Gefitinib- Indications, Dosage, Precautions, and Mechanism

Overview:

Gefitinib has received approval from the FDA or food and drug administration for first-line treatment of metastatic non-small cell lung cancer or NSCLC. Gefitinib is sold under the brand name IRESSA® and is manufactured by AstraZeneca. Gefitinib is a drug that is an inhibitor of epidermal growth factor receptor or EGFR, tyrosine kinase and has been indicated for the first-line treatment of patients who are suffering from metastatic non-small cell lung cancer or NSCLC. The efficacy, as well as the safety of Gefitinib, has been assessed in several trials with an array of racial backgrounds. Extreme caution should be taken into consideration when prescribing Gefitinib to patients who are suffering from hepatic impairment.

Gefitinib for Doctors

Gefitinib is an inhibitor of tyrosine kinase that is indicated as the first-line treatment for patients who have been suffering from metastatic non-small cell lung cancer or NSCLC whose tumors have epidermal growth factor receptor or EGFR. The limitation of the use of Gefitinib is that the safety and efficacy have not yet been established in those patients whose tumors have epidermal growth factor receptor mutations. The chemical name of Gefitinib is 4-Quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl) propoxy, and it has the molecular formula of C22H24ClFN4O3, which is having a relative molecular mass of 446.9 daltons. The drug is a white-colored powder and is a free base. Gefitinib can be defined as a sparingly soluble drug at a pH of 1. Still, it is practically insoluble above the pH of 7, with its solubility decreasing steadily between a pH of 4 and 6. In solvents that are not aqueous, Gefitinib is a freely soluble substance in glacial acetic acid and dimethyl sulfoxide. It is also soluble in pyridine and sparingly soluble in tetrahydrofuran, methanol, and ethanol, along with ethyl acetate, propane-2-ol, and acetonitrile. Gefitinib tablets are marketed and sold as brown film coated tablets that contain 250 mg of the drug and are only for oral administration.

The inactive ingredients of the tablet are mentioned below.

• Lactose monohydrate.

• Microcrystalline.

• Cellulose.

• Croscarmellose sodium.

• Povidone.

• Sodium lauryl sulfate.

• Magnesium stearate.

• Hypromellose.

• Polyethylene glycol 300.

• Titanium dioxide.

• Red ferric oxide.

• Yellow ferric oxide.

Indications

Gefitinib has been indicated for the first-line treatment of those patients who have been suffering from metastatic non-small cell lung cancer or NSCLC and whose tumors have epidermal growth factor receptor or EGFR exon 19 deletions or exon 21 substitution mutations as per the FDA approval.

Limitations:

The safety and efficacy of Gefitinib have not yet been established in those patients who have been diagnosed with metastatic non-small cell lung cancer with epidermal growth factor mutations other than exon 21 or exon 19 substitution mutation.

Contraindications:

There are no documented contraindications of Gefitinib.

Administration and Dosage:

Before administration, patient selection for the first-line treatment of metastatic non-small cell lung cancer with Gefitinib is purely based on the presence of epidermal growth factor exon 19 deletions or even exon 21 mutations present in their tumor or their plasma specimens. The recommended dose of Gefitinib is 250 mg to be administered orally once per day with or without food. A missed dose must not be taken within 12 hours of the next scheduled dose. In case a patient has difficulty swallowing the medications, immerse it in four to eight ounces of water and stir the same for approximately 15 minutes. They must drink the solution immediately. An alternative method of administration is through a nasogastric tube. In case there is any kind of adverse drug reaction after the administration of this drug, mentioned below are the dose modifications that must be done accordingly.

• Gefitinib must be kept on hold for a period of 14 days in case there are pulmonary symptoms of acute cough, fever, skin rashes, keratosis, and dyspnea, along with an elevated level of ALT or alanine aminotransferase and AST or aspartate aminotransferase or even a severe case of diarrhea.

• Gefitinib must be permanently discontinued in case there is a confirmed interstitial lung disease, severe impairment of the hepatic system, gastrointestinal perforation, and persistent ulcerative keratitis.

Precautions

The patient must make sure to inform the healthcare provider about any of the below-mentioned conditions that may require precautionary measures to be taken on the patient as well as the end of the healthcare provider.

• Interstitial lung disease or ILD.

• Lung infiltration.

• Pneumonitis.

• Acute respiratory distress syndrome.

• Pulmonary fibrosis.

Adverse Reactions:

• Hepatotoxicity.

• Increased alanine aminotransferase or ALT.

• Increased aspartate aminotransferase or AST.

• Increased bilirubin.

• Fatal hepatotoxicity.

• Worsening of liver function.

• Severe hepatic impairment.

• Gastrointestinal perforation.

• Severe or persistent form of diarrhea.

• Ocular disorders.

• Keratitis.

• Corneal erosion.

• Aberrant eyelash growth.

• Conjunctivitis.

• Blepharitis.

• Dry eyes.

• Bullous eruptions.

• Exfoliative skin disorders.

• Toxic epidermal necrolysis.

• Stevens-Johnson syndrome.

• Erythema multiforme.

• Dermatitis bullous.

• Blistering of the skin.

• Embryo-fetal toxicity.

Clinical Trials:

After the clinical trials that have been conducted to study the safety and effectiveness of Gefitinib, the below-mentioned reactions have come into the picture.

• Nausea.

• Asthenia.

• Pyrexia.

• Alopecia.

• Hemorrhage.

• Epistaxis.

• Hematuria.

• Dry mouth.

• Dehydration.

• Allergic reactions.

• Angioedema.

• Urticaria.

• Elevations in blood creatinine levels.

• Pancreatitis.

It should be noted that the clinical trials of Gefitinib had been conducted under varying conditions, and thus, the adverse reaction rates that have been observed in the clinical trials cannot be directly compared against the rates in the clinical trials of any other drug and additionally may not reflect the rates observed during practice. All the results of the study on Gefitinib are from 2462 patients with non-small cell lung cancer who had received 250 mg of Gefitinib on a daily monotherapy basis in three randomized clinical studies. The characteristics of the individuals who participated in the trial are- a median age of around 57 years or age of fewer than 65 years and a mix of Asians, smokers, and non-smokers.

Drug Interactions:

• Drugs that are known to be a potent inducer of CYP3A4 generally increase the metabolism of Gefitinib and decrease the plasma concentration of Gefitinib. In such cases, the dosage of Gefitinib is to be increased to 500 mg regularly in those patients who are receiving drugs that are strong CYP3A4 inducers such as Rifampicin, Phenytoin, and tricyclic antidepressant. Gefitinib can be resumed at a dosage of 250 mg for seven days just after discontinuation.

• Drugs that are known to be strong inhibitors of CYP3A4, such as Ketoconazole and Itraconazole, have the tendency to drastically decrease the metabolism of Gefitinib and inversely increase the plasma concentration of Gefitinib plasma concentrations.

• Proton pump inhibitors, histamine H2-receptor antagonists, antacids, and other drugs that increase gastric acidity may have the tendency to reduce the plasma concentrations of Gefitinib, and thus, concomitant use must be avoided or reduced.

• The International Normalized Ratio or INR elevations along with hemorrhage have been reported in a few patients who were taking Warfarin while on therapy with Gefitinib. Such patients should be carefully monitored for the presence of any kind of change in their prothrombin time.

Drug Interaction With Special Population:

Pregnancy:

Based on the mechanism of action of Gefitinib and the studied animal data, Gefitidine can cause fetal harm after the oral administration of the drug to a pregnant patient, such as fetotoxicity and neonatal death at those doses that are even below the recommended human dose. Thus a piece of advice to pregnant females on the potential risk to the development of the fetus or even the potential risk for loss of pregnancy must be given.

Lactation:

There is no clear-cut evidence of the presence of Gefitidine in human milk, and thus nothing can be established about the safety and effectiveness of this drug in lactating patients. However, lab rats were found to have a higher concentration of Gefitidine in their milk, hence, it is suggested not to prescribe Gefitidine to lactating individuals.

Reproductive Potential:

Gefitinib has been known and studied to reduce the reproductive capacity in both males and females. Keeping this in mind, contraception is suggested during and after the therapy with Gefitidine.

Pediatric Use:

The safety and effectiveness of Gefitidine in a pediatric group of patients have not yet been established.

Geriatric Use:

The safety and effectiveness of Gefitidine in a geriatric group of patients have not yet been established.

Renal Impairment:

The safety and effectiveness of Gefitidine in the group of patients who have mild to the severe renal impairment have not yet been established.

Hepatic Impairment:

There has not been any kind of established result, either positive or negative, in patients suffering from hepatic impairment. In the studies conducted over Gefitidine, several patients had shown an increase in the plasma concentration of the drug while being excreted. Thus, care and consideration must be taken while therapy with Gefitidine in patients known to be diagnosed with hepatic impairment.

Overdose:

After studying the changes in patients who were given an increased dose of Gefitidine, it has been established that the clinical manifestations of overdosage of the drug are parallel to the adverse effects of Gefitidine.

Mechanism of Action

The epidermal growth factor receptor or EGFR is a receptor that is expressed on the surface of the cell of both normal as well as cancer cells, and thus, it plays a significant role in the processes of cell growth and cell proliferation. There are a few of the epidermal growth factor receptor activating mutations such as exon 19 deletion exon 21 point mutation L858R within the non-small cancer lung cancer cells that have been identified as the major contributing factor to the promotion of tumor cell growth and blocking of apoptosis, as well as, directly increasing the production of angiogenic factors and thus facilitating the processes of metastasis. Gefitinib is known to reversibly inhibit the kinase activity of such activating mutations of epidermal growth factor receptors, thus preventing autophosphorylation of tyrosine residues that are associated with such receptors and eventually interfering with the blocking of epidermal growth factor receptor-dependent proliferation. It should additionally be noted that the Gefitinib binding affinity for epidermal growth factor receptor exon 19 deletion or exon 21 point mutation L858R mutations is much higher than its affinity for the wild-type epidermal growth factor receptor.

Pharmacokinetics:

Absorption and Distribution:

The average oral bioavailability of Gefitinib is around 60 %, with the peak plasma levels at roughly three to seven hours after dosing and being evenly distributed throughout the entire body.

Metabolism and Elimination:

Gefitinib is degraded in an extensive hepatic metabolism manner within the human body, with several metabolites being identified in the human plasma. Five specific metabolites had been completely identified in fecal extracts. The primary site of Gefitinib clearance is the liver with a plasma clearance and an elimination half-life of roughly 48 hours post intravenous administration. A steady-state plasma concentration of Gefitinib is achieved within ten days after regular dosing of the drug. Excretion is predominantly via feces and renal elimination.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

The drug Gefitinib has been thoroughly tested for genotoxicity in several series of in vitro assays, and under any of these conditions or any of these assays, Gefitinib did not seem to cause any sort of genetic damage.

Gefitinib for Patients

Gefitinib, marketed under the name IRESSA and is a prescription drug that is used for the treatment of people who are suffering from and have been diagnosed with non-small cell lung cancer or NSCLC, which has widely spread to other parts of the body and have specific kinds of abnormal epidermal growth factor receptor or EGFR genes, as well as not having any kind of previous treatment for cancer.

Ingredients:

Active ingredient:

• Gefitinib.

Inactive ingredients:

• Lactose monohydrate.

• Microcrystalline cellulose.

• Croscarmellose sodium.

• Povidone.

• Sodium lauryl sulfate.

• Magnesium stearate.

Indications and Contraindications:

Gefitinib has been indicated for the first-line treatment of those patients who have been suffering from metastatic non-small cell lung cancer or NSCLC and whose tumors have epidermal growth factor receptor or EGFR exon 19 deletions or exon 21 substitution mutations as per the FDA approval. There are not any known contraindications of Gefitinib..

Side-effects:

In case of any of the below-mentioned side effects, the drug must be immediately stopped, and the patient is advised to consult their respective healthcare provider at the very earliest.

• Severe nausea.

• Hepatotoxicity.

• Increased alanine aminotransferase or ALT.

• Increased aspartate aminotransferase or AST.

• Increased bilirubin.

• Fatal hepatotoxicity.

• Worsening of liver function.

• Severe hepatic impairment.

• Gastrointestinal perforation.

• Severe or persistent form of diarrhea.

• Ocular disorders.

• Keratitis.

• Corneal erosion.

• Aberrant eyelash growth.

• Conjunctivitis.

• Blepharitis.

• Dry eyes.

• Bullous eruptions.

• Exfoliative skin disorders.

• Toxic epidermal necrolysis.

• Stevens-Johnson syndrome.

• Erythema multiforme.

• Dermatitis bullous.

• Blistering of the skin.

• Embryo-fetal toxicity.

• Asthenia.

• Pyrexia.

• Alopecia.

• Hemorrhage.

• Epistaxis.

• Hematuria.

• Dry mouth.

• Dehydration.

• Allergic reactions.

• Angioedema.

• Urticaria.

• Elevations in blood creatinine levels.

• Pancreatitis.

Storage and Handling:

Gefitinib tablets are marketed and sold as brown film-coated tablets that contain 250 mg of the drug and are only for oral administration. The drug is to be stored at a controlled room temperature of anywhere between 20 degrees Celsius to 25 degrees Celsius.