SYNONYM(S):

ZD1839

COMMON TRADE NAME(S):

IRESSA(r)

CLASSIFICATION:

epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor

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

MECHANISM OF ACTION:

Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TK). It binds to ATP and prevents autophosphorylation and kinase activation. This results in inhibition of proliferation and angiogenesis, and induction of apoptosis.

1-3

PHARMACOKINETICS:

Interpatient variability 54% for steady state trough concentration
Oral Absorption 60% bioavailability; not significantly altered by food; bioavailability reduced by 47% when gastric pH >5
time to peak plasma concentration 3 - 7 h
Distribution extensively distributed
cross blood brain barrier no information found
volume of distribution 1400 - 1600 L
plasma protein binding 90% (serum albumin and a 1 -acid glycoprotein) ; not concentration dependent
Metabolism extensive hepatic metabolism via CYP3A4
active metabolite(s) O-desmethyl gefitinib (1/14 the potency of gefitinib)
inactive metabolite(s) yes
Excretion fecal and urinary excretion
urine <4%
feces 86% 3
terminal half life 30.5 - 41 h
clearance 500 mL/min
Gender no information found
Elderly no clinically significant difference
Children no information found
Ethnicity no information found

Adapted from standard reference1 unless specified otherwise.

USES:

Primary uses: Other uses:

*Lung cancer, non-small cell1-3 Head and neck4

*Health Canada approved indication

February 2006

SPECIAL PRECAUTIONS:

Use with caution in patients with hepatic impairment,1,3 idiopathic pulmonary fibrosis,1,3 and those at risk for QT interval prolongation.1 Gefitinib is cleared primarily by the liver; therefore, gefitinib exposure may be increased in patients with hepatic dysfunction. However, it was shown that following gefitinib 250 mg daily in patients with moderate to severe hepatic dysfunction due to liver metastases, gefitinib pharmacokinetics (time to steady state, total plasma clearance or steady state concentration) were similar for the groups with normal and impaired hepatic function.1 The influence of non-cancer related hepatic impairment (due to cirrhosis or hepatitis) on the pharmacokinetics of gefitinib has not been evaluated.1

Carcinogenicity: 1,3

Carcinogenicity studies have not been conducted with gefitinib.

Mutagenicity: Not mutagenic in mammalian in vitro mutation test. Not clastogenic in mammalian in vitro and in vivo chromosome tests.1

Fertility: 1

Animal studies have shown a reduction in female fertility at a dose of 20 mg/kg/day.

Pregnancy: FDA Pregnancy Category D.2,3 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

is not recommended. Animal studies have shown levels of gefitinib and its metabolites were 11- to 19-fold higher in milk than in blood.

SIDE EFFECTS:

ORGAN SITE SIDE EFFECT ONSET
Dose-limiting 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)
blood/bone marrow febrile neutropenia thrombocytopenia (severe 1%) E
cardiovascular (arrhythmia) atrial fibrillation (severe 1%) E
bundle branch block (severe 1%) E
QT prolongation E
cardiovascular (general) angioedema (<0.01%) I
peripheral edema (severe 1%) E
constitutional symptoms weight loss (2-3%) E
dermatology/skin acne (13-25%, severe 0%) E
alopecia (1-10%) D
dry skin (13-27%) E
epidermal necrolysis (<0.1%) D
erythema multiforme (<0.1%) D
exfoliative dermatitis (4-8%,severe 0%) E
nail disorder (4%, severe 0%) E
pruritus (8-30%, severe 0%) E
rash (43-47%, severe 1%) E

February 2006

ORGAN SITE SIDE EFFECT ONSET
Dose-limiting 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)
seborrhea (6%, severe 1%) E
urticaria (<0.01%) I
gastrointestinal emetogenic potential: low moderate
anorexia (7-9%, severe 0%) E
constipation (severe 1%) E
dehydration (1-10%, severe 1%) E
diarrhea (40-48%, severe 1%) E
mouth ulceration (1%) 3 E
nausea (13%, severe 1%) E
pancreatitis (<0.1%) E D
rectal disorder (severe 1%) E
stomatitis (8%) E
vomiting (6-12%, severe 1%) E
hemorrhage epistaxis (2%, severe 1%) E
hematuria (6%) E
other sites (rare) E
hepatic alkaline phosphatase increase (severe 1%) E
ALT/SGPT increased (1-13%, severe 1.9%) E
AST/SGOT increased (1-11%, severe 0% ) E
musculoskeletal asthenia (6-8%, severe 1%) E
ocular/visual blepharitis (1-5%) E
conjunctivitis (1-4%) E
corneal erosion (<1%) D L
pain abdominal pain (3%) E
pain (2-10%) E
pulmonary dyspnea (severe 1%) E
interstitial lung disease (0.3 -2%) I E
renal/genitourinary scrotal edema (severe 1%) E

Adapted from references1,3 unless specified otherwise. Interstitial lung disease (ILD) is rare (0.3 - 2%), but potentially fatal.1-3 Patients often present with acute onset of dyspnea, at times accompanied by cough or low-grade fever, usually becoming severe within a short time and requiring hospitalization.1-3 Risk factors of fatal outcome from ILD include concurrent idiopathic pulmonary fibrosis/interstitial pneumonitis/pneumoconiosis/ radiation pneumonitis/drug-induced pneumonitis.1 Management of confirmed ILD includes discontinuation of gefitinib.1-3 QT interval prolongation has been observed.1 The clinical significance of these findings is not clear. Caution is advised when using gefitinib, especially in patients:1

February 2006

known to be at risk of developing QT interval prolongation (e.g. hypokalemia, hypomagnesemia, bundle branch block, sinus node dysfunction) co-administered drugs known to induce QT interval prolongation co-administered drugs known to inhibit gefitinib metabolism with a known baseline QT interval >460 msec

Asymptomatic increases in liver transaminases 1,3

have been observed in gefitinib-treated patients; therefore, periodic liver function testing is recommended. Caution is advised when using gefitinib in the presence of mild to moderate increases in liver transaminases. Discontinuation should be considered if changes are severe.

General intolerance:

poorly tolerated diarrhea or skin reactions

: may be managed with a brief (up to 14 days) interruption of therapy. Reinstate the 250 mg daily dose once toxicity has resolved.

1-3

ocular symptoms

: should have therapy interrupted and symptoms evaluated. Consider reinstating the 250 mg daily dose once toxicity has resolved.

1-3

acute onset or worsening of respiratory symptoms

: should have gefitinib therapy interrupted and prompt investigation initiated. If interstitial lung disease is confirmed, discontinue gefitinib.

1-3

INTERACTIONS:

AGENT EFFECT MECHANISM MANAGEMENT
grapefruit or grapefruit may increase plasma level may inhibit CYP3A4 avoid grapefruit and
juice of gefitinib metabolism of gefitinib in grapefruit juice
the intestinal wall
histamine H 2 -receptor antagonists (e.g. ranitidine, famotidine, cimetidine), proton pump inhibitors may decrease plasma level of gefitinib sustained elevation of gastric pH use with caution
itraconazole 5,6 increases plasma level of inhibits CYP3A4 use with caution
gefitinib metabolism of gefitinib
metoprolol 1 metoprolol level increased by 30 to 35% decrease d CYP2D6 metabolism of metoprolol none (clinically non- significant)
rifampin 5,6 decreases plasma level of induces CYP3A4 an increase in gefitinib
gefitinib metabolism of gefitinib dose has been
suggested 2,3 ; however, the
clinical significance of
doing this is unclear 7
warfarin enhanced anticoagulant effect unknown monitor PT or INR closely

Adapted from reference6 unless specified otherwise.

CYP3A4 inhibitors may decrease metabolism and increase gefitinib plasma concentrations. Concurrent administration of drugs that inhibit CYP3A4 (eg, ketoconazole, clarithromycin, erythromycin, protease inhibitors) may significantly increase exposure to gefitinib.6

CYP3A4 inducers may increase metabolism and decrease gefitinib plasma concentrations. Concurrent administration of drugs that induce CYP3A4 (eg, carbamazepine, phenytoin, barbiturates, St. John's Wort) may significantly reduce exposure to gefitinib.6

SUPPLY AND STORAGE:

Tablets:

250 mg; store at room temperature.

February 2006

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.

Adults: BCCA usual dose noted in bold, italics

Oral: 250 mg PO once daily. May be taken with or without food.

1-3

Dosage in renal failure:

no adjustment required

Dosage in hepatic failure:

no adjustment required for hepatic failure due to liver metastases

severe increases in liver transaminases warrant discontinuation of gefitinib1

Dosage in elderly

no adjustment required

Dosage in dialysis

no information found

References:

  1. AstraZeneca, Canada. Iressa Product Monograph. Mississauga, Ontario; 2003.

  2. McEvoy G, editor. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2004.

  3. AstraZeneca, UK. Iressa Product Insert. Cheshire, England; 2003.

  4. Cohen EE, Rosen F, Stadler WM, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003; 21(10):1980-7.

  5. Swaisland H, Smith R, Farebrother J, et al. The effect of the induction and inhibition of CYP3A4 on the pharmacokinetics of single oral doses of ZD1839 ('Iressa'), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in healthy male volunteers. Proceedings of the American Society of Clinical Oncology 2002; 21:83a (abstract 328).

  6. Repchinsky C, editor. Compendium of Pharmaceuticals and Specialties. Ottawa, Ontario: Canadian Pharmacists Association; 2005.

  7. Nevin Murray, MD. Personal Communication. BC Cancer Agency Lung Tumor Group 2004; 25 October, 2004.