Giotrif

Afatinib.

Each film-coated tablet contains 40 mg, 30 mg, or 20 mg of Afatinib (=free base) corresponding to 59.12 mg, 44.34 mg, or 29.56 mg 2-butenamide, N-[4-[3(-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)- 2-butenedioate (1:2) (= afatinib dimaleate).
Excipients/Inactive Ingredients: Tablet Core: Lactose monohydrate, microcrystalline cellulose (E460), colloidal anhydrous silica (E551), crospovidone, magnesium stearate (E470b).
Film Coating: Hypromellose 2910 (E464), macrogol 400, titanium dioxide (E171), talc (E553b), polysorbate 80 (E433), colourant containing indigo carmine (E132), aluminium hydroxide (only used for 40 mg and 30 mg tablets).

Pharmacotherapeutic Group: Other antineoplastic agents-protein kinase inhibitors. ATC Code: L01XE13.
Pharmacology: Pharmacodynamics: Cardiac Electrophysiology: GIOTRIF at doses of 50 mg daily did not result in significant prolongation of the QTcF interval after single and multiple administrations in patients with relapsed or refractory solid tumours. There were no cardiac safety findings of clinical concern suggesting that GIOTRIF does not have a relevant effect on the QTcF interval.
Mechanism of Action: Afatinib is a potent and selective, irreversible ErbB Family Blocker. Afatinib covalently binds to and irreversibly blocks signalling from all homo- and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4.
Pharmacodynamic Effects: Aberrant ErbB signalling triggered by, for instance, EGFR mutations and/or amplification, HER2 amplification or mutation and/or ErbB ligand overexpression contributes to the malignant phenotype in subsets of patients across multiple cancer types. In preclinical disease models with ErbB pathway deregulation, afatinib as a single agent effectively blocks ErbB receptor signalling resulting in tumour growth inhibition or tumour regression. NSCLC models with either L858R or Del 19 EGFR mutations are particularly sensitive to afatinib treatment. Afatinib retains significant anti-tumour activity in NSCLC cell lines in vitro and tumour models in vivo (xenografts or transgenic models) driven by mutant EGFR isoforms known to be resistant to the reversible EGFR inhibitors erlotinib and gefitinib such as T790M.
Clinical Trials: GIOTRIF in Patients Naïve to EGFR TKI Treatment: LUX-Lung 3 (1200.32): In the first-line setting, the efficacy and safety of GIOTRIF in patients with EGFR mutation-positive locally advanced or metastatic NSCLC (stage IIIB or IV) were assessed in a global, randomised, multicentre, open-label trial (LUX-Lung 3). Patients naive to prior systemic treatment for their advanced or metastatic disease were screened for the presence of 29 different EGFR mutations using a polymerase chain reaction (PCR) based method (TheraScreen: EGFR29 Mutation Kit, Qiagen Manchester Ltd). Patients (N=345) were randomised (2:1) to receive GIOTRIF 40 mg orally once daily (N=230) or up to 6 cycles pemetrexed/cisplatin (N=115). Randomisation was stratified according to EGFR mutation status (L858R; Del 19; other) and race (Asian; non-Asian). Mean duration of treatment was 336 and 105 days for the GIOTRIF and chemotherapy arms, respectively.
The primary endpoint of PFS (independent review, 221 events) showed statistically significant improvement in the median PFS between patients treated with GIOTRIF and patients treated with chemotherapy (11.1 vs. 6.9 months). When comparing the pre-specified subgroup of common (L858R or Del 19) EGFR mutations, the difference in PFS was further pronounced (13.6 vs. 6.9 months). The percentage of patients alive and without progression (PFS rate) at 12 months was 46.5% in patients treated with GIOTRIF and 22% in patients treated with chemotherapy for the overall trial population, and 51.1% vs. 21.4% in the subgroup of common mutations.
The subgroup of "other" (uncommon) mutations was small (N=37; 11%) and genetically heterogeneous (10 different molecular subtypes with unequal distribution between the treatment groups) thereby limiting the value and interpretation of the pooled statistical analyses in this subset. Individual responses and prolonged disease stabilisation were observed in some patients with uncommon mutations.
The Kaplan-Meier curve of primary PFS analysis is shown in figure and efficacy results are summarised in Table 1. At the same time of primary analysis a total of 45 (20%) patients treated with GIOTRIF and 3 (3%) patients treated with chemotherapy were known to be alive and progression-free and are censored in figure. (See figure and Table 1).


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PFS benefit was accompanied by improvement in disease-related symptoms, as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ-C30 and QLQ-LC13). GIOTRIF significantly delayed the time to deterioration for pre-specified symptoms of cough (HR 0.6; p=0.0072) and dyspnoea (HR 0.68; p=0.0145) by more than 7 months when compared with chemotherapy. Time to deterioration of pain was also longer with GIOTRIF but did not reach statistical significance (HR 0.83; p=0.1913). Significantly more patients treated with GIOTRIF compared with those treated with chemotherapy had improvement for dyspnoea (64% vs. 50%; p=0.0103). A trend favouring GIOTRIF was observed for pain (59% vs. 48%; p=0.0513), with individual items of pain reaching significance ('Have pain': 56.0% vs. 40.0%; p=0.0095; 'Pain in chest': 51.0% vs. 37.0%; p=0.0184; 'Pain in arm or shoulder': 41.0% vs. 26.0%; p=0.0103). For cough, numerically more patients improved on GIOTRIF (67% vs. 60%; p=0.2444).
Mean scores over time for health-related quality of life (HRQoL) were measured using the EORTC QLQC30. Mean scores over time for overall quality of life and global health status were significantly better for GIOTRIF compared with chemotherapy. Mean scores were significantly better in 3 of the 5 functioning domains (physical, role, cognitive) and showed no difference in the emotional and social functioning domains.
LUX-Lung 2 (1200.22): Lux-Lung 2 was an open label single arm Phase II trial which investigated the efficacy & safety of GIOTRIF in 129 EGFR TKI-naïve patients with locally advanced or metastatic lung adenocarcinoma (stage IIIB or IV) with EGFR mutations. Patients were enrolled in the first-line (N=61) or second-line setting (N=68) (i.e. after failure of 1 prior chemotherapy regimen). Patients were centrally screened for EGFR mutations.
The primary endpoint was ORR. Secondary endpoints included PFS, DCR and OS.
In 61 patients treated in the first-line setting, confirmed ORR was 65.6% and DCR was 86.9% according to independent review. The median PFS was 12.0 months by independent review and 15.6 months by investigator assessment. Median OS was not reached in the first-line population. Efficacy was similarly high in the group of patients who had received prior chemotherapy (N=68; ORR 57.4%; PFS by independent review 8 months and by investigator assessment 10.5 months; DCR 77.9%). Median OS in the second line patients was 23.3 months (95% CI 18.5-38).
Pharmacokinetics: Absorption and Distribution: Following oral administration of GIOTRIF, maximum concentrations (C_max) of afatinib are observed approximately 2 to 5 hours post dose. Mean C_max and AUC_0-∞ values increased slightly more than 50 mg GIOTRIF. Systemic exposure to afatinib is decreased by 50% (C_max) and 39% (AUC_0-∞), when administered with a high-fat meal compared with administration in the fasted state. Based on population pharmacokinetic data derived from clinical trials in various tumour types, an average decrease of 26% in AUC_Τ,ss was observed when food was consumed within 3 hours before or 1 hour after taking GIOTRIF. Therefore, food should not be consumed for at least 3 hours before and at least 1 hour after taking GIOTRIF (see Dosage & Administration and Interactions). After administration of GIOTRIF, the mean relative bioavailability was 92% (adjusted gMean ratio of AUC_0-∞) when compared to an oral solution.
In vitro binding of afatinib to human plasma proteins is approximately 95%.
The volume of distribution was 1,940 L for single dose treatment and 2,770 L at steady state. The absolute bioavailability of GIOTRIF is unknown.
Metabolism and Excretion: Enzyme-catalyzed metabolic reactions play a negligible role for afatinib in vivo. Covalent adducts to proteins are the major circulating metabolites of afatinib. Following administration of an oral solution of 15 mg afatinib, 85.4% of the dose was recovered in the faeces and 4.3% in urine. The parent compound afatinib accounted for 88% of the recovered dose. The apparent terminal half-life is 37 hours. Steady state plasma concentrations of afatinib are achieved within 8 days of multiple dosing of afatinib resulting in an accumulation of 2.77-fold (AUC) and 2.11-fold (C_max).
Renal Impairment: Less than 5% of a single dose of afatinib is excreted via the kidneys. The safety, pharmacokinetics and efficacy of GIOTRIF have not been studied specifically in patients with renal impairment. Based on population pharmacokinetic data derived from clinical trials in various tumour types, no dose adjustments appear necessary in patients with mild or moderate renal impairment (see Population Pharmacokinetic Analysis in Special Populations as follows and Dosage & Administration).
Hepatic Impairment: Afatinib is eliminated mainly by biliary/faecal excretion. Subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment had similar exposure in comparison to healthy volunteers following a single dose of 50 mg GIOTRIF. This is consistent with population pharmacokinetic data derived from clinical trials in various tumour types (see Population Pharmacokinetic Analysis in Special Populations as follows). No starting dose adjustments appear necessary in patients with mild or moderate hepatic impairment (see Dosage & Administration). The pharmacokinetics of afatinib had not been studied in subjects with severe (Child-Pugh C) hepatic dysfunction (see Precautions).
Population Pharmacokinetic Analysis in Special Populations: A population pharmacokinetic analysis was performed in 927 cancer patients (764 with NSCLC) receiving GIOTRIF monotherapy. No starting dose adjustment is considered necessary for any of the following covariates tested.
Age: No significant impact of age (range: 28-87 years) the pharmacokinetics of afatinib could be observed.
Body Weight: Plasma exposure (AUC_t,ss) was increased by 26% for a 42 kg patient (2.5th percentile) and decreased by 22% for a 95 kg patient (97.5th percentile) relative to a patietn weighing 62 kg (median body weight of patients in the overall patient population).
Gender: Female patients had a 15% higher plasma exposure (AUC_Τ,ss, body weight corrected) than male patients.
Race: There was no statistically significant difference in afatinib pharmacokinetics between Asian and Caucasian patients. Also, no obvious difference in pharmacokinetics for American Indian/Alaska native or Black patients could be detected based on the limited data available in these populations (6 and 9 out of 927 patients included in the analysis, respectively).
Renal Impairment: Exposure to GIOTRIF moderately increased with lowering the creatinine clearance (CrCl), i.e. for a patient with a CrCl of 60 or 30 mL/min exposure (AUC_Τ,ss) to afatinib increased by 13% and 42%, respectively, and decreased by 6% and 20% for a patient with CrCl of 90 or 120 mL, respectively, compared to a patient with the CrCl of 79 mL/min (median CrCl of patients in the overall patient population analysed).
Hepatic Impairment: Patients with mild and moderate hepatic impairment as identified by abnormal liver tests did not correlate with any significant change in afatinib exposure.
Other Patient Characteristics/Intrinsic Factors: Other patient characteristics/intrinsic factors found with a significant impact on afatinib exposure were: ECOG performance score, lactate dehydrogenase levels, alkaline phosphatase levels and total protein. The individual effect sizes of these covariates were considered not clinically relevant. Smoking history, alcohol consumption, or presence of liver metastases had no significant impact on the pharmacokinetics of afatinib.
Pharmacokinetic Drug Interactions: Drug Transporters: P-glycoprotein (P-gp): Effect of P-gp Inhibitors and Inducers on Afatinib: Two trials were conducted to assess the effect of ritonavir, a potent inhibitor of P-gp, on the pharmacokinetics of afatinib. In one trial, the relative bioavailability of afatinib was investigated when ritonavir (200 mg b.i.d for 3 days) was given either simultaneously or 6 hours after a single dose of 40 mg GIOTRIF. The relative bioavailability of afatinib was 119% (AUC_0-∞) and 104% (C_max) when administered simultaneously with ritonavir and 111% (AUC_0-∞) and 105% (C_max) when ritonavir was administered 6 hours after GIOTRIF. In a second trial when ritonavir (200 mg b.i.d for 3 days) was administered 1 hour before a single dose of 20 mg GIOTRIF, exposure to afatinib increased by 48% (AUC_0-∞) and 39% (C_max) (see Dosage & Administration, Precautions, and Interactions).
Pre-treatment with rifampicin (600 mg q.d. for 7 days), a potent inducer of P-gp, decreased the plasma exposure to afatinib by 34% (AUC_0-∞) and 22% (C_max) after administration of a single dose of 40 mg GIOTRIF (see Precautions and Interactions).
Effect of Afatinib on P-gp Substrates: Based on in vitro data, afatinib is a moderate inhibitor of P-gp. It is considered unlikely that GIOTRIF treatment will result in changes of the plasma concentrations of other P-gp substrates.
Breast Cancer Resistance Protein (BCRP): In vitro studies indicated that afatinib is a substrate and an inhibitor of the transporter BCRP.
Drug Uptake Transport Systems: In vitro data indicated that drug-drug interactions with afatinib due to inhibition of OATB1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and OCT3 transporters are considered unlikely.
Drug Metabolising Enzymes: Cytochrome P450 (CYP) Enzymes: Effect of CYP Enzymes Inducers and Inhibitors on Afatinib: In vitro data indicated that drug-drug interactions with afatinib due to inhibition or induction of CYP enzymes by concomitant medicines are considered unlikely. In humans, it was found that enzyme-catalyzed metabolic reactions play a negligible role for the metabolism of afatinib. Approximately 2% of the afatinib dose was metabolized by FMO3 and the CYP3A4-dependent N-demethylation was too low to be quantitatively detected.
Effect of Afatinib on CYP Enzymes: Afatinib is not an inhibitor or an inducer of CYP enzymes. Therefore, GIOTRIF is unlikely to affect the metabolism of other medicines that are dependent on CYP enzymes.
UDP-glucuronosyltransferase 1A1 (UGT1A1): In vitro data indicated that drug-drug interactions with afatinib due to inhibition of UGT1A1 are considered unlikely.
Toxicology: Oral administration of single doses to mice and rats indicated a low acute toxic potential of afatinib. In oral repeated-dose studies for up to 26 weeks in rats or 52 weeks in minipigs, the main effects were identified in the skin (dermal changes, epithelial atrophy and folliculitis in rats), the gastrointestinal tract (diarrhoea, erosions in the stomach, epithelial atrophy in rats and minipigs) and the kidneys (papillary necrosis in rats). Depending on the finding, these changes occurred at exposures below, in the range of or above clinically relevant levels. Additionally, in various organs pharmacodynamically mediated atrophy of epithelia was observed in both species.
Reproduction Toxicity: Based on the mechanism of action, GIOTRIF has the potential to cause foetal harm. The embryofoetal development studies performed on afatinib revealed no indication of teratogenicity up to dose levels including maternal death. Changes identified were restricted to skeletal alterations consisting of incomplete ossifications/unossified elements (rat) and abortions at maternally toxic dose, reduced foetal weights as well as mainly visceral and dermal variations (rabbit). The respective total systemic exposure (AUC) was either slightly above (2.2 times in rats) or below (0.3 times in rabbits) compared with levels in patients.
Radiolabelled afatinib administered orally to pregnant rats on Day 11 of lactation was excreted into milk of the dams. The average concentrations in milk at time points 1 h and 6 h post dose were approximately 80- and 150-fold above the respective concentration in plasma.
A fertility study in male and female rats by the oral route up to the maximum tolerated dose revealed no significant impact on fertility. The total systemic exposure (AUC_0-24) that could be achieved in male and female rats was in the range or less than that observed in patients (1.3 times and 0.51 times, respectively).
A study in rats by the oral route up to the maximum tolerated doses revealed no significant impact on pre-/postnatal development. Effects were limited to lower birth weight and body weight gain of offspring but without materially affecting the attainment of developmental landmarks, sexual maturation or performance with behavioural assessments. The highest total systemic exposure (AUC_0-24) that could be achieved in female rats was less than that observed in patients (0.23 times).
Phototoxicity: An in vitro 3T3 phototoxicity test with afatinib was performed. It was concluded that GIOTRIF may have phototoxicity potential.
Carcinogenicity: Carcinogenicity studies have not been conducted with GIOTRIF.
A marginal response to afatinib was observed in a single tester strain of a bacterial (Ames) mutagenicity assay. However, no mutagenic or genotoxic potential could be identified in an in vitro chromosomal aberration test at non-cytotoxic concentrations as well as the in vivo bone marrow micronucleus assay, the in vivo Comet assay and an in vivo 4-week oral mutation study in the Muta Mouse.

GIOTRIF as monotherapy is indicated for the treatment of locally advanced or metastatic non-squamous non-small cell lung carcinoma with adenocarcinoma is predominantly, Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, TKI-naive adult patients.
Limitation of Use: Safety and efficacy of GIOTRIF have not been established in patients whose tumors have other EGFR mutations.

Dosing Considerations: GIOTRIF treatment should be continued until disease progression or until no longer tolerated by the patient (See Table 2).
Recommended Starting Dose: 40 mg orally once daily.
Dose Adjustment for Adverse Reactions: Symptomatic adverse drug reactions (e.g. severe/ persistent diarrhea or skin related adverse reactions) may be successfully managed by treatment interruption and dose reductions of GIOTRIF as outlined in Table 2.


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Use of P-glycoprotein (P-gp) Inhibitors: Concurrent use of strong P-gp inhibitors or inducers with GIOTRIF should be avoided. If P-gp inhibitors need to be taken, they should be administered simultaneously with or after GIOTRIF.
Patients should be closely monitored for GIOTRIF-related toxicities that may warrant GIOTRIF dose adjustment.
For patients with emesis, a replacement dose of GIOTRIF is NOT to be taken to make up any potential loss. Take the next dose as scheduled.
Interstitial Lung Disease (ILD): See Respiratory, Interstitial Lung Disease under Precautions.
Missed Dose: If a dose of GIOTRIF is missed, it should be taken during the same day as soon as the patient remembers. However, if the next scheduled dose is due within 8 hours then the missed dose must be skipped.
Children: Treatment of children or adolescents with GIOTRIF is not recommended.
Renal Impairment: Renal impairment increases exposure to afatinib. No starting dose adjustment is recommended, although patients with moderate renal impairment may be at greater risk of drug-associated toxicities. Close monitoring is recommended in this patient population.
GIOTRIF treatment in patients with severely impaired renal function (<30 ml/min creatinine clearance) is not recommended.
Hepatic Impairment: Adjustment to the starting dose is not recommended in patients with mild or moderate hepatic impairment. GIOTRIF treatment is not recommended in patients with severe (Child-Pugh C) hepatic impairment.
Administration: Take GIOTRIF on an empty stomach at least 1 hour before or 3 hours after eating. Tablets should be swallowed whole with water.

Symptoms: The highest dose of GIOTRIF studied in a limited number of patients in Phase I clinical trials was 160 mg once daily for 3 days and 100 mg once daily for 2 weeks. The adverse reactions observed at this dose were primarily dermatological (rash/acne) and gastrointestinal events (especially diarrhoea). Overdose in 2 healthy adolescents involving the ingestion of 360 mg each of GIOTRIF (as part of a mixed drug ingestion) was associated with adverse drug reactions of nause, vomiting, asthenia, dizziness, headache, abdominal pain and elevated amylase (<1.5 times ULN). Both subjects recovered from these adverse events.
Treatment: There is no specific antidote for overdose with GIOTRIF. In cases of suspected overdose, GIOTRIF should be withheld and supportive care instituted. If indicated, elimination of unabsorbed afatinib may be achieved by emesis or gastric lavage.

GIOTRIF is contraindicated in patients with known hypersensitivity to afatinib or to any of the excipients.

Assessment of EGFR Mutation Status: When assessing the EGFR mutation status of a patient, it is important that a well-validated and robust methodology is chosen to avoid false negative or false positive determinations.
Diarrhoea: Diarrhoea, including severe diarrhoea, has been reported during treatment with GIOTRIF (see Side Effects). Diarrhoea may result in dehydration with or without renal impairment, which in rare cases has resulted in fatal outcomes. Diarrhoea usually occurred within the first 2 weeks of treatment. Grade 3 diarrhoea most frequently occurred within the first 6 weeks of treatment. Proactive management of diarrhoea including adequate hydration combined with anti-diarrhoeal especially within the first 6 weeks of the treatment is important and should start at first signs of diarrhoea. Antidiarrhoeal agents (e.g. loperamide) should be used and if necessary their dose should be escalated to the highest recommended approved dose. Antidiarrhoeal agents should be readily available to the patients so that treatment can be initiated at first signs of diarrhoea and continued until loose bowel movements cease for 12 hours. Patients with severe diarrhoea may require interruption and dose reduction or discontinuation of therapy with GIOTRIF (see Dosage & Administration). Patients who become dehydrated may require administration of intravenous electrolytes and fluids.
Skin Related Adverse Events: Rash/acne has been reported in patients treated with GIOTRIF (see Side Effects). In general, rash manifests as a mild or moderate erythematous and acneiform rash, which may occur or worsen in areas exposed to sun. For patients who are exposed to sun, protective clothing, and/or use of sun screen is advisable. Early intervention (e.g. emollients, antibiotics) of dermatologic reactions can facilitate continuous GIOTRIF treatment. Patients with prolonged or severe skin reactions may also require temporary interruption of therapy, dose reduction (see Dosage & Administration), additional therapeutic intervention, and referral to a specialist with expertise in managing these dermatologic effects. Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome. GIOTRIF treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.
Female Gender, Lower Body Weight, and Underlying Renal Impairment: Higher exposure to afatinib has been observed in female patients, patients with lower body weight and those with underlying renal impairment (see Pharmacology: Pharmacokinetics under Actions). This could result in a higher risk of developing EGFR mediated adverse events such as diarrhoea, rash/acne and stomatitis. Closer monitoring is recommended in patients with these risk factors.
Interstitial Lung Disease (ILD): There have been reports of ILD or ILD-like events (such as Lung infiltration, Pneumonitis, Acute respiratory distress syndrome, Alveolitis allergic), including fatalities, in patients receiving GIOTRIF for treatment of NSCLC. Drug related ILD-like events were reported in 0.7% of more than 3,800 patients treated. CTCAE Grade ≥3 ILD-like events, regardless of causality, were reported in 1% of patients (see Side Effects). Patients with a history of ILD have not been studied. Careful assessment of all patients with an acute onset and/ or unexplained worsening of pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude ILD. GIOTRIF should be interrupted pending investigation of these symptoms. If ILD is diagnosed, GIOTRIF should be permanently discontinued and appropriate treatment instituted as necessary (see Dosage & Administration).
Severe Hepatic Impairment: Hepatic failure, including fatalities, has been reported during treatment with GIOTRIF in less than 1% of patients. In these patients, confounding factors have included pre-existing liver disease and/or comorbidities associated with progression of underlying malignancy. Periodic liver function testing is recommended in patients with pre-existing liver disease. GIOTRIF dose interruption may become necessary in patients who experience worsening of liver function (see Dosage & Administration). In patients who develop severe hepatic impairment while taking GIOTRIF, treatment should be discontinued.
Keratitis: Symptoms 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 GIOTRIF should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GIOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration (see Side Effects).
Left Ventricular Function: Left ventricular dysfunction has been associated with HER2 inhibition. Based on the available clinical trial data, there is no suggestion that GIOTRIF causes an adverse effect on cardiac contractility. However, GIOTRIF has not been studied in patients with abnormal left ventricular ejection fraction (LVEF) or those with significant cardiac history. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including an assessment of LVEF at baseline and during GIOTRIF treatment, should be considered. In patients that develop relevant cardiac signs/symptoms during treatment, cardiac monitoring including LVEF assessment should be considered.
In patients with an ejection fraction below the institution's lower limit of normal, cardiac consultation as well as GIOTRIF treatment interruption or discontinuation should be considered.
P-glycoprotein (P-gp) Interactions: Strong inhibitors of P-gp if administered prior to GIOTRIF may lead to increased exposure to afatinib and therefore should be used with caution. If P-gp inhibitors need to be taken, they should be administered simultaneously with or after GIOTRIF. Concomitant treatment with strong inducers of P-gp may decrease exposure to afatinib (see Pharmacology: Pharmacokinetics under Actions, Dosage & Administration, and Interactions).
Lactose: GIOTRIF contains lactose. Patients with rare hereditary conditions of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive or operate machinery have been performed.
Impairment of Fertility: Fertility studies in humans have not been performed with GIOTRIF. Available nonclinical toxicology data have shown effects on reproductive organs at higher doses (see Pharmacology: Toxicology under Actions). Therefore, an adverse effect of GIOTRIF therapy on human fertility cannot be excluded.

Use in Pregnancy: Nonclinical studies with afatinib have shown no signs of teratogenicity up to and including maternally lethal dose levels. Adverse changes were restricted to overtly toxic dose levels (see Pharmacology: Toxicology under Actions).
There are no studies in pregnant women using GIOTRIF. The potential risk for humans is thus unknown. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with GIOTRIF. Adequate contraceptive methods should be used during therapy and for at least 2 weeks after the last dose. If GIOTRIF is used during pregnancy or if the patient becomes pregnant while receiving GIOTRIF, the patient should be apprised of the potential hazard to the foetus.
Use in Lactation: Based on nonclinical data (see Pharmacology: Toxicology under Actions), it is likely that afatinib is excreted in human milk. A risk to the nursing child cannot be excluded. Mothers should be advised against breast-feeding while receiving GIOTRIF.

Adverse Drug Reaction Overview: The safety evaluation of GIOTRIF is based on the data from more than 3,865 patients, including 2,135 NSCLC patients treated with GIOTRIF monotherapy at or above the recommended dose. The types of adverse drug reactions (ADRs) were generally associated with the EGFR inhibitory mode of action of afatinib. The most frequent ADRs were diarrhea and skin related adverse events as well as stomatitis and paronychia. ILD-like adverse reactions were reported in 0.7% in all GIOTRIF treated patients and 1.3% of patients treated with GIOTRIF in the pivotal clinical trial. Overall, dose reduction led to a lower frequency of common adverse reactions. In patients treated with once daily GIOTRIF 40 mg dose reductions due to ADRs occurred in 57% of the patients. Discontinuation due to ADRs diarrhea and rash was 1.3% and 0% respectively. Bullous, blistering and exfoliative skin conditions have been reported including rare case suggestive of Steven-Johnson.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Pivotal Phase III Trial (LUX-Lung 3): In the pivotal LUX-Lung 3 study, a total of 229 patients not previously treated with an EGFR inhibitor (EGFR TKI-naïve patients) were treated with GIOTRIF with a starting dose of 40 mg once daily until disease progression or intolerance. In the control arm, a total of 111 patients received pemetrexed/cisplatin up to 6 cycles. The median duration of treatment were 336 and 105 days in the GIOTRIF and chemotherapy arms, respectively. Adverse event reported in ≥10% of GIOTRIF treated patients are presented in Table 3 as follows. The incidence of diarrhea and rash AEs was higher in the GIOTRIF treated patients than in those treated with pemetrexed/cisplatin.
Overall, serious AEs were reported in 28.8% patients. The most frequent serious AEs (≥1%) were diarrhea (6.6%), vomiting (4.8%), dyspnea (1.7%), fatigue (1.7%), dehydration (1.3%), pneumonia (1.3%), and stomatitis (1.3%). Fatal adverse events related to GIOTRIF included one event each of dyspnea, ARDS (ILD), sepsis and death (not otherwise specified).
Clinical trial of GIOTRIF excluded patients with an abnormal left ventricular ejection fraction (LVEF), i.e., below the institutional lower limit of normal. In LUX-Lung 3, all patients were evaluated for LVEF at screening and every 9 weeks thereafter in the GIOTRIF-treated group and as needed in the pemetrexed/cisplatin group. More GIOTRIF-treated patients (2.2%; n=5) experienced ventricular dysfunction (defined as diastolic dysfunction, left ventricular dysfunction, or ventricular dilation; all < Grade 3) compared to the chemotherapy-treated patients (0.9%; n=1).
From pooled data of 2,135 NSCLC patients treated with GIOTRIF monotherapy, events of cardiac failure (acute left ventricular failure, cardiac failure, and diastolic dysfunction) assessed as drug related by the investigator have been reported uncommonly (<1%).
Dose reduction due to AEs occurred in 57% of GIOTRIF-treated patients. Overall dose reduction appeared to have led to a lower frequency of common adverse events (e.g. after first dose reduction, frequency for diarrhea regardless of causality decreased from 96% to 52%).
The most common (>1%) AEs leading to dose reduction in patients treated with GIOTRIF included diarrhea (19.7%), rash (19.2%), paronychia (13.1%), stomatitis (10%), decreased appetite (3.1%), vomiting (3.1%), palmar-plantar erythrodysesthesia syndrome (1.7%), ALT increase (1.3%), AST increase (1.3%), glomerular filtration rate (GFR) decreased (1.3%), nausea (1.3%), and pruritus (1.3%).
Discontinuation of GIOTRIF therapy due to AEs occurred in 14% of patients.
Discontinuation of GIOTRIF therapy due to ADRs occurred in 8% patients. The most common (≥0.5%) AEs that led to discontinuation in the pivotal study were diarrhea (1.3%), dyspnea (0.9%), ILD (0.9%), pleural effusion (0.9%), pneumonia (0.9%) and paronychia (0.9%). (See Tables 3 and 4.)


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Adverse Events Considered Drug Related to GIOTRIF by the Investigator in 1 to 10% patients in LUX-Lung 3 (All Grades): Infection and Infestations: Cystitis (4%), rhinitis (2%), cellulitis (1%), herpes zoster (1%), upper respiratory tract infection (1%).
Blood and Lymphatic System Disorders: Anemia (3%), leukopenia (2%).
Gastrointestinal Disorders: Dyspepsia (4%), dry mouth (4%), abdominal pain (3%), constipation (3%), abdominal distension (2%), abdominal pain upper (2%), gastritis (2%), gastroesphageal reflux disease (2%), dysphagia (1%), abdominal discomfort (1%), gingival bleeding (1%), proctalgia (1%), tongue ulceration (1%).
Hepatobiliary Disorders: Hepatic functions abnormal (2%).
Nervous System Disorder: Dysgeusia (7%), headache (5%), dizziness (4%), hypoesthesia (2%).
Musculoskeletal and Connective Tissue Disorders: Muscle spasm (3%), back pain (2%), myalgia (2%), arthralgia (1%), musculoskeletal chest pain (1%).
Skin and Subcutaneous Tissue Disorders: Alopecia (10%), Palmar-Plantar erythrodysesthesia syndrome (7%), nail disorder (5%), hypertrichosis (3%), pain of skin (3%), skin hyperpigmentation (1%).
Renal and Urinary Disorders: Renal impairment/renal failure (4%), proteinuria (1%).
Eye Disorders: Conjunctivitis (8%), dry eye (5%), keratitis (2%), blepharitis (2%), lacrimation increased (2%), cataract (1%), eye discharge (1%), vision blurred (1%).
Investigations: Alanine aminotransferase increased (7%), aspartate aminotransferase increased (5%), blood alkaline phosphatase increased (2%), hemoglobin decreased (1%).
General Disorders and Administration Site Conditions: Pyrexia (5%), asthenia (4%), edema peripheral (3%), edema (2%), xerosis (2%), chest pain (1%).
Psychiatric Disorders: Insomnia (5%).
Metabolism and Nutritions Disorders: Hypokalemia (6%), dehydration (2%).
Respiratory, Thoratic and Mediastinal Disorders: Rhinorrhea (10%), Cough (3%), nasal dryness (3%), dyspnea (2%), oropharyngeal pain (2%), hemoptysis (1%), interstitial lung disease (1%).
Vascular Disorders: Hypertension (2%).
Injury, Poisoning and Procedural Complications: Wound (1%).
Clinically Important, Afatinib-Related AEs <1% Include: Blood and Lymphatic System Disorders: Lymphopenia, neutropenia.
Cardiac Disorders: Mitral valve incompetence.
Gastrointestinal Disorders: Pancreatitis acute.
General Disorders and Administration Site Conditions: Death.
Infections and Infestations: Sepsis.
Investigations: Blood amylase increased, blood creatine phosphokinase increased, neutrophil count decreased.
Metabolism and Nutrition Disorders: Hypocalcaemia, hyponatraemia.
Respiratory, Thoracic and Mediastinal Disorders: Pulmonary embolism.
Skin and Subcutaneous Tissue Disorders: Hyperkeratosis.

P-glycoprotein (P-gp) Interactions: Based on in vitro data, afatinib is a substrate of P-gp. Based on clinical data, concomitant administration of strong P-gp inhibitors or inducers may alter exposure to afatinib. Results of a drug interaction trial demonstrated that GIOTRIF can be safely combined with P-gp inhibitors (such as ritonavir) as long as the inhibitor is administered simultaneously with or after GIOTRIF. If administered prior to GIOTRIF, strong P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) may increase exposure to afatinib and should be used with caution. (see Pharmacology: Pharmacokinetics under Actions, Dosage & Administration, and Precautions ).
Strong P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital or St. John's Wort) may decrease exposure to afatinib. (see Pharmacology: Pharmacokinetics under Action and Precautions).
Food Effect on Afatinib: Co-administration of a high-fat meal with GIOTRIF resulted in a significant decrease of exposure to afatinib by about 50% in regard to C_max and 39% in regard to AUC_0-∞. GIOTRIF should be administered without food (see Pharmacology: Pharmacokinetics under Action and Dosage & Administration).

Store below 30°C. Store in the original package in order to protect from moisture and light.

Targeted Cancer Therapy

L01EB03 - afatinib ; Belongs to the class of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Used in the treatment of cancer.