PRESCRIBING INFORMATION

To be sold by retail on the prescription of an Oncologist only

Gefitinib Tablets IP 250 mg

GEFTICIP Tablets

1.    GENERIC NAME:

Gefitinib Tablets IP 250 mg

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION:

Each film coated tablet contains:

Gefitinib IP ………………………. 250 mg

Excipients ………………………… q.s

Colours: Ferric oxide USP-NF Red, Ferric oxide USP-NF Yellow & Titanium Dioxide IP

3.    DOSAGE FORM & STRENGTH:

250 mg tablets for oral use

4.    CLINICAL PARTICULARS:

4.1.        Therapeutic Indications

GEFTICIP  Tablets are indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have activating mutation of the EGFRTK

4.2.       Posology and Method of Administration

Treatment with GEFTICIP  Tablets should be initiated and supervised by a physician experienced in the use of anti-cancer therapies. Select patients for the first-line treatment of metastatic NSCLC with GEFTICIP  based on the presence of EGFR exon 19 deletions or exon 21 L858R mutations in their tumor or plasma specimens. If these mutations are not detected in a plasma specimen, test tumor tissue if feasible.

Posology

The recommended posology of gefitinib is one 250 mg tablet once a day. If a dose is missed, it should be taken as soon as the patient remembers. If it is less than 12 hours to the next dose, the patient should not take the missed dose. Patients should not take a double dose (two doses at the same time) to make up for a forgotten dose.

Paediatric Population

The safety and efficacy of gefitinib in children and adolescents aged less than 18 years have not been established. There is no relevant use of gefitinib in the paediatric population in the indication of NSCLC.

Hepatic Impairment

Patients with moderate to severe hepatic impairment (Child-Pugh B or C) due to cirrhosis have increased plasma concentrations of gefitinib. These patients should be closely monitored for adverse events. Plasma concentrations were not increased in patients with elevated aspartate transaminase (AST), alkaline phosphatase or bilirubin due to liver metastases.

Renal Impairment

No dose adjustment is required in patients with impaired renal function at creatinine clearance >20 ml/min. Only limited data are available in patients with creatinine clearance ≤ 20 ml/min and caution is advised in these patients.

Elderly

No dose adjustment is required on the basis of patient age.

CYP2D6 Poor Metabolizers

No specific dose adjustment is recommended in patients with known CYP2D6 poor metabolizer genotype, but these patients should be closely monitored for adverse events.

Dose Adjustment due to Toxicity

Patients with poorly tolerated diarrhoea or skin adverse reactions may be successfully managed by providing a brief (up to 14 days) therapy interruption followed by reinstatement of the 250 mg dose. For patients unable to tolerate treatment after a therapy interruption, gefitinib should be discontinued and an alternative treatment should be considered.

Method of Administration

The tablet may be taken orally with or without food, at about the same time each day. The tablet can be swallowed whole with some water or if dosing of whole tablets is not possible, tablets may be administered as a dispersion in water (non-carbonated). No other liquids should be used. Without crushing it, the tablet should be dropped in half a glass of drinking water. The glass should be swirled occasionally, until the tablet is dispersed (this may take up to 20 minutes). The dispersion should be drunk immediately after dispersion is complete (i.e. within 60 minutes). The glass should be rinsed with half a glass of water, which should also be drunk. The dispersion can also be administered through a naso-gastric or gastrostomy tube.

4.3.        Contraindications

• Hypersensitivity to the active substance or to any of the excipients
• Breast-feeding

4.4.       Special Warnings and Precautions for Use

When considering the use of Gefitinib as a treatment for locally advanced or metastatic NSCLC, it is important that EGFR mutation assessment of the tumour tissue is attempted for all patients. If a tumour sample is not evaluable, then circulating tumour DNA (ctDNA) obtained from a blood (plasma) sample may be used.

Only robust, reliable and sensitive test(s) with demonstrated utility for the determination of EGFR mutation status of tumours or ctDNA should be used to avoid false negative or false positive determinations.

Interstitial Lung Disease (ILD)

Interstitial lung disease (ILD), which may be acute in onset, has been observed in 1.3% of patients receiving gefitinib, andsome cases have been fatal (see section 4.8). If patients experience worsening of respiratory symptoms such as dyspnoea, cough and fever, Gefitinib should be interrupted and the patient should be promptly investigated. If ILD is confirmed, Gefitinib should be discontinued and the patient treated appropriately.

In a Japanese pharmacoepidemiological case control study in 3159 patients with NSCLC receiving gefitinib or chemotherapy who were followed up for 12 weeks, the following risk factors for developing ILD (irrespective of whether the patient received Gefitinib or chemotherapy) were identified: smoking, poor performance status (PS ≥ 2), CT scan evidence of reduced normal lung (≤ 50%), recent diagnosis of NSCLC (< 6 months), pre-existing ILD, older age (≥ 55 years old) and concurrent cardiac disease. An increased risk of ILD on gefitinib relative to chemotherapy was seen predominantly during the first 4 weeks of treatment (adjusted OR 3.8; 95% CI 1.9 to 7.7); thereafter the relative risk was lower (adjusted OR 2.5;95% CI 1.1 to 5.8). Risk of mortality among patients who developed ILD on gefitinib or chemotherapy was higher inpatients with the following risk factors: smoking, CT scan evidence of reduced normal lung (≤ 50%), pre-existing ILD, olderage (≥ 65 years old), and extensive areas adherent to pleura (≥ 50%).

Hepatotoxicity and Liver Impairment

Liver function test abnormalities (including increases in alanine aminotransferase, aspartate aminotransferase, bilirubin) have been observed, uncommonly presenting as hepatitis. There have been isolated reports of hepatic failure which in some cases led to fatal outcomes. Therefore, periodic liver function testing is recommended. Gefitinib should be used cautiously in the presence of mild to moderate changes in liver function. Discontinuation should be considered if changes are severe.

Impaired liver function due to cirrhosis has been shown to lead to increased plasma concentrations of gefitinib.

In patients who received Gefitinib across clinical trials, 11.4% of patients had increased alanine aminotransferase (ALT), 7.9% of patients had increased aspartate aminotransferase (AST), and 2.7% of patients had increased bilirubin. Grade 3 or higher liver test abnormalities occurred in 5.1% (ALT), 3.0% (AST), and 0.7% (bilirubin) of patients. The incidence of fatal hepatotoxicity was 0.04%.

Obtain periodic liver function testing. Withhold Gefitinib in patients with worsening liver function and discontinue in patients with severe hepatic impairment.

Interactions with other Medicinal Products

CYP3A4 inducers may increase metabolism of gefitinib and decrease gefitinib plasma concentrations. Therefore, concomitant administration of CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampicin, barbiturates or herbal preparations containing St John's wort/Hypericum perforatum) may reduce efficacy of the treatment and should be avoided.

In individual patients with CYP2D6 poor metaboliser genotype, treatment with a potent CYP3A4 inhibitor might lead to increased plasma levels of gefitinib. At initiation of treatment with a CYP3A4 inhibitor, patients should be closely monitored for gefitinib adverse reactions.

International normalised ratio (INR) elevations and/or bleeding events have been reported in some patients taking warfarin together with gefitinib. Patients taking warfarin and gefitinib concomitantly should be monitored regularly for changes in prothrombin time (PT) or INR.

Medicinal products that cause significant sustained elevation in gastric pH, such as proton-pump inhibitors and h-antagonists may reduce bioavailability and plasma concentrations of gefitinib and, therefore, may reduce efficacy. Antacids if taken regularly close in time to administration of gefitinib may have a similar effect.

Data from phase II clinical trials, where gefitinib and vinorelbine have been used concomitantly, indicate that gefitinib may exacerbate the neutropenic effect of vinorelbine.

Lactose

Gefitinib contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

Sodium

Gefitinib contains less than 1 mmol (23 mg) of sodium per tablet, that is to say it is essentially 'sodium-free'.

Gastrointestinal Perforation

Gastrointestinal perforation occurred in three (0.1%) of the 2462 gefitinib-treated patients across clinical trials. Permanently discontinue gefitinib in patients who develop gastrointestinal perforation.

Severe or Persistent Diarrhea

Grade 3 or 4 diarrhea occurred in 3% of 2462 gefitinib-treated patients across clinical trials. Withhold gefitinib for severe or persistent (up to 14 days) diarrhea.

Ocular Disorders including Keratitis

Ocular disorders [keratitis (0.1%), corneal erosion and aberrant eyelash growth (0.2%), conjunctivitis, blephritis and dry eye (6.7%)] occurred in the 2462 gefitinib-treated patients across clinical trials. The incidence of Grade 3 ocular disorders was 0.1%. Interrupt or discontinue gefitinib for severe, or worsening ocular disorders.

Bullous and Exfoliative Skin Disorders

Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme have been reported from treatment with gefitinib. Erythema multiforme and dermatitis bullous have been reported in two patients (0.08%) across NSCLC trials (Study 2, Study 3 and Study 4). Gefitinib treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.

Embryo-fetal Toxicity

Based on its mechanism of action and data from animal reproduction studies gefitinib can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with gefitinib and for at least two weeks following completion of therapy.

Further Precautions for Use

Patients should be advised to seek medical advice immediately if they experience severe or persistent diarrhoea, nausea, vomiting or anorexia as these may indirectly lead to dehydration. These symptoms should be managed as clinically indicated.

Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist.

If a diagnosis of ulcerative keratitis is confirmed, treatment with gefitinib should be interrupted, and if symptoms do notresolve, or if symptoms recur on reintroduction of gefitinib, permanent discontinuation should be considered.

In a phase I/II trial studying the use of gefitinib and radiation in paediatric patients, with newly diagnosed brain stem glioma or incompletely resected supratentorial malignant glioma, 4 cases (1 fatal) of Central Nervous System (CNS) haemorrhages were reported from 45 patients enrolled. A further case of CNS haemorrhage has been reported in a child with an ependymoma from a trial with gefitinib alone. An increased risk of cerebral haemorrhage in adult patients with NSCLC receiving gefitinib has not been established.

Gastrointestinal perforation has been reported in patients taking gefitinib. In most cases this is associated with other known risk factors, including concomitant medications such as steroids or NSAIDs, underlying history of GI ulceration, age, smoking or bowel metastases at sites of perforation.

4.5.       Drug Interactions

The metabolism of gefitinib is via the cytochrome P450 isoenzyme CYP3A4 (predominantly) and via CYP2D6.

Active Substances that may Increase Gefitinib Plasma Concentrations

In vitro studies have shown that gefitinib is a substrate of p-glycoprotein (Pgp). Available data do not suggest any clinical consequences to this in vitro finding.

Substances that inhibit CYP3A4 may decrease the clearance of gefitinib. Concomitant administration with potent inhibitors of CYP3A4 activity (e.g. ketoconazole, posaconazole, voriconazole, protease inhibitors, clarithromycin, telithromycin) may increase gefitinib plasma concentrations. The increase may be clinically relevant since adverse reactions are related to dose and exposure. The increase might be higher in individual patients with CYP2D6 poor metaboliser genotype. Pre-treatment with itraconazole (a potent CYP3A4 inhibitor) resulted in an 80% increase in the mean AUC of gefitinib in healthy volunteers. In situations of concomitant treatment with potent inhibitors of CYP3A4 the patient should be closely monitored for gefitinib adverse reactions.

There are no data on concomitant treatment with an inhibitor of CYP2D6 but potent inhibitors of this enzyme might cause increased plasma concentrations of gefitinib in CYP2D6 extensive metabolisers by about 2-fold. If concomitant treatment with a potent CYP2D6 inhibitor is initiated, the patient should be closely monitored for adverse reactions.

Active Substances that may Reduce Gefitinib Plasma Concentrations

Substances that are inducers of CYP3A4 activity may increase metabolism and decrease gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. Concomitant medicinal products that induce CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, barbiturates or St John's wort, Hypericum perforatum), should be avoided. Pre-treatment with rifampicin (a potent CYP3A4 inducer) in healthy volunteers reduced mean gefitinib AUC by 83%.

Substances that cause significant sustained elevation in gastric pH (e.g., proton pump inhibitors, histamine H -receptor antagonists, and antacids) may reduce gefitinib plasma concentrations and thereby reduce the efficacy of gefitinib. High doses of short-acting antacids may have a similar effect if taken regularly close in time to administration of gefitinib. Concomitant administration of gefitinib with ranitidine at a dose that caused sustained elevations in gastric pH ≥ 5 resulted in a reduced mean gefitinib AUC by 47% in healthy volunteers. Avoid concomitant use of gefitinib with proton pump inhibitors, if possible. If treatment with a proton-pump inhibitor is required, take gefitinib 12 hours after the last dose or 12 hours before the next dose of the proton-pump inhibitor. Take gefitinib 6 hours after or 6 hours before an H -receptor antagonist or an antacid.

Active Substances that may have their Plasma Concentrations Altered by Gefitinib

In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. In a clinical trial in patients, gefitinib was co-administered with metoprolol (a CYP2D6 substrate). This resulted in a 35% increase in exposure to metoprolol. Such an increase might potentially be relevant for CYP2D6 substrates with narrow therapeutic index. When the use of CYP2D6 substrates are considered in combination with gefitinib, a dose modification of the CYP2D6 substrate should be considered especially for products with a narrow therapeutic window.

Gefitinib inhibits the transporter protein BCRP in vitro, but the clinical relevance of this finding is unknown.

Hemorrhage in Patients taking Warfarin

International Normalized Ratio (INR) elevations and/or hemorrhage have been reported in some patients taking warfarin while on Gefitinib therapy. Patients taking warfarin should be monitored regularly for changes in prothrombin time or INR.

Other Potential Interactions

International normalized ratio (INR) elevations and/or bleeding events have been reported in some patients concomitantly taking warfarin.

4.6.       Use in Special Populations

Renal Impairment

Less than four percent (<4%) of gefitinib and its metabolites are excreted via the kidney. No clinical studies were conducted with gefitinib in patients with severe renal impairment.

Hepatic Impairment

The systemic exposure of gefitinib was compared in patients with mild, moderate, or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification) and healthy subjects with normal hepatic function (N=10/group). The mean systemic exposure (AUC0-∞) was increased by 40% in patients with mild impairment, 263% in patients with moderate impairment, and 166% in patients with severe hepatic impairment. Monitor adverse reactions when gefitinib is administered to patients with moderate and severe hepatic impairment.

In a study comparing 13 patients with liver metastases and moderate hepatic impairment (addition of CTC grade of baseline AST/SGOT, ALP, and bilirubin equals 3 to 5) to 14 patients with liver metastases and normal hepatic function, the systemic exposure of gefitinib was similar.

Pregnancy

Risk Summary

Based on its mechanism of action and animal data, gefitinib can cause fetal harm when administered to a pregnant woman. In animal reproductive studies, oral administration of gefitinib from organogenesis through weaning resulted in fetotoxicity and neonatal death at doses below the recommended human dose. Advise pregnant women of the potential hazard to a fetus or potential risk for loss of the pregnancy.

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and miscarriage is 15-20% of clinically recognized pregnancies.

Lactation

Risk Summary

It is not known whether gefitinib is excreted in human milk. Animal studies indicate the gefitinib and its metabolites are present in rat milk at a concentration higher than those in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from gefitinib, advise women to discontinue breast-feeding during treatment with gefitinib.

Females and Males of Reproductive Potential

Contraception

Based on its mechanism of action and animal data, gefitinib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with gefitinib and for at least two weeks following completion of therapy.

Infertility

Gefitinib may result in reduced fertility in females of reproductive potential.

Pediatric Use

The safety and effectiveness of gefitinib in pediatric patients have not been established.

Geriatric Use

Of the 823 patients enrolled in two randomized, active-controlled clinical trials 374 patients (45%) were 65 years and older, and 93 patients (11%) were 75 years and older. No overall differences in safety were observed between patients 65 years and older and those younger than 65 years. There is insufficient information to assess for differences in efficacy between older and younger patients.

4.7.        Effects on Ability to Drive and Use Machines

During treatment with gefitinib, asthenia has been reported. Therefore, patients who experience this symptom should be cautious when driving or using machines.

4.8.       Undesirable Effects

The most frequently reported adverse drug reactions (ADRs), occurring in more than 20% of the patients, are diarrhoea and skin reactions (including rash, acne, dry skin and pruritus). ADRs usually occur within the first month of therapy and are generally reversible. Approximately 8% of patients had a severe ADR (common toxicity criteria (CTC) grade 3 or 4). Approximately 3% of patients stopped therapy due to an ADR.

Interstitial lung disease (ILD) has occurred in 1.3% of patients, often severe (CTC grade 3-4). Cases with fatal outcomes have been reported.

Frequencies of occurrence of undesirable effects are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data)

Metabolism and Nutrition Disorders:

Very common: Anorexia mild or moderate (CTC grade 1 or 2).

Eye Disorders:

Common: Conjunctivitis, blepharitis, and dry eye, mainly mild (CTC grade 1).

Uncommon: Corneal erosion, reversible and sometimes in association with aberrant eyelash growth, keratitis (0.12%).

Vascular Disorders:

Common: Haemorrhage, such as epistaxis and haematuria.

Respiratory, Thoracic and Mediastinal Disorders:

Common: Interstitial lung disease (1.3%), often severe (CTC grade 3-4). Cases with fatal outcomes have been reported.

Gastrointestinal Disorders:

Very common: Diarrhoea, mainly mild or moderate (CTC grade 1 or 2); vomiting, mainly mild or moderate (CTC grade 1 or 2); nausea, mainly mild (CTC grade 1) and stomatitis, predominantly mild in nature (CTC grade 1).

Common: Dehydration, secondary to diarrhoea, nausea, vomiting or anorexia; dry mouth*, predominantly mild (CTC grade 1).

Uncommon: Pancreatitis and gastrointestinal perforation.

Hepatobiliary Disorders:

Very common: Elevations in alanine aminotransferase, mainly mild to moderate.

Common: Elevations in aspartate aminotransferase, mainly mild to moderate; elevations in total bilirubin, mainly mild to moderate.

Uncommon: Hepatitis**.

Skin and Subcutaneous Tissue Disorders:

Very common: Skin reactions, mainly a mild or moderate (CTC grade 1 or 2) pustular rash, sometimes itchy with dry skin, including skin fissures, on an erythematous base.

Common: Nail disorder, alopecia, allergic reactions (1.1%), including angioedema and urticarial.

Uncommon: Palmar-plantar erythrodysaesthesia syndrome

Rare: Bullous conditions including toxic epidermal necrolysis, Stevens Johnson syndrome and erythema multiforme, cutaneous vasculitis.

Renal and Urinary Disorders:

Common: Asymptomatic laboratory elevations in blood creatinine, proteinuria and cystitis.

Rare: Haemorrhagic cystitis.

General Disorders and Administration Site Conditions:

Very common: Asthenia, predominantly mild (CTC grade 1).

Common: Pyrexia.

The frequency of adverse drug reactions relating to abnormal laboratory values is based on patients with a change frombaseline of 2 or more CTC grades in the relevant laboratory parameters.

*This adverse reaction can occur in association with other dry conditions (mainly skin reactions) seen with gefitinib.

**This includes isolated reports of hepatic failure which in some cases led to fatal outcomes.

Interstitial Lung Disease (ILD)

In the INTEREST trial, the incidence of ILD type events was 1.4% (10) patients in the gefitinib group versus 1.1% (8) patients in the docetaxel group. One ILD-type event was fatal, and this occurred in a patient receiving gefitinib.

In the ISEL trial, the incidence of ILD-type events in the overall population was approximately 1% in both treatment arms. The majority of ILD-type events reported was from patients of Asian ethnicity and the ILD incidence among patients of Asian ethnicity receiving gefitinib therapy and placebo was approximately 3% and 4% respectively. One ILD-type event was fatal, and this occurred in a patient receiving placebo.

In a post-marketing surveillance study in Japan (3350 patients) the reported rate of ILD-type events in patients receiving gefitinib was 5.8%. The proportion of ILD-type events with a fatal outcome was 38.6%.

In a phase III open-label clinical trial (IPASS) in 1217 patients comparing Gefitinib to carboplatin/paclitaxel doublet chemotherapy as first-line treatment in selected patients with advanced NSCLC in Asia, the incidence of ILD-type events was 2.6% on the Gefitinib treatment arm versus 1.4% on the carboplatin/paclitaxel treatment arm.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

To report any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

4.9.       Overdose

There is no specific treatment in the event of overdose of gefitinib. However, in phase I clinical trials, a limited number of patients were treated with daily doses of up to 1000 mg. An increase of frequency and severity of some adverse reactions was observed, mainly diarrhoea and skin rash. Adverse reactions associated with overdose should be treated symptomatically; in particular severe diarrhoea should be managed as clinically indicated. In one study a limited number of patients were treated weekly with doses from 1500 mg to 3500 mg. In this study gefitinib exposure did not increase with increasing dose, adverse events were mostly mild to moderate in severity, and were consistent with the known safety profile of gefitinib.

5.    PHARMACOLOGICAL PROPERTIES

5.1.       Mechanism of Action

The epidermal growth factor (EGF) and its receptor (EGFR [HER1; ErbB1]) have been identified as key drivers in the process of cell growth and proliferation for normal and cancer cells. EGFR activating mutation within a cancer cell is an important factor in promotion of tumour cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis.

Gefitinib is a selective small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and is an effective treatment for patients with tumours with activating mutations of the EGFR tyrosine kinase domain regardless of line of therapy. No clinically relevant activity has been shown in patients with known EGFR mutation-negative tumours.

5.2 Pharmacodynamic Properties

The common EGFR activating mutations (Exon 19 deletions; L858R) have robust response data supporting sensitivity to gefitinib; for example a progression free survival HR (95% CI) of 0.489 (0.336, 0.710) for gefitinib vs. doublet chemotherapy [WJTOG3405]. Gefitinib response data is sparser in patients whose tumours contain the less common mutations; the available data indicates that G719X, L861Q and S7681 are sensitising mutations; and T790M alone or exon 20 insertions alone are resistance mechanisms.

Gefitinib reversibly inhibits the kinase activity of wild-type and certain activating mutations of EGFR, preventing autophosphorylation of tyrosine residues associated with the receptor, thereby inhibiting further downstream signaling and blocking EGFR-dependent proliferation.

Gefitinib binding affinity for EGFR exon 19 deletion or exon 21 point mutation L858R mutations is higher than its affinity for the wild-type EGFR. Gefitinib also inhibits IGF and PDGF-mediated signaling at clinically relevant concentrations; inhibition of other tyrosine kinase receptors has not been fully characterized.

Resistance

Most NSCLC tumours with sensitising EGFR kinase mutations eventually develop resistance to gefitinib treatment, with a median time to disease progression of 1 year. In about 60% of cases, resistance is associated with a secondary T790M mutation for which T790M targeted EGFR TKIs may be considered as a next line treatment option. Other potential mechanisms of resistance that have been reported following treatment with EGFR signal blocking agents include: bypass signalling such as HER2 and MET gene amplification and PIK3CA mutations. Phenotypic switch to small cell lung cancer has also been reported in 5-10% of cases.

Circulating Tumour DNA (ctDNA)

In the IFUM trial, mutation status was assessed in tumour and ctDNA samples derived from plasma, using the Therascreen EGFR RGQ PCR kit (Qiagen). Both ctDNA and tumour samples were evaluable for 652 patients out of 1060 screened. The objective response rate (ORR) in those patients who were tumour and ctDNA mutation positive was 77% (95% CI: 66% to86%) and in those who were tumour only mutation positive 60% (95% CI: 44% to 74%).

• Pharmacokinetic Properties

Absorption

Following oral administration of gefitinib, absorption is moderately slow and peak plasma concentrations of gefitinib typically occur at 3 to 7 hours after administration. Mean absolute bioavailability is 59% in cancer patients. Exposure to gefitinib is not significantly altered by food. In a trial in healthy volunteers where gastric pH was maintained above pH 5, Gefitinib exposure was reduced by 47%, likely due to impaired solubility of gefitinib in the stomach.

Distribution

Gefitinib has a mean steady-state volume of distribution of 1400 l indicating extensive distribution into tissue. Plasma protein binding is approximately 90%. Gefitinib binds to serum albumin and alpha 1-acid glycoprotein.

In vitro data indicate that gefitinib is a substrate for the membrane transport protein Pgp.

Biotransformation

In vitro data indicate that CYP3A4 and CYP2D6 are the major P450 isozyme involved in the oxidative metabolism of gefitinib.

In vitro studies have shown that gefitinib has limited potential to inhibit CYP2D6. Gefitinib shows no enzyme induction effects in animal studies and no significant inhibition (in vitro) of any other cytochrome P450 enzyme.

Gefitinib is extensively metabolised in humans. Five metabolites have been fully identified in excreta and 8 metabolites in plasma. The major metabolite identified was O-desmethyl gefitinib, which is 14-fold less potent than gefitinib at inhibiting EGFR stimulated cell growth and has no inhibitory effect on tumour cell growth in mice. It is therefore considered unlikely that it contributes to the clinical activity of gefitinib.

The formation of O-desmethyl gefitinib has been shown, in vitro, to be via CYP2D6. The role of CYP2D6 in the metabolic clearance of gefitinib has been evaluated in a clinical trial in healthy volunteers genotyped for CYP2D6 status. In poor metabolisers no measurable levels of O-desmethyl gefitinib were produced. The levels of exposure to gefitinib achieved in both the extensive and the poor metaboliser groups were wide and overlapping but the mean exposure to gefitinib was 2-fold higher in the poor metaboliser group. The higher average exposures that could be achieved by individuals with no active CYP2D6 may be clinically relevant since adverse effects are related to dose and exposure.

Elimination

Gefitinib is excreted mainly as metabolites via the faeces, with renal elimination of gefitinib and metabolites accounting for less than 4% of the administered dose.

Gefitinib total plasma clearance is approximately 500 ml/min and the mean terminal half-life is 41 hours in cancer patients. Administration of gefitinib once daily results in 2- to 8-fold accumulation, with steady-state exposures achieved after 7 to 10doses. At steady-state, circulating plasma concentrations are typically maintained within a 2- to 3-fold range over the 24-hour dosing interval.

Specific Populations

From analyses of population pharmacokinetic data in cancer patients, no relationships were identified between predictedsteady-state trough concentration and patient age, body weight, gender, ethnicity or creatinine clearance (above 20ml/min).Hepatic Impairment:

Hepatic Impairment

In a phase I open-label study of single dose gefitinib 250 mg in patients with mild, moderate or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification), there was an increase in exposure in all groups compared with healthy controls. An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib.

Gefitinib has been evaluated in a clinical trial conducted in 41 patients with solid tumours and normal hepatic function, or moderate or severe hepatic impairment (classified according to baseline Common Toxicity Criteria grades for AST, alkaline phosphatase and bilirubin) due to liver metastases. It was shown that following daily administration of 250 mg gefitinib, time to steady-state, total plasma clearance (C_maxss and steady-state exposure (AUC_24ss) were similar for the groups with normal and moderately impaired hepatic function. Data from 4 patients with severe hepatic impairment due to liver metastases suggested that steady-state exposures in these patients are also similar to those in patients with normal hepatic function.

CYP2D6 Poor Metabolizer

CYP2D6 metabolizes gefitinib to O-desmethyl gefitinib in vitro. In healthy CYP2D6 poor metabolizers, O-desmethyl gefitinib concentration was not measurable and the mean exposure to gefitinib was 2-fold higher as compared to the extensive metabolizers. This increase in exposure in CYP2D6 poor metabolizers may be clinically important because some adverse drug reactions are related to higher exposure of gefitinib. No dose adjustment is recommended in patients with a known CYP2D6 poor metabolizer genotype, but these patients should be closely monitored for adverse reactions. The impact of CYP2D6 inhibiting drugs on gefitinib pharmacokinetics has not been evaluated. However, similar precautions should be used when administering CYP2D6 inhibitors with gefitinib because of the possibility of increased exposure in these patients.

An exploratory exposure response analysis showed an increase in the incidence of interstitial lung disease (ILD) with a greater than 2-fold increase in the gefitinib exposure.

Drugs Affecting Gastric pH

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 on Day 15 of gefitinib dosing (500 mg daily for 28 days) in patients with solid tumors.

Preclinical Data

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to the clinical exposure levels and with possible relevance to clinical use were as follows:

- Corneal epithelia atrophy and corneal translucencies

- Renal papillary necrosis

- Hepatocellular necrosis and eosinophilic sinusoidal macrophage infiltration

Data from non-clinical (in vitro) studies indicate that gefitinib has the potential to inhibit the cardiac action potential repolarisation process (e.g. QT interval). Clinical experience has not shown a causal association between QT prolongation and gefitinib.

A reduction in female fertility was observed in the rat at a dose of 20 mg/kg/day.

Published studies have shown that genetically modified mice, lacking expression of EGFR, exhibit developmental defects, related to epithelial immaturity in a variety of organs including the skin, gastrointestinal tract and lung. When gefitinib was administered to rats during organogenesis, there were no effects on embryofetal development at the highest dose (30 mg/kg/day). However, in the rabbit, there were reduced fetal weights at 20 mg/kg/day and above. There were no compound-induced malformations in either species. When administered to the rat throughout gestation and parturition, there was a reduction in pup survival at a dose of 20 mg/kg/day.

Following oral administration of C-14 labelled gefitinib to lactating rats 14 days post-partum, concentrations of radioactivity in milk were 11-19 fold higher than in blood.

Gefitinib showed no genotoxic potential.

A 2-year carcinogenicity study in rats resulted in a small but statistically significant increased incidence of hepatocellular adenomas in both male and female rats and mesenteric lymph node haemangiosarcomas in female rats at the highest dose (10 mg/kg/day) only. The hepatocellular adenomas were also seen in a 2-year carcinogenicity study in mice, which demonstrated a small increased incidence of this finding in male mice at the mid dose, and in both male and female mice at the highest dose. The effects reached statistical significance for the female mice, but not for the males. At no-effect levels in both mice and rats there was no margin in clinical exposure. The clinical relevance of these findings is unknown.

The results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential.

6.    NONCLINICAL PROPERTIES

6.1 Animal Toxicology or Pharmacology

Gefitinib has been tested for genotoxicity in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the conditions of these assays, gefitinib did not cause genetic damage.

In a two-year carcinogenicity study in mice, administration of gefitinib at a dose of 270 mg/m²/day (approximately twice the recommended daily dose of 250 mg on a mg/m² basis; dose reduced from 375 mg/m²/day from week 22) caused hepatocellular adenomas in females. In a two-year carcinogenicity study in rats, administration of gefitinib at 60 mg/m²/day (approximately 0.4 times the recommended daily clinical dose on a mg/m² basis) caused hepatocellular adenomas and hemangiomas/hemagiosarcomas of the mesenteric lymph nodes in female rats. The clinical relevance of these findings is unknown.

In a dedicated fertility study in rats at doses ≥120 mg/m² (approximately equal to the recommended human dose of gefitinib on a mg/m2 basis), animals presented with an increased incidence of irregular estrous, decreased corpora lutea, and decreases in uterine implants and live embryos per litter.

7.    DESCRIPTION

Gefitinib is a kinase inhibitor. The chemical name of gefitinib is 4-Quinazolinamine N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4-morpholinyl) propoxy] and the following structural formula:

Gefitinib has the molecular formula C₂₂H₂₄ClFN₄O₃, a relative molecular mass of 446.9 daltons and is a white-colored powder. Gefitinib is a free base. The molecule has pKas of 5.4 and 7.2. Gefitinib can be defined as sparingly soluble at pH 1, but is practically insoluble above pH 7, with the solubility decreasing sharply between pH 4 and pH 6. In non-aqueous solvents, gefitinib is freely soluble in glacial acetic acid and dimethyl sulfoxide, soluble in pyridine, sparingly soluble in tetrahydrofuran, and slightly soluble in methanol, ethanol (99.5%), ethyl acetate, propan-2-ol and acetonitrile.

8.    PHARMACEUTICAL PARTICULARS

8.1 List of Excipients

Inactive Ingredients: Lactose monohydrate, Microcrystalline cellulose PH 101, Croscarmellose sodium, Sodium lauryl sulfate, Polyvinyl  Pyrrolidone K-30, Iso propyl alcohol, Magnesium stearate, Crospovidone

Tablet coating: Hydroxy propyl methyl cellulose 15, Talc, Titanium dioxide, Triacetin, Isopropyl alcohol, Dichloromethane, Yellow iron oxide (E172), Red iron oxide (E172)

Colours: Ferric oxide USP-NF Red, Ferric oxide USP-NF Yellow & Titanium Dioxide IP

8.2 Incompatibilities

Not applicable

8.3 Shelf-life

24 months

8.4 Packing Information

Container Pack of 10 Tablets & 30 Tablets

8.5 Storage and Handling Instructions

Store below 30°C. Protect from light and moisture.

Keep out of reach of children.

9.    PATIENT COUNSELLING INFORMATION

1. What Gefitinib is and what it is used for

Gefitinib which blocks a protein called ‘epidermal growth factor receptor’ (EGFR). This protein is involved in the growth and spread of cancer cells.

Gefitinib is used to treat adults with non-small cell lung cancer. This cancer is a disease in which malignant (cancer) cells form in the tissues of the lung.

2. What you need to know before you take Gefitinib

Do not take Gefitinib

• if you are allergic to gefitinib or any of the other ingredients of this medicine.
• if you are breast-feeding.

Warnings and precautions

Talk to your doctor or pharmacist before taking Gefitinib.

• if you have ever had any other lung problems. Some lung problems may get worse during treatment with Gefitinib.
• if you have ever had problems with your liver.

Children and adolescents

Gefitinib is not indicated in children and adolescents under 18 years.

Other medicines and Gefitinib

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

In particular, tell your doctor or pharmacist if you are taking any of the following medicines:

• Phenytoin or carbamazepine (for epilepsy).
• Rifampicin (for tuberculosis).
• Itraconazole (for fungal infections).
• Barbiturates (a type of medicine used for sleeping problems).
• Herbal remedies containing St John’s wort (Hypericum perforatum, used for depression and anxiety).
• Proton-pump inhibitors, H2-antagonists and antacids (for ulcers, indigestion, heartburn and to reduce acids in the stomach).

These medicines may affect the way Gefitinib works.

• Warfarin (a so-called oral anticoagulant, to prevent blood clots). If you are taking a medicine containing this active substance, your doctor may need to do blood tests more often.

If any of the above applies to you, or if you are not sure, check with your doctor or pharmacist before taking Gefitinib.

Pregnancy, breast-feeding and fertility

Talk to your doctor before taking this medicine if you are pregnant, may become pregnant or are breast-feeding.

It is recommended that you avoid becoming pregnant during treatment with Gefitinib because

Gefitinib could harm your baby.

Do not take Gefitinib if you are breast-feeding. This is for the safety of your baby.

Driving and using machines

You may feel weak while taking treatment with Gefitinib. If this happens, do not drive or use any tools or machines.

Gefitinib contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

Gefitinib contains sodium

This medicine contains less than 1 mmol (23 mg) of sodium per dose, that is to say it is essentially ‘sodium-free’.

3. How to take Gefitinib

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

• The recommended dose is one 250 mg tablet per day.
• Take the tablet at about the same time each day.
• You can take the tablet with or without food.
• Do not take antacids (to reduce the acid level of your stomach) 2 hours before or 1 hour after taking Gefitinib.

If you have trouble swallowing the tablet, dissolve it in half a glass of still (non-fizzy) water. Do not use any other liquids. Do not crush the tablet. Swirl the water until the tablet has dissolved.

This may take up to 20 minutes. Drink the liquid straight away. To make sure that you have drunk all of the medicine, rinse the glass very well with half a glass of water and drink it.

If you take more Gefitinib than you should

If you have taken more tablets than you should, talk to a doctor or pharmacist straight away.

If you forget to take Gefitinib

What to do if you forget to take a tablet depends on how long it is until your next dose.

• If it is 12 hours or more until your next dose: take the missed tablet as soon as you remember.

Then take the next dose as usual.

• If it is less than 12 hours until your next dose: skip the missed tablet. Then take the next tablet at the usual time.

Do not take a double dose (two tablets at the same time) to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Tell your doctor immediately if you notice any of the following side effects-you may need urgent medical treatment:

• Allergic reaction (common), particularly if symptoms include swollen face, lips, tongue or throat, difficulty to swallow, hives, nettle rash and difficulty breathing.
• Serious breathlessness, or sudden worsening breathlessness, possibly with a cough or fever. This may mean that you have an inflammation of the lungs called ‘interstitial lung disease’. This may affect about 1 in 100 patients taking Gefitinib and can be life-threatening.
• Severe skin reactions (rare) affecting large areas of your body. The signs may include redness, pain, ulcers, blisters, and shedding of the skin. The lips, nose, eyes and genitals may also be affected.
• Dehydration (common) caused by long term or severe diarrhoea, vomiting (being sick), nausea (feeling sick) or loss of appetite.
• Eye problems (uncommon), such as pain, redness, watery eyes, light sensitivity, changes in vision or ingrowing eyelashes. This may mean that you have an ulcer on the surface of the eye (cornea).

Tell your doctor as soon as possible if you notice any of the following side effects:

Very common: may affect more than 1 in 10 people

• Skin reactions such as an acne-like rash, which is sometimes itchy with dry and/or cracked skin.
• Loss of appetite.
• Red or sore mouth.
• Increase of a liver enzyme known as alanine aminotransferase in a blood test; if too high, your doctor may tell you to stop taking Gefitinib.

Common: may affect up to 1 in 10 people

• Dry mouth
• Dry, red or itchy eyes.
• Red and sore eyelids.
• Nail problems.
• Hair loss.
• Bleeding (such as nose bleed or blood in your urine).
• Protein in your urine (shown in a urine test).
• Increase of bilirubin and the other liver enzyme known as aspartate aminotransferase in a blood test; if too high, your doctor may tell you to stop taking Gefitinib.
• Increase of creatinine levels in a blood test (related to kidney function).
• Cystitis (burning sensations during urination and frequent, urgent need to urinate).

Uncommon: may affect up to 1 in 100 people

• Inflammation of the pancreas. The signs include very severe pain in the upper part of the stomach area and severe nausea and vomiting.
• Inflammation of the liver. Symptoms may include a general feeling of being unwell, with or without possible jaundice (yellowing of the skin and eyes). This side effect is uncommon; however, some patients have died from this.
• Gastrointestinal perforation.
• Skin reaction on the palms of the hands and soles of the feet including tingling, numbness, pain, swelling or reddening (known as palmar-plantar erythrodysaesthesia syndrome or hand and foot syndrome).

Rare: may affect up to 1 in 1,000 people

• Inflammation of the blood vessels in the skin. This may give the appearance of bruising or patches of non-blanching rash on the skin.
• Haemorrhagic cystitis (burning sensations during urination and frequent, urgent need to urinate with blood in the urine).

Reporting of side effects

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

To report any side effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 18002677779. By reporting side-effects, you can help provide more information on the safety of this product.

5. How to store Gefitinib

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, blister and overwrap foil after EXP. The expiry date refers to the last day of that month.

Store in the original package in order to protect from moisture.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help to protect the environment.

6. Contents of the pack and other information

What Gefitinib contains

• The active substance is gefitinib. Each tablet contains 250 mg of gefitinib.

10.    DETAILS OF MANUFACTURER

Manufactured by:

Hetero Labs Limited (Unit -I),

Village: Kalyanpur, Chakkan Road, Tehsil: Baddi,

Distt.: Solan, Himachal Pradesh-173 205.

Marketed by:

Cipla House,

Peninsula Business Park,

Ganpatrao Kadam Marg,

Lower Parel, Mumbai - 400 013 INDIA

11.    DETAILS OF PERMISSION OR LICENCE NUMBER WITH DATE

MNB/06/328 dated 15.01.2021

12.    DATE OF REVISION

21 June 2023