Each film-coated tablet contains :
Gefitinib IP 250 mg
Colors: Red Oxide Iron, Yellow Oxide of Iron & Titanium Dioxide IP
Gefinib is an anlinoquinazoline with the chemical name 4-Quinazolinamine,
N-(3-chloro-4 fluorophenyl)-7-methoxy-6(3-4 morpholin)propoxy).
Molecular Formula : C22 H24CIFN2O3
Molecular Weight : 446.9
The mechanism of the clinical antitumor action of Gefitinb is not fully characterized. Gefitinib inhibits the intracellular phosphonylation of numerous tyrosine kinases associated with transmembrane cell surface receptors. including the tyrosin kinases associated with the epidermal growth facto receptor (EGFR-TK). EGFR is expressed on the cell surface of many normals cells and cancer cells. No clinical studies have been performed that demonstrate a correlation between EGFR receptor expression and response to Gefitinib.
Gefitinib is absorbed slowly after oral administration with meal biovaliability of 60% Elimination is by metabolism (primarily CYP3A4) and excretion in feces. The elimination half-life is about 48 hours. Daily oral administration if Gefitinib to cancer patients resulted in a 2-fold accumulation compared to single dose administration. Steady state plasma concentrations are archeive within 10 days.
Absorption and Distribution :
Gefitinib is slowly absorbed. with peak plasma levels occuring 3-7 hours after dosing and mean oral biovaliability of 60% Biovailability is not significantly altered by food. Gefitinib us 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 indepen-dent of drug concentrations.
Metabolism and Elimination :
Gefitinb undergoes extensive hepatic metabolism In humans, predominantly by CYP3A4. Three sites of biotransformation have been indentified : metabolism of the N-propoxymor pholino-group, demethylation of the methoxy-substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolities were indentified in human plasma. Only O-desmethyl Gefitinib has exposure comporable to Gefitinib. Gefinitib is cleared primarily by the liver, with total plasma clearance and elimation half-life values of 595 mL/min and 48 hours, respectively, after intravenous administration, Excretion is predominantly via the feces (85%), with renal elimination of drug and metabolism accounting for less than 4% of the administration dose.
Special Populations :
In population based data analysis, no relationship between predicated steady state trough
concentration and patient age, bodyweight, gender, ethnicity ir creatinine clearance.
Pediatric : There are no pharmacokinetic data in paediatric patients.
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 elevated (4 patients) levels of one or more these biochemical parameters. Patients with moderately and severely elevated biochemical liver abnormalities had Gefitinib pharmacokinetics similar to individuals without liver abnormalities.
Renal Impairment :
No clinical studies were conducted with Gefitinib in patients severely compromised renal function. Gefitinib and its metabolites are not significantly excreted via the kidney (<4%).
Gefitinib is indicated as monotherapy for the treatment of patients with locally advanced of 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. There are no controlled trials demonstrating a clinical benefit. such as improvement in disease-related symptoms or increased survival. Results from two large, controlled, randomized trials in first-line treatment of non-small cell lung cancer showed no benefit from adding Gefitinib to doublet, platinum based chemotherapy. Therefore, Gefitinib is not indicated for use in this setting.
He recommended daily dose of Gefitinib is one 250 mg tablet with or without food. Higher doses do not give a better response and cause increased toxicity.
DOSAGE ADJUSTMENT :
Patients with poorly tolerated diarrhea (sometimes associated with dehydration) or skin adverse drug reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg daily dose. In the event of acute onset or worsening of pulmonary symptoms (dyspnea, cough, fever), Gefitinib should be interrupted and a prompt investigation of these symptoms should occur and appropriate treatment initated. If interstitial lung disease Isconfirmed, Gefitinib should be discontinued and the patient treated appropriately. Patients who develop onset of new eye symptoms such as pain should be medically evaluated and managed appropriately, including Gefitinib therapy interruption and removal of an aberrant eyelash if present. After symptoms and eye changed have resolved the decision should be made concerning reinstatement of the 250 mg daily dose. In patients receiving a potent CYP3A4 inducer such as rifampicin or phenytoin, a dose increase to 500 mg daily should be carefully monitored, No dosage adjustment is required on the basis of patient age, body weight, gender, ethnicity or renal function, or in patients with moderate to severe hepatic impairement due to liver metastases.
Pulmonary Toxicity :
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 23,000 patients treated with Gefitinib in a US expanded access program and about 1% in the studies of first line se in NSCLC (but with similar rates in both treatment and placebo groups). Reports have described the adverse event as interstitial pneumonia, pneumonitisand alveolitis. Patients often present with the acute onset of dyspnea, sometimes associated with cough or lowgrade 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 to have an increased mortality compared to those without concurrent idiopathic pulmonary fibrosis.
In the event of acute or worsening of pulmonary symptoms (dyspnea, cough, fever), Gefitinib therapy shouldbe 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.
Pregnancy Category D: Gefitinib may cause fetal ham 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 active. This effect was more several at 20mg/kg and was accompanied by high neonatal mortality soon after parturition. In this study a dose of 1 mg/kg caused no adverse effects. 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
Pregnancy Category D : Gefitinib may cause fetal ham 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 active. This effect was more several at 20mg/kg and was accompanied by high neonatal mortality soon after parturition. In this study a dose of 1 mg/kg caused no adverse effects. 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.
Hepatotoxicity : Asymptomatic increases in liver transaminases have been observed in Gefitinib treated patients. therefore,periodic liver function (transaminases, bilarubin, and alkaline phosphate) testing should be considered.Discontinuation Gefitinib should be considered if changes are severe. Patients with Hepatic Impairment In vitro and in vivo evidence suggest that Gefitinib is cleared primarily by the liver. Therefore, Gefitinib exposure may be increased in patients with hepatic dysfunction. In patients with liver metastases and and moderately to severely elevatedbiochemical liver abnormalities, however, Gefitinib pharmacokinetics were similar to the pharmacokinetics of individuals without liver abnomalities. The influence of non-cancer related hepatic impairment on the pharmacokinetics of Gefitinib has not been evaluated.
Carcinogenesis, Mutagenesis, Impairment of Fetility
Gefinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma and human lymphocyte) assays and an in vivo micronueus test. Under the conditions of these assays. Gefitinib did not cause genetic damage.
Carcinogenicity studies have not been conducted with Gefitinib.
Pregnancy Category D
Nursing Mothers :
It is know whether Gefitinib is excreted in human milk. Following oral administration of carbon – 14 labeled Gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of Gefitinib and its metabolities were 11- to – 19 – fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, women should be advised against breast-feeding while receiving Gefitinib therapy
Pediatric Use :
Gefitinib is not indicated for use in pediatric patients as safety and effectiveness have not been established. In clinical trials of Gefitinib alone or with radiation in pediatric patients with primary central Nervous System (CNS) tumors, cases of CNS hemorrhage and death have been reported. There is insufficient data inpediatric patients to establish a causal relationship. There is no evidence to suggest increased risk of cerebal hemorrhage in adult patients with NSCLC receiving Gefitinib.
Geriatric Use :
Of the total number of patients participating in trials of second and third line Gefitinib treatment of NSCLC, 65% were aged 64 years or less, 30.5% were aged 65 to 74 years, and 5% of patients were aged 75 years or older. No differences in safetyor efficacy were observed between younger and older patients.
Patients with Several Renal Impairment :
The effect of several renal impairment on the pharmacokinetics of Gefitinib is not known. Patients with severe renal impairment should be treated with caution when given Gefitinib.
The safety database includes 941 patients from clinical trials and approximately 23,000 patients in the Expanded access program.
Table 1 includes drug-related adverse events with an incidence of >5% for the 216 patients who received either 250 mg or 500 mg of Gefitinib monotherapy for treatment of NSCLC. The most common adverse events reported at the recommended ?250 mg daily dose were diarrhea, rash, acne, dry skin, nausea, and vomiting. The 500 mg dose showed higher rate for most of these adverse events. Table 2 provides drug – related adverse events with an incidence of >5% by CTC grade for the patients who received the 50 mg/day dose of Gefitinib monotherapy for treatment of NSCLC. Only 2% of patients stopped therapy due to an adverse drug reaction (ADR.) The onset of these ADRs occured within the first month of therapy.
Table 1 : Drug Related adverse events with an Incidence of >5% in either 250 mg or 500 mg dose group
Number (%) of Patients
Drug-related adverse events*250mg/day (N=102)%500 mg/day (N=114)%
|Diarrhea||49 (48)76 (67)|
|Rash||44 (43)61 (54)|
|Acne||25 (25)37 (33)|
|Dry Skin||13 (13)||30 (26)|
|Nausea||13 (13)||20 (18)|
|Vomiting||12 (12)||10 (9)|
|Pruritus||8 (8)||10 (9)|
|Anorexia||7 (7)||11 (10)|
|Asthenia||6 (6)||5 (4)|
|Weight Loss||3 (3)||6 (5)|
*A patient may have had more than I drug related event..
Table 2 : Drug Related adverse events > 5% at 250 mg dose by Worst CTC Grade (n=102)
Adverse EventAll GradesCTC Grade 1CTC Grade 2CTC Grade 3CTC Grade 4
Other adverse events reported at an incidence of <5% in patients who received either 25mg or 500 mg as montherapy for treatment of NSCLC (along with their frequency at the 250 mg recommended dose) include the following peripheral edema (2%), amblyopia (2%), dyspnea (2%), conjunctivitis (1%). vesiculobullious rash (1%), and mouth ulceration (1%). In patients receiving Gefitinib therapy, there were reports of eye pain and corneal erosion/ulcer, sometimes in association with aberrant evelash growth. Hemorrhages, such as epistaxis and hematuria have been reported in patients receiving Gefitinib. There were also rate reports of pancreatitis and very rare reports of comeal membrane sloughing, ocular ischemia/hemorrhage, toxic epidemalnecrolysis, erythema multiforme, and allergic reactions, including angioedema and urticaria. Data form non-clinical (in vitro and in vivo) studies indicate that Gefitinib has the potential to inhibit the cardiac action potential repolarization process eg. QT interval). The clinical relevance of these findings is unknown.
In human liver microsome studies, Gefitinib had no inhibitory effect on CYP2C9, and CYP3A4 and CYP3A4, activities at concentrations ranging from 2-500 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. Concomitant administration of itraconazole (200 mg QD for 12 days). an inhibitor of CYP3A4, with Gefitinib (250 mg single dose) to healthy male volunteers, increased mean Gefitinib AUC by 88%. 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%.
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 regulatory for changes in prothrombin tine or INR.
Phase II clinical trial data, where Gefitinib and vinorelbine have been used concomitantly indicated that
Gefitinib may exacerbate the neutropenic effect of vicnorelbine.
He acute toxicity of Gefitinib up to 500 mg in clinical studies has been low. In non clinical studies, a single dose of 12,000 mg/m2 (about 80 times the recommended clinical dose on a mg/m3 basis) was lethal to rats. Half this dose caused no mortality in mice.
There is no specific treatment for a gefitinib overdose and possible symptoms of overdose are not established. However, in Phase
1 clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg, An increase in frequency and severity of some adverse reactions was observed, mainly diarrhea and skin rash. Adverse reactions associated with overdose should be treated symptomatically: in particular , severe diarrhea should be managed appropriately.
CONTRAINDCATIONS : Gefitinib is contraindicated in patients with severe hypersensitivity to Gefitinib or to any other component of Gefitinib.
Store protected from light & moisture. Keep out of reach of children.
A strip of 10 tablets.