GEFTINAT吉非替尼片剂说明书全文(中英对照翻译)

GEFTINAT

吉非替尼片剂说明书全文（ 中英对照翻译）

Hepatic Impairment: The influence of hepatic metastases with

elevation Table 1: Demographic and Disease Characteristics INDICATIONS

AND USAGE For the use only of a Cancer Specialist or a Hospital or an

Institution of serum aspartate aminotransferase (AST/SGOT), alkaline

phosphatase, Gefitinib Dose GEFITINAT is indicated as monotherapy for

the treatment of patients GEFTINAT* and bilirubin has been evaluated in

patients with normal (14 patients), 250 mg/day 500 mg/day with locally

advanced or metastatic non-small cell lung cancer after (Gefitinib

Tablets IP) moderately elevated (13 patients) and severely elevated (4

patients) Characteristic N=66(%) N=76(%) failure of both platinum-based

and docetaxel chemotherapies. levels of one or more of these biochemical

parameters. Patients with ------------- ---------------------------------

------ ----------------------- The effectiveness of Gefitinib is based on

objective response rates (see Composition moderately and severely

elevated biochemical liver abnormalities had Age Group CLINICAL

PHARMACOLOGY - Clinical Studies section). There are no Each film coated

tablet contains: Gefitinib IP 250 mg gefitinib pharmacokinetics similar

to individuals without liver 18-64controlled trials demonstrating a

clinical benefit, such as improvement years 43 (65) 43 (57)

abnormalities (see PRECAUTIONS section). in disease-related symptoms or

increased survival. 64-74 years 19 (29) 30 (39) DESCRIPTION Results from

two large, controlled, randomized trials in first- line 75 years and

above 4 (6) 3 (4) GEFTINAT (gefitinib tablets IP) contain 250 mg of

gefitinib IP and are Renal Impairment: No clinical studies were

conducted with Gefitinib in Sex treatment of non-small cell lung cancer

showed no benefit from adding available as reddish brown film-coated

tablets engraved with GEFTINAT patients with severely compromised renal

function (see PRECAUTIONS Male 38 (58) 41 (54) GEFTINAT to doublet,

platinum-based chemotherapy. Therefore, on one side and 250 on another

side tor daily oral administration. section). Gefitinib and its

metabolites are not significantly excreted via GEFTINAT is not indicated

for use in this setting. Female 28 (42) 35(46) Gefitinib is an

anilinoquinazoline with the chemical name 4-Quinazolin the kidney(<4%).

Race amine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3- 4-morpholin]

CONTRAINDICATIONS White 61 (92) 68(89) propoxy]. It has the molecular

formula C22H24C1F4O3,a relative Drug- Drug Interactions: In human liver

microsome studies, gefitinib had Black 1 (2) 2 (3) GEFTINAT is

contraindicated in patients with severe hypersensitivity to molecular

mass of 446.9 and is a white- colored powder. Gefitinib is a no

inhibitory effect on CYPIA2, CYP2C9, and CYP3A4 activities at

Asian/Oriental 1 (2) 2 (3) gefitinib or to any other component of

GEFTINAT. free base. concentrations ranging from 2-5000 ng/ mL. At the

highest concentration Hispanic 0 (0) 3 (4) studied (5000 ng/mL),

gefitinib inhibited CYP2C19 by 24% and WARNINGS Other 3 (5) 1 (1)

CLINICAL PHARMACOLOGY CYP2D6 by 43%. Exposure to metoprolol, a substrate

of CYP2D6, was Pulmonary Toxicity Smoking History Mechanism of Action:

The mechanism of the clinical antitumor action of increased by 30% when

it was given in combination with gefitinib (500 Yes (Previous or current

smoker) 45 (68) 62 (82) Cases of interstitial lung disease (ILD) have

been observed in patients gefitinib is not fully characterized.

Gefitinib inhibits the intracellular mg daily for 28 days) in patients

with solid tumors. Rifampicin, an No (Never smoked) 21 (32) 14 (18)

receiving Gefitinib at an overall incidence of about 1%. Approximately

phosphorylation of numerous tyrosine kinases associated with inducer of

CYP3A4, reduced mean AUC of gefitinib by 85% in healthy Baseline WHO

Performance Status 1/3 of the cases have been fatal. The reported

incidence of ILD was transmembrane cell surface receptors, including the

tyrosine kinases male volunteers (see PRECAUTIONS-Drug Interactions and

DOSAGE about 2% in the Japanese post- marketing experience, about 0.3% in

0 14 (21) 9(12) associated with the epidermal growth factor receptor

(EGFRTK). EGFR AND ADMINISTRATION-Dosage Adjustment sections).

approximately 23,000 patients treated with Gefitinib in a US expanded 1

36 (55) 53(70) is expressed on the cell surface of many normal cells and

cancer cells. Concomitant administration of itraconazole (200 mg QD for

12 days), an access program and about 1% in the studies of first-line

use in NSCLC 2 15 (23) 14 (18) No clinical studies have been performed

that demonstrate a correlation inhibitor of CYP3A4, with gefitinib (250

mg single dose) to healthy Not Recorded 1(2) 0(0) (but with similar

rates in both treatment and placebo groups). Reports between EGFR

receptor expression and response to gefitinib. male volunteers,

increased mean gefitinib AUC by 88% (see Tumor Histology have described

the adverse event as interstitial pneumonia, pneumonitis PRECAUTIONS-

Drug Interactions section). Co-administration of high and alveolitis.

Patients often present with the acute onset of dyspnea, Squamous 9(14)

11 (14) Pharmacokinetics : Gefitinib is absorbed slowly after oral

administration doses of ranitidine with sodium bicarbonate (to maintain

the gastric pH sometimes associated with cough or low-grade fever, often

becoming Adenocarcinoma 47(71) 50 (66) with mean bioavailability of 60%.

Elimination is by metabolism above pH 5.0) reduced mean gefitinib AUC by

44% (see severe within a short time and requiring hospitalization. ILD

has Undifferentiated 6(9) 4 (5) (primarily CYP3A4) and excretion in

feces. The elimination halt-life is PRECAUTIONS-Drug Interactions

section). Large Cell 1 (2) 2(3) occurred in patients who have received

prior radiation therapy (31% of about 48 hours. Daily oral

administration of gefitinib to cancer patients International Normalized

Ratio (INR) elevations and/or bleeding events Squamous and

Adenocarcinoma 3 (5) 7 (9) reported cases), prior chemotherapy (57% of

reported patients), and no resulted in a 2- fold accumulation compared

to single dose have been reported in some patients taking warfarin while

on Gefitinib Not Recorded 0 (0) 2 (3) previous therapy (12% of reported

cases). Patients with concurrent administration. Steady state plasma

concentrations are achieved within therapy. Patients taking warfarin

should be monitored regularly for idiopathic pulmonary fibrosis whose

condition worsens while receiving Current DIsease Status 10 days.

changes in prothrombin time or INR (see PRECAUTIONS-Drug Gefitinib have

been observed to have an increased mortality compared to Locally

Advanced 11 (17) 5 (7) Interactions and ADVERSE REACTIONS sections).

Metastatic 55 (83) 71 (93) those without concurrent idiopathic pulmonary

fibrosis. Absorption and Distribution: ---------------------------------

------ ------------------------------------ In the event of acute onset

or worsening of pulmonary symptoms Gefitinib is slowly absorbed, with

peak plasma levels occurring 3-7 Clinical Studies : Non-Small Cell Lung

Cancer (NSCLC) - A multicenter Table 2 shows tumor response rates and

response duration. The overall (dyspnea, cough, fever), Gefitinib

therapy should be interrupted and a hours after dosing and mean oral

bioavailability of 60%. Bioavailability clinical trial in the United

States evaluated the tumor response rate of prompt investigation of

these symptoms should occur. If interstitial response rate for the 250

and 500 mg doses combined was 10.6% (95% is not significantly altered by

food. Gefitinib is extensively distributed Gefitinib 250 and 500 mg/day

in patients with advanced non-small cell lung disease is confirmed,

Gefitinib should be discontinued and the Cl: 6%, 16.8%). Response rates

appeared to be highly variable in throughout the body with a mean steady

state volume of distribution of lung cancer whose disease had progressed

after at least two prior patient treated appropriately (see PRECAUTIONS-

Information for subgroups of the treated population: 5.1% (4/79) in

males, 17.5% (11/63) 1400L following intravenous administration. In

vitro binding of gefitinib chemotherapy regimens including a platinum

drug and docetaxel. in females, 4.6% (5/108) in previous or current

smokers, 29.4% (10/34) Patients, ADVERSE REACTIONS and DOSAGE AND to

human plasma proteins (serum albumin and al-acid glycoprotein) is

Gefitinib was taken once daily at approximately the same time each day.

in nonsmokers, 12.4% (12/97) with adenocarcinoma histology, and 6.7%

ADMINISTRATION-Dosage Adjustment sections). 90% and is independent of

drug concentrations. Two hundred and sixteen patients received Gefitinib,

102 (47%) and 114 (3/45) with other NSCLC histologies. Similar

differences in response (53%) receiving 250 mg and 500 mg daily doses,

respectively. Study Pregnancy Category D were seen in a multinational

study in patients who had received 1 or 2 Metabolism and Elimination:

Gefitinib undergoes extensive hepatic patient demographics and disease

characteristics are summarized in Gefitinib may cause fetal harm when

administered to a pregnant woman. prior chemotherapy regimens, at least

1 of which was platinum-based. In metabolism in humans, predominantly by

CYP3A4. Three sites of Table 1. Forty-one percent of the patients had

received two prior responders, the median time from diagnosis to study

randomization was A single dose study in rats showed that gefitinib

crosses the placenta biotransformation have been identified: metabolism

of the N-propoxy treatment regimens, 33% three prior treatment regimens,

and 25% four 16.7 months (range 8 to 34 months). after an oral dose of 5

mg/kg (30 mg/m2 , about 1/5 the recommended morpholino-group,

demethylation of the methoxy- substituent on the or more prior treatment

regimens. Effectiveness of Gefitinib as third line human dose on a mg/m2

basis). When pregnant rats were treated with 5 Table 2 : Efficacy

Results quinazoline, and oxidative defluorination of the halogenated

phenyl therapy was determined in the 142 evaluable patients with

documented mg/kg from the beginning of organogenesis to the end of

weaning gave ------------------- ----------------------------------------

---------------- group. Five metabolites were identified in human plasma.

Only disease progression on platinum and docetaxel therapies or who had

had birth, there was a reduction in the number of offspring born alive.

This Avaliable Patients O-desmethyl gefitinib has exposure comparable to

gefitinib. Although unacceptable toxicity on these agents. 250 mg 500 mg

Combined effect was more severe at 20 mg/kg and was accompanied by high

this metabolite has similar EGFR-TK activity to gefitinib in the

isolated (N=66) (N=76) (N=142) neonatal mortality soon after parturition,

In this study a dose of 1 enzyme assay, it had only l/14 of the potency

of gefitinib in one of the Objective Tumor Response 13.6 7.9 10.6 mg/kg

caused no adverse effects. cell- based assays. Rate (%) In rabbits, a

dose of 20 mg/kg/day (240 mg/m2 , about twice the Gefitinib is cleared

primarily by the liver, with total plasma clearance recommended dose in

humans on 1 mg/m2 basis) caused reduced fetal 95% Cl (%) 6.4-24.3 3.0-

16.4 6.0-16.8 and elimination half-life values of 595 mL/min and 48

hours, Median Duration of Objective weight. There are no adequate and

well-controlled studies in pregnant respectively, after intravenous

administration. Excretion is Response(months) 8.9 4.5 7.0 women using

Gefitinib. If Gefitinib is used during pregnancy or if the predominantly

via the feces (86%), with renal elimination of drug and Range (months)

4.6-18.6+ 4.4-7.6 4.4-18.6+ patient becomes pregnant while receiving

this drug, she should be metabolites accounting for less than 4% of the

administered dose. -------------------------------------------------- ---

---------------------- apprised of the potential hazard to the fetus or

potential risk for loss of +=data are ongoing the pregnancy. Special

Populations: In population based data analyses, no relationships Non-

Small Cell Lung Cancer (NSCLC); Studies of First-line Treatment were

identified between predicted steady state trough concentration and in

patient age, body weight, gender, ethnicity or creatinine clearance.

Combination with Chemotherapy- Two large trials were conducted in

Pediatric: There are no pharmacokinetic data in pediatric patients.

chemotherapy-naive patients with stage III and IV non-small cell lung

cancer. Two thousand one hundred thirty patients were randomized to

receive Gefitinib 250 mg daily, Gefitinib 500 mg daily, or placebo in

combination with platinum-based chemotherapy regimens. The

chemotherapies given in these first- line trials were gemcitabine and

cis- platinum (N=1093) or carboplatin and paclitaxel (N=1037). The

addition of Gefitinib did not demonstrate any increase, or trend toward

such an increase, in tumor response rates, time to progression, or

overall survival.

PRECAUTIONS Pregnancy Table 4 - Drug Related Adverse Events 5% at

250 mg OVERDOSAGE Hepatotoxicity Pregnancy Category D (see WARNINGS and

PRECAUTIONS- dose by Worst CTC Grade (n=102) The acute toxicity of

Gefitinib up to 500 mg in clinical studies has Asymptomatic increases in

liver transaminases have been observed in Information for Patients

sections). % of patients been low. In non-clinical studies, a single

dose of 12,000 mg/m2 (about Gefitinib treated patients; therefore,

periodic liver function --------------- ---------------------------------

------ --------------------- 80 times the recommended clinical dose on a

mg/m2 basis) was lethal to (transaminases, bilirubin, and alkaline

phosphatase) testing should be Nursing Mothers Adverse ALL CTC CTC CTC

CTC rats. Half this dose caused no mortality in mice. considered.

Discontinuation of Gefitinib should be considered if changes It is not

known whether Gefitinib is excreted in human milk. Following Event

Grades Grade 1 Grade 2 Grade 3 Grade 4 There is no specific treatment

for an GEFTINAT overdose and possible are severe. oral administration of

carbon-14 labeled gefitinib to rats 14 days ------------------------ ----

----------------------------------- ------------ symptoms of overdose are

not established. However, in phase l clinical postpartum, concentrations

of radioactivity in milk were higher than in Diarrhea 48 41 6 1 0 trials,

a limited number of patients were treated with daily doses of up to

Patients with Hepatic Impairment blood. Levels of gefitinib and its

metabolites were 11-to-19-fold higher Rash 43 39 4 0 0 1000 mg. An

increase in frequency and severity of some adverse In vitro and in vivo

evidence suggest that gefitinib is cleared primarily in milk than in

blood, after oral exposure of lactating rats to a dose of 5 Acne 25 19 6

0 0 reactions was observed, mainly diarrhea and skin rash. Adverse

reactions by the liver. Therefore, gefitinib exposure may be increased

in patients mg/kg. Because many drugs are excreted in human milk and

because of Dry Skin 13 12 1 0 0 associated with overdose should be

treated symptomatically; in with hepatic dysfunction. In patients with

liver metastases and the potential for serious adverse reactions in

nursing infants, women Nausea 13 7 5 1 0 particular, severe diarrhea

should be managed appropriately. moderately to severely elevated

biochemical liver abnormalities, should be advised against breast-

feeding while receiving Gefitinib Vomiting 12 9 2 1 0 however, gefitinib

pharmacokinetics were similar to the therapy. Pruritus 8 7 1 0 0 DOSAGE

AND ADMINISTRATION pharmacokinetics of individuals without liver

abnormalities(see Anorexia 7 3 4 0 0 The recommended daily dose of

GEFITINIB is one 250 mg tablet with CLINICAL PHARMACOLOGY/Pharmaco

kinetics - Special Pediatric Use Asthenia 6 2 2 1 1 or without food.

Higher doses do not give a better response and cause Populations

section). The influence of non-cancer related hepatic Safety and

effectiveness of Gefitinib in pediatric patients have not been ---------

------- -------------------------------------------------- ---------

increased toxicity. impairment on the pharmacokinetics of gefitinib has

not been evaluated. studied. Other adverse events reported at an

incidence of <5% in patients who received either 250 mg or 500 mg as

monotherapy for treatment of Dosage Adjustment Information for Patients

Geriatric Use NSCLC (along with their frequency at the 250 mg

recommended dose) Patients with poorly tolerated diarrhea (sometimes

associated with Patients should be advised to seek medical advice

promptly if they Of the total number of patients participating in trials

of second- and include the following: peripheral edema (2%), amblyopia

(2%), dyspnea dehydration) or skin adverse drug reactions may be

successfully develop third-line Gefitinib treatment of NSCLC, 65% were

aged 64 years or less, (2%), conjunctivitis (1%), vesiculobullous rash

(1%), and mouth managed by providing a brief (up to 14 days) therapy

interruption 1) severe or persistent diarrhea, nausea, anorexia, or

vomiting, as these 30.5% were aged 65 to 74 years, and 5% of patients

were aged 75 years ulceration (1%). followed by reinstatement of me 250

mg daily dose. have sometimes been associated with dehydration; or older.

No differences in safety or efficacy were observed between In the event

of acute onset or worsening of pulmonary symptoms 2) an onset or

worsening of pulmonary symptoms, ie, shortness of breath younger and

older patients. Interstitial Lung Disease (dyspnea, cough, fever),

GEFTINAT therapy should be interrupted and or cough; Cases of

interstitial lung disease (ILD) have been observed in patients a prompt

investigation of these symptoms should occur and appropriate 3) an eye

irritation; or, Patients with Severe Renal Impairment receiving

Gefitinib at an overall incidence of about l%. Approximately treatment

initiated. If interstitial lung disease is confirmed, GEFTINAT 4) any

other new symptom (see WARNINGS- Pulmonary Toxicity, The effect of

severe renal impairment on the pharmacokinetics of 1/3 0f the cases have

been fatal. The reported incidence of ILD was should be discontinued and

the patient treated appropriately (see ADVERSE REACTIONS and DOSAGE AND

gefitinib is not known. Patients with severe renal impairment should be

about 2% in the Japanese post-marketing experience, about 0.3% in

WARNINGS- Pulmonary Toxicity, PRECAUTIONS-Information for

ADMINISTRATION-Dosage Adjustment sections). treated with caution when

given GEFTINAT. approximately 23,000 patients treated with Gefitinib in

a US expanded Patients and ADVERSE REACTIONS sections). Women of

childbearing potential must be advised to avoid becoming access program

and about l% in the studies of first- line use in NSCLC Patients who

develop onset of new eye symptoms such as pain should be pregnant (see

WARNINGS-Pregnancy Category D). ADVERSE REACTIONS (but with similar

rates in both treatment and placebo groups). Reports medically evaluated

and managed appropriately, The safety database includes 941 patients

from clinical trials and have described the adverse event as

interstitial pneumonia, pneumonitis including GEFTINAT therapy

interruption and removal of an aberrant Drug Interactions approximately

23,000 patients in the Expanded Access Program. Table 3 and alveolitis.

Patients often present with the acute onset of dyspnea, eyelash if

present. After symptoms and eye changes have resolved, the Substances

that are inducers of CYP3A4 activity increase the includes drug-related

adverse events with an incidence of 5% for the 216 sometimes associated

with cough or low-grade fever, often becoming decision should be made

concerning reinstatement of the 250 mg daily metabolism of gefitinib and

decrease its plasma concentrations. In patients who received either 250