Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Erlotinib is an EGFR-specific tyrosine kinase inhibitor.1 It inhibits EGFR autophosphorylation and therefore EGF- dependent cell proliferation. Erlotinib blocks cell-cycle progression in the G1 phase. Specificity with regard to other tyrosine kinase inhibitors is unknown.2

PHARMACOKINETICS:

SPECIAL PRECAUTIONS:

Contraindications: 4

Erlotinib tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Carcinogenicity: 1,4

Mutagenicity: Not mutagenic in Ames test and mammalian in vitro mutation test.3 Erlotinib is not clastogenic in mammalian in vitro and in vivo chromosome tests.3

Fertility: 1

Animal studies show embryotoxicity, but not impaired fertility, teratogenicity, or abnormal pre- or postnatal physical or behavioural development.

Pregnancy: FDA Pregnancy Category D.4 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding 1

Use with caution 1

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.9

ORGAN SITE	SIDE EFFECT		ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
coagulation	INR elevations, bleeding events			E
constitutional symptoms	fatigue (52%, severe 18%)			E
constitutional symptoms	weight loss (12%) 10			E
dermatology/skin	dry skin (12%)			E
	erythema (18%) 10			E
		hair changes (<1%) 3 ; including hirsutism and eyelash/eyebrow			D
		changes 3			D
		nail changes (<10%) 3 ; including paronychia and brittle and loose				D
		nails 3				D
	pruritis (13%)			E
	rash (75%, severe 9%)			E 1
gastrointestinal	emetogenic potential: rare
gastrointestinal	anorexia (52%, severe 9%)				D

ORGAN SITE	SIDE EFFECT	ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
	diarrhea (54%, severe 7%)		E 1
	dyspepsia (12%) 10		E
	dysphagia (12%) 10		E
	nausea (33%)		E
	stomatitis (17%)		E
hemorrhage	gastrointestinal hemorrhage (2%)		E
hepatic	asymptomatic increases in liver transaminases (1-10%)		E
infection	infection (24%, severe 4%)		E	D
neurology	anxiety (21%) 10		E
	depression (16%) 10		E
	insomnia (12%) 10		E
ocular/visual	conjunctivitis (12%, severe < 1%)		E
ocular/visual	keratoconjunctivitis sicca (12%)		E
pain	arthralgia (14%) 10		E
	headache (17%) 11		E
	dyspnea (41%, severe 28%)		E
	interstitial lung disease (0.6%)		E 1	D 1

Adapted from standard reference1 unless specified otherwise. Rash is the most common side effect of erlotinib therapy. Generally a mild to moderate papulopustular rash, primarily on the face, neck, and upper torso, it usually occurs during the first two weeks of treatment.12 The mechanism is unknown and management is based on anecdotal evidence. General measures should include washing with tepid water and application of emollients.13 Anti-acne or anti-rosacea agents can be started if dry skin is not a concern. Sun exposure should be minimized and/or sun protection should be employed to reduce the incidence of hyperpigmentation. Patients with severe skin reactions may require a dose reduction or temporary interruption of therapy.1 Moderate or severe diarrhea should be treated with loperamide.1 The suggested regimen is 4 mg at first onset, then 2 mg every 2-4 hours until diarrhea-free for 12 hours.12 In some cases, erlotinib dose reduction may be necessary.1 In the event of severe or persistent diarrhea, nausea, anorexia, or vomiting associated with dehydration, erlotinib therapy should be interrupted and appropriate measures should be taken to treat the dehydration. Interstitial lung disease (ILD) is rare, but potentially fatal.1 In one pivotal trial, the incidence of serious ILD was 0.8% in both the erlotinib arm and the placebo arm; the overall incidence is 0.6%. ILD may present 5 days to more than 9 months after initiating erlotinib, and may be diagnosed as pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis, pulmonary fibrosis, acute respiratory distress syndrome, or lung infiltration. Most cases are associated with confounding factors such as prior chemotherapy or radiotherapy, pre-existing lung disease, or pulmonary infections. Erlotinib therapy should be discontinued if ILD is diagnosed, and put on hold if ILD is suspected.

INTERACTIONS:

Erlotinib is a major CYP3A4 substrate and therefore drugs that are CYP3A4 inhibitors (e.g., calcium channel blockers, azole antifungals, macrolide antibiotics, fluoroquinolone antibiotics, and some HIV antivirals) could potentially increase the pharmacological effects of erlotinib.1 Drugs that induce CYP3A4 (e.g., barbiturates, anticonvulsants, glucocorticoids, St. John's Wort, and some HIV antivirals) could potentially decrease the pharmacological effects of erlotinib. Erlotinib is also a minor CYP1A2 substrate.

SUPPLY AND STORAGE:

100 mg or 150 mg film-coated tablets. Store at room temperature. Tablets contain lactose.

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Oral: 150 mg PO once daily1,14 BCCA usual dose noted in bold, italics Take at least one hour before or two hours after the ingestion of food.1 When dose reduction is necessary, the dose should be reduced in 50 mg increments.1

modify according to protocol by which patient is being treated; if no guidelines

Children: Oral: safety and effectiveness in pediatric patients has not been studied4

Interpatient variability	24% higher clearance rate in smokers lower clearance rate associated with increased bilirubin and a 1 -acid glycoprotein no clinically significant differences observed for different body weights
Oral Absorption		pH-dependent solubility 3	; 59% bioavailability
	food may increase bioavailability to almost 100%, 4 but highly variable 5
	time to peak plasma concentration			4 h
Distribution	extensively distributed, including tumour tissues
	cross blood brain barrier?			not fully characterized, but preliminary studies show efficacy in glioblastoma multiforme 6 and malignant glioma 7
	volume of distribution			232 L
	plasma protein binding			95% (albumin and a 1 -acid glycoprotein)
Metabolism	80-95% hepatic metabolism by CYP3A4 also metabolized by hepatic CYP1A2 and pulmonary isoform CYP1A1
	active metabolite(s)			OSI-420 (O-demethylated metabolite) 8
	inactive metabolite(s)			no information found
Excretion	predominantly in bile
	urine			< 9%
	feces			> 90%
	terminal half life			36.2 h
	clearance			4.47 L/h
Gender	no clinically significant differences observed
Elderly	no clinically significant differences observed
Children	no information found
Ethnicity	no clinically significant differences observed

AGENT		EFFECT		MECHANISM		MANAGEMENT
	antacids, H 2		reduced pharmacological		pH-dependent solubility;		avoid concurrent use; for antacids, separate administration by 2 hours
	blockers, or		effect of erlotinib		reduced erlotinib plasma
	proton pump				levels; reduced AUC
	inhibitors 3	(46%) and C max (61%)
		when omeprazole
		administered concurrently
grapefruit or grapefruit juice 1		may increase plasma level of erlotinib		may inhibit CYP3A4 metabolism of erlotinib in the intestinal wall		avoid grapefruit and grapefruit juice
ketoconazole 1		increases plasma levels of erlotinib		inhibits hepatic CYP3A4 metabolism of erlotinib		decrease dose of erlotinib if toxicity is observed; use caution with other CYP3A4 inhibitors
rifampin 1		decreases plasma levels of erlotinib		induces hepatic CYP3A4 metabolism of erlotinib		clinical significance unclear; if possible, consider other treatments without CYP3A4 inducing activity
warfarin 1		may increase INR and bleeding events		unknown		monitor INR and adjust warfarin dose as needed

SYNONYM(S):

COMMON TRADE NAME(S):

CLASSIFICATION: