What Is Gefitinib?
Gefitinib is a very effective cancer medicine. It works by blocking a protein called EGFR (epidermal growth factor receptor). Some cancer cells depend on these proteins for their growth. By blocking these proteins, Gefitinib helps control cancer growth. Gefitinib is only effective in patients whose cancer has specific EGFR gene mutations. So, testing to detect mutations is required before treatment starts.
It is usually taken as a tablet once a day. You might develop diarrhea, skin reactions, and liver issues, which are common side effects. However, doctors monitor them carefully, as they can be severe too.
Approval Details
Gefitinib has received FDA (Food and Drug Administration) approval for first-line treatment of metastatic NSCLC (non-small cell lung cancer). The approval is limited to only those patients whose tumors have specific EGFR (epidermal growth factor receptor) mutations. It is basically an inhibitor of the tyrosine kinase enzyme.
The efficacy and safety of Gefitinib have been assessed in several trials across a range of racial backgrounds. Extreme caution should be taken into consideration when prescribing Gefitinib to patients who are suffering from hepatic impairment.
For Patients
Gefitinib is a cancer medicine. This is used to treat certain lung cancers. It is quite helpful for those who are suffering from and have been diagnosed with non-small cell lung cancer, which has widely spread to other parts of the body. Even if you have advanced NSCLC, that alone will not make you the best candidate for this drug. Only if you have certain specific epidermal growth factor receptor (EGFR) gene mutations, may your doctor consider Gefitinib. Understanding the definition of Gefitinib will help you determine when its use is appropriate and effective.
Why Is Gefitinib Used?
Gefitinib is often advised by the doctor as the first choice of treatment for those patients who have been suffering from metastatic non-small cell lung cancer, or NSCLC. Also, they should have epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletions or exon 21 substitution mutations. Gefitinib cures cancer when used for the right patient.
Still confused, consult an oncologist and see if you can go for Gefitinib therapy.
Things to Inform Your Doctor:
If you have any medical issues, such as breathing problems, vision issues, or liver disease, you must inform your doctor beforehand.
If you are pregnant or planning to be soon, please let us know as well. Gefitinib can harm your pregnancy and your unborn baby in the womb.
If you take any other medicine, even a health supplement, you should inform your doctor.
If you are a lactating woman, inform them also. It may not be safe to breastfeed while you are on Gefitinib.
Side Effects:
Here are some of the common side effects of Gefitinib:
Eye issues like watery eyes, redness, light sensitivity, etc.
Skin reactions.
Breathing issues (due to lung inflammation).
Liver problems (due to liver inflammation).
Tear in the intestine or stomach (medically known as abdominal perforation).
Fertility issues in females.
Some side effects are very serious, so whenever you experience any abnormal reactions, consult your doctor.
Storage and Handling:
Gefitinib tablets are marketed and sold as brown, film-coated tablets containing 250 mg of the drug and intended for oral administration. You have to keep the pill under controlled room temperature of anywhere between 20 degrees Celsius and 25 degrees Celsius.
For Doctors
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. It has a relative molecular mass of 446.9 daltons. The drug is a white-colored powder and is a free base.
Gefitinib is sparingly soluble at pH 1. Still, it is practically insoluble above pH 7, with solubility decreasing steadily between pH 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 containing 250 mg of the drug and intended 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 patients who have been suffering from metastatic NSCLC. It is not indicated for all metastatic NSCLC cases. This drug is indicated only for tumors with mutations in the epidermal growth factor receptor, particularly exon 19 deletions or exon 21 substitution mutations. Gefitinib use is therefore restricted to only those who satisfy this indication.
Limitations:
For epidermal growth factor receptor mutations apart from exon 19 deletions or exon 21 substitution mutations, the safety and efficacy of Gefitinib have not yet been established.
Contraindications:
There are no documented contraindications of Gefitinib.
Administration and Dosage:
Before administration, the first step is patient selection. Patient selection for first-line treatment of metastatic NSCLC with Gefitinib is based solely on the presence of EGFR mutations (exon 19 deletion or exon 21 substitution) in tumor or plasma specimens.
The recommended dose of Gefitinib is 250 mg, administered orally once daily with or without food.
An alternative method of administration is through a nasogastric tube. However, in case the patient develops any adverse reactions, certain modifications in the drug dose must be followed.
A missed dose must not be taken within 12 hours of the next scheduled dose. In case a patient has difficulty swallowing the medication, immerse it in four to eight ounces of water and stir it for approximately 15 minutes. They must drink the solution immediately.
Overdose:
After studying the changes in patients who were given an increased dose of Gefitinib, it has been established that the clinical manifestations of overdosage of the drug are parallel to the adverse effects of Gefitinib.
Mechanism of Action
The epidermal growth factor receptor is expressed on the surface of both normal and cancer cells. It plays a significant role in cell growth and proliferation. Some cases of non-small cell lung cancer have epidermal growth factor receptor-activating mutations, such as exon 19 deletions or exon 21 substitution mutations (L858R). These mutations have been identified as major contributors to tumor cell growth.
In addition, these mutations also block normal cell death (apoptosis). This will eventually increase the production of angiogenic factors, thereby facilitating metastasis.
Gefitinib is known to reversibly inhibit the kinase activity of such activating mutations of epidermal growth factor receptors. This will prevent the autophosphorylation of tyrosine residues associated with these receptors.
This blocks the downstream signaling and epidermal growth factor receptor-dependent proliferation. So, Gefitinib mechanism of action primarily works through blocking the EGFR protein.
Pharmacokinetics:
1. Absorption and Distribution:
Gefitinib’s mean oral bioavailability is approximately 60%. The peak plasma levels are reached at roughly three to seven hours after dosing. Its bioavailability isn’t altered to a clinically significant level by the presence of food.
2. Metabolism and Elimination:
Five specific metabolites were fully identified in fecal extracts, while plasma revealed eight metabolites. The primary site of Gefitinib clearance is the liver, with complete plasma clearance and an elimination half-life of approximately 48 hours after intravenous administration. A steady-state plasma concentration of Gefitinib is achieved within 10 days of regular dosing. Excretion is predominantly via feces (about 86%) and renal elimination (about 4%).
3. Carcinogenesis, Mutagenesis, Impairment of Fertility:
The drug Gefitinib has been thoroughly tested for genotoxicity in several series of in vitro assays. Under any of these conditions or any of these assays, Gefitinib did not seem to cause any sort of genetic damage.
Precautions and Warnings
Interstitial lung disease is seen in around 1.3 percent of cases that were under Gefitinib therapy. Therefore, ask the patient to report new-onset or worsening pulmonary symptoms, such as breathlessness and cough. Hepatoxicity is often reported with Gefitinib. Therefore, routine liver function tests must be performed to monitor patients’ liver function.
In case the patient complains of abdominal pain, screen them for abdominal perforation.
Diarrhea, though a common expected side effect, if severe, needs proper attention.
The patient must inform the healthcare provider of any of the following conditions if they have them. Those with these conditions may require precautionary measures:
Interstitial lung disease or ILD
Lung infiltration.
Pneumonitis.
Acute respiratory distress syndrome.
Pulmonary fibrosis.
Adverse Reactions:
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:
The clinical trial with Gefitinib reported the following side effects:
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. Therefore, the adverse reaction rates observed in the clinical trials cannot be directly compared with those in any other drug's clinical trials.
All the results of the study on Gefitinib are from 2462 patients with non-small cell lung cancer. They were given 250 mg of Gefitinib as monotherapy in three randomized clinical studies. The characteristics of the individuals who participated in the trial are:
A median age of around 57 years.
Age less than 65 years old.
A mix of Asians, smokers, and non-smokers.
Drug Interactions:
Drugs that are known to be potent inducers of CYP3A4 (such as Rifampin, Phenytoin, Carbamazepine, or St. John’s Wort) generally increase the metabolism of Gefitinib and decrease the plasma concentration of Gefitinib. In such cases, concomitant use is generally not advised. If prescribed, appropriate dose adjustments must be made.
Drugs known to be strong CYP3A4 inhibitors (such as Ketoconazole and Itraconazole) can drastically reduce Gefitinib metabolism. This would bring up the plasma concentration of Gefitinib.
Proton pump inhibitors, histamine H2-receptor antagonists, antacids, and other drugs that increase gastric acidity may reduce Gefitinib plasma concentrations. Therefore, concomitant use must be either avoided or carefully managed.
The International Normalized Ratio, or INR, elevations, along with bleeding issues, have been reported in a few patients who were taking Warfarin while on therapy with Gefitinib. Such patients should be carefully monitored for any change in their prothrombin time.
Special Population:
Pregnancy: Based on the mechanism of action of Gefitinib and the studied animal data, Gefitinib can cause fetal harm after the oral administration of the drug to a pregnant patient. Fetotoxicity and neonatal death might occur at 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 evidence of Gefitinib in human milk. Therefore, nothing can be established about the safety and effectiveness of this drug in lactating patients. However, in animal studies, lab rats were found to have higher Gefitinib concentrations in their milk; therefore, it is recommended not to prescribe Gefitinib to lactating individuals.
Reproductive Potential: Gefitinib has been shown to reduce reproductive capacity in both males and females.
Pediatric Use: The safety and effectiveness of Gefitinib in pediatric patients have not yet been established.
Geriatric Use: The safety and effectiveness of Gefitinib in geriatric patients have not yet been established.
Renal Impairment: The safety and effectiveness of Gefitinib in patients with mild to severe renal impairment have not yet been established.
Hepatic Impairment: No established results, either positive or negative, have been reported in patients with hepatic impairment. In studies with Gefitinib, several patients showed an increase in plasma drug concentration during excretion. Thus, care and consideration must be taken while administering therapy with Gefitinib in patients known to be diagnosed with hepatic impairment.
