maintenance treatment after having received first-line platinum-based (other than gemcitabine + cisplatin) doublets chemotherapy for locally advanced or metastatic NSCLC
• Locally advanced or metastatic (stage 4) bronchial adenocarcinoma whose tumours have demonstrated EGFR activating mutations and who have never smoked and had ECOG performance status of 0 – 1
• Locally advanced, unresectable or metastatic pancreatic cancer

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Fertility
• Renal impairment
• Hepatic impairment
• Elderly
• Porphyria
• Smokers
• EGFR mutation status test sensitivity/reliability
• Concomitant or prior chemotherapy
• Prior radiotherapy
• Pre-existing parenchymal lung disease
• Metastatic lung disease
• Pulmonary infections
• Aggravating risk factors for diarrhoea/dehydration
• Pre-existing liver disease
• History of peptic ulcer disease
• History of diverticular disease
• History of keratitis, ulcerative keratitis or severe dry eye
• Concomitant use of contact lenses
• Low expression levels of UGT1A1
• Genetic glucuronidation disorders e.g. Gilbert's disease
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

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

Used for the treatment of

Non-small cell lung cancer (NSCLC)
- Locally advanced or metastatic NSCLC with epidermal growth factor receptor type 1 (EGFR) activating mutation after failure of at least one prior chemotherapy regimen (Erlotinib was not effective after platinum-based therapy that included gemcitabine)
- First-line treatment of patients with locally advanced or metastatic non- small cell lung cancer (NSCLC) with EGFR activating mutations
- Monotherapy for the maintenance treatment of patients having received first-line platinum-based (other than gemcitabine + cisplatin) doublets chemotherapy for locally advanced or metastatic NSCLC
- Switch maintenance treatment in patients with locally advanced or metastatic NSCLC with EGFR activating mutations and stable disease after first-line chemotherapy

In patients with tumours without EGFR activating mutations, erlotinib is indicated when other treatment options are not considered suitable

No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with EGFR-negative tumours

EGFR mutation testing should be performed prior to initiation of erlotinib in chemonaive patients with advanced or metastatic NSCLC and bronchial adenocarcinoma

Bronchial adenocarcinoma
- First-line treatment of patients with locally advanced or metastatic (stage 4) bronchial adenocarcinoma whose tumours have demonstrated EGFR activating mutations and who have never smoked and had ECOG performance status of 0–1

No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with EGFR-negative tumours

EGFR mutation testing should be performed prior to initiation of erlotinib in chemonaive patients with advanced or metastatic NSCLC and bronchial adenocarcinoma

Pancreatic cancer (additional agent required)
- First-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer

No survival advantage could be shown for patients with locally advanced disease

Consult specialist for dosages and regimens

When prescribing erlotinib, factors associated with prolonged survival should be taken into account

Not established for use in children below 18 years

Pregnancy

• Caution
• There are no adequate data for the use of erlotinib in pregnant women. Studies in animals have shown no evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancy can not be excluded as rat and rabbit studies have shown increased embryo/foetal lethality. The potential risk for humans is unknown
• Women of childbearing potential must be advised to avoid pregnancy while on erlotinib. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy
• Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus

Breastfeeding

• Caution, not recommended
• It is not known whether erlotinib is excreted in human milk. No studies have been conducted to assess the impact of erlotinib on milk production or its presence in breast milk. As the potential harm to the breastfeeding infant is unknown, mothers should be advised against breastfeeding while receiving erlotinib and for at least 2 weeks after the final dose

Fertility

• Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on fertility can not be excluded as animal studies have shown effects on reproductive parameters. The potential risk for humans is unknown

Renal Impairment

• Caution; no information available
  Based on pharmacokinetic data no dose adjustments may be necessary for patients with mild or moderate renal impairment
  Use of erlotinib in patients with severe renal impairment is not recommended

Hepatic Impairment

• Mid to moderate: Caution; no dose adjustment recommended
  Dose reduction or interruption of erlotinib should be considered if severe adverse reactions occur
• Severe: Caution; no information available
  Use of erlotinib in patients with severe hepatic dysfunction is not recommended

Elderly

• Caution, no information available

Porphyria Information

• Possibly porphyrinogenic (PSP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Neuropathy
• Headache
• Fatigue
• Cerebral haemorrhage
• Cerebrovascular accidents
• Cerebral infarction
• Ischaemic stroke
• Transient ischaemic attack

Respiratory Disorders

• Dyspnoea
• Cough
• Epistaxis
• Interstitial lung disease (ILD) (including fatalities)
• ILD-like events
  - Pneumonitis
  - Radiation pneumonitis
  - Hypersensitivity pneumonitis
  - Interstitial pneumonia
  - Interstitial lung disease
  - Obliterative bronchiolitis
  - Pulmonary fibrosis
  - Acute Respiratory Distress Syndrome (ARDS)
  - Alveolitis
  - Lung infiltration

Gastrointestinal Disorders

• Diarrhoea (can lead to dehydration, hypokalemia and renal failure including fatalities)
• Nausea and vomiting
• Flatulence
• Dyspepsia
• Stomatitis
• Abdominal pain
• Gastrointestinal bleeding (including fatalities)
• Gastrointestinal perforations (including fatalities)

Hepatobiliary Disorders

• Abnormal liver function tests
  - Increased alanine aminotransferase
  - Increased aspartate aminotransferase
  - Increased bilirubin
• Hepatic failure (including fatalities)

Genitourinary Disorders

• Renal impairment
• Nephritis
• Proteinuria

Endocrine and Metabolic Disorders

• Anorexia
• Decreased weight

Skin and Subcutaneous Tissue Disorders

• Rash
• Dermatitis acneiform
• Alopecia
• Acne/ Dermatitis acneiform
• Paronychia
• Folliculitis
• Skin fissures
• Pruritus
• Dry skin
• Hirsutism
• Eyebrow changes
• Brittle and loose nails
• Mild skin reactions such as hyperpigmentation
• Palmar plantar erythrodysaesthesia syndrome
• Stevens-Johnson syndrome (including fatalities)
• Toxic epidermal necrolysis (including fatalities)
• Severe bullous, blistering or exfoliating conditions

Immune, Blood and Lymphatic System Disorders

• Infection
  - Severe infections, with or without neutropenia
  - Pneumonia
  - Sepsis
  - Cellulitis
• Fever
• Rigors

Sensory Disorders

• Keratoconjunctivitis sicca
• Conjunctivitis
• Keratitis
• Conjunctivitis
• Eyelash changes (in-growing eyelashes, excessive growth and thickening of the eyelashes)
• Corneal perforations
• Corneal ulcerations
• Uveitis
• Eye inflammation
  Lacrimation
• Light sensitivity
• Blurred vision
• Eye pain
• Red eye

• Potent CYP3A4 inhibitors
• Azole antifungals
• Ketoconazole
• Itraconazole
• Voriconazole
• Protease inhibitors
• Erythromycin
• Clarithromycin
• Potent CYP3A4 inducers
• Rifampicin
• Phenytoin
• Carbamazepine
• Barbiturates
• St. John's Wort (Hypericum perforatum)
• CYP3A4 substrates
• CYP2C8 substrates
• Potent CYP1A2 inhibitors
• UGT1A1 substrates
• Coumarin-derived anticoagulants
• Warfarin
• Statins
• P-glycoprotein inhibitors
• Cyclosporine
• Verapamil
• Proton pump inhibitors
• Omeprazole
• H2-receptor antagonists
• Ranitidine
• Antacids
• Capecitabine
• Proteasome inhibitors
• Bortezomib
• Nonsteroidal anti-inflammatory drugs
• Corticosteroids
• Anti-angiogenic agents
• Taxane based chemotherapy
• Ciprofloxacin
• Fluvoxamine
• Midazolam
• Hepatotoxic medications
• Cigarette smoking

• Renal function
• Hepatic function
• Ophthalmic examination

Specific cases may require

• Electrolytes
• Prothrombin time
• International normalized ratio

Tyrosine kinase inhibitors (TKI) and cerebrovascular adverse events safety concern:

• TKI containing medicines may have different kinase inhibition profiles and/or off target binding profiles, with some TKIs approved for very similar indications and others approved for different indications
• Although many adverse events/side effects/toxicities could not be explained by a class related adverse event or a related off-target kinase inhibition effect, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events
• The abovementioned cerebrovascular adverse events may occur in patients on treatment with TKI containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs
• Patients on treatment with TKI containing medicine should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events
• Treatment with TKI containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class related cerebrovascular adverse events

Erlotinib is an epidermal growth factor receptor/human epidermal growth factor receptor type 1 (EGFR also known as HER1) tyrosine kinase inhibitor. Erlotinib potently inhibits the intracellular phosphorylation of EGFR. EGFR is expressed on the cell surface of normal cells and cancer cells. In non-clinical models, inhibition of EGFR phosphotyrosine results in cell stasis and/or death.

EGFR mutations may lead to constitutive activation of anti-apoptotic and proliferation of signalling pathways. The potent effectiveness of erlotinib in blocking EGFR-mediated signalling in these EGFR mutation positive tumours is attributed to the tight binding of erlotinib to the ATP-binding site in the mutated kinase domain of the EGFR. Due to the blocking of downstream-signalling, the proliferation of cells is stopped, and cell death is induced through the intrinsic apoptotic pathway. Tumour regression is observed in mouse models of enforced expression of these EGFR activating mutations.

Tablet 25mg

• Erlocip 25 (Cipla Medpro)
• Tarceva (Roche) originator
• Tarpib 25mg (Eurolab)
• Telonta 25mg (Teva Pharmaceuticals)

Tablet 100mg

• Ercyta 100 (Abex Pharmaceutica)
• Erlocip 100 fct (Xixia Pharmaceuticals)
• Tarceva (Roche) originator
• Tarpib 100mg (Eurolab)
• Telonta 100mg (Teva Pharmaceuticals)
• Terlot 100 (Abex Pharmaceutica)

Tablet 150mg

• Ercyta 150 ( Xixia Pharmaceuticals)
• Erlocip 150 (Cipla Medpro)
• Tarceva (Roche) originator
• Tarpib 150mg (Eurolab)
• Telonta 150mg (Teva Pharmaceuticals)
• Terlot 150 (Abex Pharmaceutica)