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易瑞沙说明书
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你可能喜欢易瑞沙（GEFTINAT）英文说明书（前半部分）
GEFTINAT(Gefitinib
Tablets)印度产的易瑞沙
Composition
Each film coated tadlet contains:Gefitinib 250 mg
DESCRIPTION
GEFTINAT (gefitinib tablets) contain 250 mg of gefitinib and are
available as reddish brown film-coated tablets for daily oral
administration. Gefitinib is an anilinoquinazoline with the
chemical name 4-Quinazolinamine, N- (3-chloro-4-fluorophenyl)
-7-methoxy-6- (3-4-morpholin) propoxy]. It has the molecular
formula C22H24C1F4O3, a relative molecular mass of 446.9 and is a
white-colored powder. gefitinib is a free base.
PHARMACOLOGY
Mechanism of Action:
The mechanism of the clinical antitumor action of gefitinib is not
fully characterized. Gefitinib the intracellular phosphorylation of
numerous tyrosine kinases associated with transmembrane cell
surface receptors, including the tyrosine kinases associated with
the epidermal growth factor receptor (EGFR-TK). EGFR is expressed
on the cell surface of many normal cells and cancer. No clinical
studies have been performed that demonstrate a correlation between
EGFR receptor expression and response to gefitinib.
Pharmacokinetics:
Gefitinib is absorbed slowly after oral administration with mean
bioavailability of 60%. Elimination is by metabolism (primarily
CYP3A4) and excretion in feces. The elimination half-life is about
48 hours. Daily oral administration of gefitinib to cancer patients
resulted in 2-fold accumulation compared to single dose
administration. Steady state plasma concentrations are achieved
within 10days.
Absorption and
Distribution:
Gefitinib is slowly absorbed, with peak plasma levels occurring 3-7
hours after dosing and mean oral bioavailability of 60%.
Bioavailability is not significantly altered by food. Gefitinib is
extensively distributed throughout the body with a mean steady
state volume of distribution of 1400 L following intravenous
administration. In vitro binding of gefitinib to human plasma
proteins( serum albumin and a1-acid glycoprotein ) is 90% and is
independent of drug concentrations.
Metabolism and
Elimination:
Gefitinib undergoes extensive hepatic metabolism in humans,
predominantly by CYP3A4.Therr sites of biotransformation have been
identified: metabolism of the N-propoxymorpholino-group,
demethylation of the methoxy-substituent on the quinazoline, and
oxidative defluorination of the halogenated phenyl group. Five
metabolites were identified in human plasma. Only o-desmethyl
gefitinib has similar EGFR-TK activity to gefitinib in the isolated
enzyme assay, it had only 1/14 of the potency of gefitinib in one
of the cell-based assays.
Gefitinib is cleared primarily by the liver, with total plasma
clearance and elimination half-life values of 595 ml/min and
48hours, respectively, after intravenous administration. Excretion
is predominantly via the feces (86%), with renal elimination of
drug and metabolites accounting for less than 4% of the
administered dose.
Populations:
In population based data analyses, no relationships were identified
between predicted steady state trough concentration and patient
age, body weight, gender, ethnicity of creatinine clearance.
Pediatric:There are no pharmacokinetic data in pediatric
Hepatic Impairment:The
influence of hepatic metastases with elevation of serum aspartate
aminotransferase (AST/SGOT), alkaline phosphatase, and bilirubin
has been evaluated in patients with normal (14 patients),
moderately elevated (13 patients) and severely
patients）levels of one or more of these biochemical
parameters. Patients with moderately and severely elevated
biochemical liver abnormalities had gefitinib pharmacokinetics
similar to individuals without liver abnormalities (see PRECAUTIONS
Renal lmpairment:No
chinical studies were conducted with Gefitinib in patients with
severly compromised renal function (see PREAUTIONS section).
Gefitinib and its metabolites are not significantly excreted via
the kidney (&4%).
Drug-Drug lnteractions:
In human liver microsome studies, gefitinib had no inhibitory
effect on CYP1A2, CYP2C9, and CYP3A4 activities at concentrations
ranging from 2-5000 ng/ml. At the highest concentration studied
(5000 ng/ml), gefitinib inhibited CYP2C19 by 24% and CYP2D6 by 43%.
Exposure to metoprolol, a substrate of CYP2D6, was increased by 30%
when it was given in combination with gefitinib (500 mg daily for
28 days) in patients with solid tumors. Rifampicin, an inducer of
CYP3A4, reduced mean AUC of gefitinib by 85% in healthy male
volunteers(see PRECAUTIOS-Drug Interactions and DOSAGE AND
ADMINISTRATION-Dosage Adjustment sections).
Concomitant administration of itraconazole (200mg QD for 12 days),
an inhibitor of CYP3A4, with gefitinib(250 mg single dose) to
healthy male volunteers, increased mean gefitinib AUC by 88%(see
PRECAUTIONS-Drug Interactions section).CO -administration of high
doses of ranitidine with sodium bicarbonate (to maintain the
gastric pH above pH 5.0) reduced mean gefitinib AUC by 44%(see
PRECAUTIONS-Drug Interactions section).
International Normalized Ratio(INR) elevations and /or bleeding
events have been reported in some patients taking warfarin while on
Gefitinib therapy. Patients taking warfarin should be monitored in
prothrombin time or INR(see PRECAUTIONS-Drug Interactions and
ADVERSE REACTIONS sections).
Clinical studies :
Non-Small cell Lung cancer (NSCLC)-A multicenter clinical trial in
the United states evaluated
the tumor respons rate of Gefitinib 250 and 500 mg/day in patients
with advanced non-small cell lung cancer whose disease had
progressed after at least two prior chemotherapy regimens including
a platinum drug and docetaxel. Gefitinib was taken once daily at
approximately the same time each day.
Two hundred and sixteen patients received Gefitinib, 102(47%) and
114 (53%) receiving 250 mg and 500 mg daily doses, respectively.
Study patient demographics and disease characteristics are
summarized in Table 1. Forty-one percent of the patients had
received two prior treatment regimens, 33% three prior treatment
regimen, and 25% four or more prior treatment regimens.
Effectiveness of Gefitinib as third line therapy was determined in
the 142 evaluable patients with documented disease progression on
platinum and docetaxel therapies or who had had unacceptable
toxicity on these agents.
Table 1:Demographic and
Disease Characteristics
Gefitinib Dose
250 mg/day 500 mg/day
Characteristic N=66(%) N=76(%)
18-64 years 43(65) 43(57)
64-74 years 19(29) 30(39)
75 years and above 4(6) 3(4)
Male 38(58) 41(54)
Female 28(42) 35(46)
White 61(92) 68(89)
Black 1(2) 2(3)
Asian/Oriental 1(2) 2(3)
Hispanic 0(0) 3(4)
Other 3(5) 1(1)
Smoking History
Yes (Previous or current smoker) 45(68) 62(82)
No (Never smoked) 21(32) 14(18)
Baseline WHO Performance Status
0 14(21) 9(12)
1 36(55) 53(70)
2 15(23) 14(18)
Not Recorded 1(2) 0(0)
Tumor Histology
Squamous 9(14) 11(14)
Adenocarcinoma 47(71) 50(66)
Undifferentiated 6(9) 4(5)
Large Cell 1(2) 2(3)
Squamous and Adenocarcinoma 3(5) 7(9)
Not Recorded 0(0) 2(3)
Current Disease Status
Locally advanced 11(17) 5(7)
Metastatic 55(83) 71(93)
Table 2 shows tumor response rates and response duration. The
overall response rate for the 250 and 500 mg doses combined was
10.6%,16.8%). Response rates appeared to be highly variable in
subgroups of the treated population: 5.1%(4/79) in males,
17.5%(11/63) in females, 4.6% (5/108) in previous or current
smokers, ) in nonsmokers, 12.4%(12/97) with
adenocarcinoma histology, and 6.7%(3/45) with other NSCLC
histologies. Similar differences in response were seen in a
multinational study in patients who had received 1 or 2 prior
chemotherapy regimens, at least 1 of which was platinum-based. In
responders, the median time from diagnosis to study randomzation
was 16.7 months (range 8 to 34 months).
Table 2: Efficacy
Available Patients
250 mg 500 mg Combined
(N=66) (N=76) (N=142)
Objective Tumor Response 13.6 7.9 10.6
95% Cl(%) 6.4-24.3 3.0-16.4 6.0-16.8
Median Duration of Objective
Response (months) 8.9 4.5 7.0
Range (months) 4.6-18.6+ 4.4-7.6 4.4-18.6+
+=data are ongoing
Non-Small cell Lung Cancer
(NSCLC); Studies of First-line Treatment in
Combination with Chemotherapy—Two large trials were conducted in
chemotherapy-na飗e patients with stage lll and IV non-small cell
lung cancer. Two thousand one hundred thirty patients were
randomized to receive Gefitinib 250 mg daily, Gefitnib 500 mg
daily, or placebo in combination with platinum-based chemotherapy
regimens. The chemotherapies given in these first-trials 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.
INDICATIONS AND
GEFITINAT is indicated as monotherapy for the treatment of patients
with locally advanced or metastatic non-small cell lung cancer
after failure of both platinum-based and docetaxel
chemotherapies.
The effectiveness of Gefitinib is based on objective response rates
(see CLINICAL PHARMACOLOGY-Clinical Studies section). There are no
controlled trials demon-strating a clinical benefit, such as
improvement in disease-related symptoms or increased
Results from two large, controlled, randomized trials in first-line
treatmint of non-small cell lung cancer showed no benefit from
adding GEFTINAT to doublet, Platinum-based chemotherapy. Therefore,
GEFTINAT is not indicated for use in this setting.
CONTRAINDICATIONS
GEFTINAT is contraindicated in patients with severe
hypersensitivity to gefitinib or to and other component of
Cases of interstitial lung disease (ILD) have been observed in
patients receiving Gefitinib at an overall incidence of about 1%.
Approximately 1/3 of the cases have been fatal. The reported
incidence of ILD was about 2%in the Japanese post-marketing
experience, about 0.3% in approximately 23,00 patients treated with
Gefitinib in a US expanded access program and about 1% in the
studies of first-line use in NSCLC(but with similar rates in both
treatment and placebo groups). Reports have described the adverse
event as interstitial pneumonia, pneumonitis and alveolitis. often
present with the acute onset or dyspnea, sometimes associated with
cough or low-grade fever, often becoming severe within a short time
and requiring hospitalization. ILD has occurred in patients who
have received prior radiation therapy (31% of reported cases),
prior chemotherapy (57% of reported patients), and no previous
therapy (12% of reported cases). Patients with concurrent
idiopathic pulmonary fibrosis whose condition worsens while
receiving Gefitinib have been observed to have an increased
mortality compared to those without concurrent idiopathic pulmonary
In the event of acute onset or worsening of pulmonary symptoms
(dyspnea, cough, fever), Gefitinib therapy should be interrupted
and a prompt investigation of these symptoms should occur. If
interstitial lung disease is confirmed, Gefitinib should be
discontinued and the patient treated appropriately (see
PRECAUTIONS-Information for Patients, ADVERSE REACTIONS and DOSAGE
AND ADMINISTRATION-Dosage Adjustment sections).
Pregnancy Category
Gefitinib may cause fetal harm when administered to a pregnant
woman. A single dose study in rats showed that gefitinib crosses
the placenta after an oral dose of 5 mg/kg (30 mg/m2 , about 1/5
the recommended human dose on a mg/m2 basis). When pregnant rats
were treated with 5 mg/kg from the beginning of organogenesis to
the end of weaning gave birth, there was a reduction in the number
of offspring born alive. This effect was more severe at 20 mg/kg
and was accompanied by high neonatal mortality soon after
parturition. In this study a dose of 1 mg/kg caused no adverse
In rabbits, a dose of 20 mg/kg/day (240 mg/m2 , about twice the
recommended dose in humans on a mg/ m2 basis ) caused reduced fetal
weight. There are no adequate and well-controlled studies in
pregnant women using Gefitinib. If Gefitinib is used during
pregnancy or if the patient becomes pregnant while receiving this
drug, she should be apprised of the potential hazard to the fetus
or potential risk for loss of the pregnancy.
PRECAUTIONS
Hepatotoxicity
Asymptomatic increases in liver transaminases have been observed in
Gefiti therefore, periodic liver function
(transaminases, bilirubin. And alkaline phosphatase) testing should
be consibered . Discontinuation of Gefitinib should be considered
if changes are severe.
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