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4.1 Therapeutic indications
Non-small cell lung cancer (NSCLC):
Tarceva is indicated for the first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR activating mutations.
Tarceva is also indicated as monotherapy for maintenance treatment in patients with locally advanced or metastatic NSCLCnon-small cell lung cancer with stable disease after 4 cycles of standard platinum-based first-line chemotherapy.
Tarceva is also indicated for the treatment of patients with locally advanced or metastatic NSCLCnon‑small cell lung cancer after failure of at least one prior chemotherapy regimen.
No survival benefit or other clinically relevant effects of the treatment have been demonstrated in patients with Epidermal Growth Factor Receptor (EGFR)-IHC negative tumours (see section 5.1).
4.2 Posology and method of administration
Non-small cell lung cancer:
EGFR mutation testing should be performed prior to initiation of Tarceva therapy in chemo-naïve patients with advanced or metastatic NSCLC.
4.4 Special warnings and precautions for use
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.
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 Tarceva should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. Tarceva 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.Very rare cases of corneal perforation or ulceration have been reported during use of Tarceva. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with Tarceva treatment which are also risk factors for corneal perforation/ulceration. Tarceva therapy should be interrupted or discontinued if patients present with acute/worsening ocular disorders such as eye pain (see section 4.8).
4.8 Undesirable effects
In an open-label, randomized phase III study, ML 20650 conducted in 154 patients, the safety of Tarceva for first-line treatment of NSCLC patients with EGFR activating mutations was assessed in 75 patients; no new safety signals were observed in these patients.
The most frequent ADRs seen in patients treated with Tarceva in study ML 20650 were rash and diarrhoea (any Grade 80% and 57%, respectively), most were Grade 1/2 in severity and manageable without intervention. Grade 3 rash and diarrhoea occurred in 9% and 4% of patients, respectively. No Grade 4 rash or diarrhoea was observed. Both rash and diarrhoea resulted in discontinuation of Tarceva in 1% of patients. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 11% and 7% of patients, respectively.
5.1 Pharmacodynamic properties
EGFR mutations may lead to constitutive activation of anti-apoptotic and proliferation signaling pathways. The potent effectiveness of erlotinib in blocking EGFR-mediated signalling in these EGFR mutation positive tumours is attributed to the tight binding of erlotinib to the ATP-binding site in the mutated kinase domain of the EGFR. Due to the blocking of downstream-signaling, the proliferation of cells is stopped, and cell death is induced through the intrinsic apoptotic pathway. Tumour regression is observed in mouse models of enforced expression of these EGFR activating mutations.
Non‑small cell lung cancer (Tarceva administered as monotherapy):
- First-line Non-Small Cell Lung Cancer (NSCLC) therapy for patients with EGFR activating mutations (Tarceva administered as monotherapy):
The efficacy of Tarceva in first-line treatment of patients with EGFR activating mutations in NSCLC was demonstrated in a phase III, randomized, open-label trial (ML20650, EURTAC). This study was conducted in Caucasian patients with metastatic or locally advanced NSCLC (stage IIIB and IV) who have not received previous chemotherapy or any systemic antitumour therapy for their advanced disease and who present mutations in the tyrosine kinase domain of the EGFR (exon 19 deletion or exon 21 mutation). Patients were randomized 1:1 to receive Tarceva 150 mg daily or up to 4 cycles of platinum based doublet chemotherapy.
The primary endpoint of investigator assessed PFS was determined at a pre-planned interim analysis (n=153, HR= 0.42, 95 % CI, 0.27 to 0.64; p<0.0001 for the Tarceva group (n=77) relative to the chemotherapy group (n=76)). A 58% reduction in the risk of disease progression or death was observed. In the Tarceva versus chemotherapy arms respectively, median PFS was 9.4 and 5.2 months and Best Overall Response Rate (CR/PR) was 54.5 % and 10.5%, p<0.0001. PFS results were confirmed by an independent review of the scans, median PFS was 10.4 months in the Tarceva group compared with 5.4 months in the chemotherapy group (HR= 0.47, 95% CI, 0.27 to 0.78; p=0.003).
The number of patients included in the investigator assessment of PFS was 129, the number of patients assessed by IRC was 107. The overall concordance rate between investigator and IRC assessment of PFS was 70 %.The overall survival data were immature at the time of interim analysis (HR= 0.80, 95 % CI, 0.47 to 1.37, p=0.4170).
In a further exploratory analysis (n=173) significant benefit was observed in PFS (HR=0.37, 95% CI, 0.27 to 0.54; p<0.0001; median PFS was 9.7 and 5.2 months) and Best Overall Response Rate (58.1 % versus 14.9%, p<0.0001) with erlotinib compared to chemotherapy. Overall survival data were still immature at the time of the exploratory updated analysis (HR= 1.04, 95 % CI, 0.65 to 1.68, p=0.8702).
- Maintenance NSCLC therapy after first-line chemotherapy (Tarceva administered as monotherapy)::
The efficacy and safety of Tarceva as maintenance after first-line chemotherapy for NSCLC was demonstrated in a randomized, double-blind, placebo-controlled trial (BO18192, SATURN). This study was conducted in 889 patients with locally advanced or metastatic NSCLC who did not progress after 4 cycles of platinum-based doublet chemotherapy. Patients were randomized 1:1 to receive Tarceva 150 mg or placebo orally once daily until disease progression. The primary endpoint of the study was progression free survival (PFS) in all patients and in patients with an EGFR IHC positive tumour. Baseline demographic and disease characteristics were well balanced between the two treatment arms. Patients with ECOG PS>1, significant hepatic or renal co-morbidities were not included in the study.
- NSCLC tTreatment after failure of at least one prior chemotherapy regimen (Tarceva administered as monotherapy): :
The effect on overall survival was explored across different patient subsets. The effect of Tarceva on overall survival was similar in patients with a baseline performance status (ECOG) of 2‑3 (HR = 0.77, 95% CI 0.6‑1.0) or 0‑1 (HR = 0.73, 95 % CI 0.6‑0.9), male (HR = 0.76, 95 % CI 0.6‑0.9) or female patients (HR = 0.80, 95 % CI 0.6‑1.1), patients < 65 years of age (HR = 0.75, 95 % CI 0.6‑0.9) or older patients (HR = 0.79, 95 % CI 0.6‑1.0), patients with one prior regimen (HR = 0.76, 95 % CI 0.6‑1.0) or more than one prior regimen (HR = 0.75, 95 % CI 0.6‑1.0), Caucasian (HR = 0.79, 95 % CI 0.6‑1.0) or Asian patients (HR = 0.61, 95 % CI 0.4‑1.0), patients with adenocarcinoma (HR = 0.71, 95 % CI 0.6‑0.9) or squamous cell carcinoma (HR = 0.67, 95 % CI 0.5‑0.9), but not in patients with other histologies (HR 1.04, 95 % CI 0.7‑1.5), patients with stage IV disease at diagnosis (HR = 0.92, 95 % CI 0.7‑1.2) or < stage IV disease at diagnosis (HR = 0.65, 95 % CI 0.5‑0.8). Patients who never smoked had a much greater benefit from erlotinib (survival HR = 0.42, 95 % CI 0.28‑0.64) compared with current or ex‑smokers (HR = 0.87, 95 % CI 0.71‑1.05).
In the 45 % of patients with known EGFR‑expression status, the hazard ratio was 0.68 (95 % CI 0.49‑0.94) for patients with EGFR‑positive tumours and 0.93 (95 % CI 0.63‑1.36) for patients with EGFR‑negative tumours (defined by IHC using EGFR pharmDx kit and defining EGFR-negative as less than 10 % tumour cells staining). In the remaining 55 % of patients with unknown EGFR‑expression status, the hazard ratio was 0.77 (95 % CI 0.61‑0.98).
10. DATE OF REVISION OF THE TEXT
18 May 201124 August 2011
BACKGROUND INFORMATION
The only changes for this version of the SPC were to section 5.3 and the Date of Revision was updated to 18 May 2011. The complete section 5.3 is shown below.
Extensive re-formatting of PIL information (following User Testing) was approved and implemented alongside this SPC change but was not associated with the new information in 5.3.
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5.3 Preclinical safety data
Chronic dosing effects observed in at least one animal species or study included effects on the cornea (atrophy, ulceration), skin (follicular degeneration and inflammation, redness, and alopecia), ovary (atrophy), liver (liver necrosis), kidney (renal papillary necrosis and tubular dilatation), and gastrointestinal tract (delayed gastric emptying and diarrhoea). Red blood cell parameters were decreased and white blood cells, primarily neutrophils, were increased. There were treatment‑related increases in ALT, AST and bilirubin. These findings were observed at exposures well below clinically relevant exposures
Based on the mode of action, erlotinib, has the potential to be a teratogen. Data from reproductive toxicology tests in rats and rabbits at doses near the maximum tolerated dose and/or maternally toxic doses showed reproductive (embryotoxicity in rats, embryo resorption and foetotoxicity in rabbits) and developmental (decrease in pup growth and survival in rats) toxicity, but was not teratogenic and did not impair fertility. These findings were observed at clinically relevant exposures.
Erlotinib tested negative in conventional genotoxicity studies. Two-year Ccarcinogenicity studies with erlotinib conducted in rats and mice were negative up to exposures exceeding human therapeutic exposure (up to 2-fold and 10-fold higher, respectively, based on Cmax and/or AUC). have not been performed.
A mild phototoxic skin reaction was observed in rats after UV irradiation.
18 May 2011
Section 6.3 Shelf life – updated from 3 to 4 years
and
Section 10 Date of Revision of the text, this was updated to 12 August 2010.
Underlined text has been added, text with strike-through deleted.
Highlighted text added at renewal.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One film‑coated tablet contains 25 mg erlotinib (as erlotinib hydrochloride).
Excipients: Each film-coated tablet contains 27.43 mg Lactose monohydrate.
For a full list of excipients, see section 6.1.
Diarrhoea (including very rare cases with a fatal outcome) has occurred in approximately 50 % of patients on Tarceva and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps. Dose reductions by 25 mg steps have not been investigated. In the event of severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, Tarceva therapy should be interrupted and appropriate measures should be taken to treat the dehydration (see section 4.8). There have been rare reports of hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration due to diarrhoea, vomiting and/or anorexia, while others were confounded by concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (concomitant medications, symptoms or diseases or other predisposing conditions including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration.
Patients receiving Tarceva are at increased risk of developing gastrointestinal perforation, which was observed uncommonly (including some cases with a fatal outcome). Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Tarceva should be permanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).
The tablets contain lactose and should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose‑galactose malabsorption.
4.5 Interaction with other medicinal products and other forms of interaction
Interaction with coumarin-derived anticoagulants including warfarin leading to increased International Normalized Ratio (INR) elevations, and bleeding events, which in some cases were fatal, including gastrointestinal bleeding have been reported in clinical studies, some associated with concomitant warfarin administration (see section 4.8) and some with concomitant NSAID administration.patients receiving Tarceva. Patients taking warfarin or other coumarin‑derivative derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.
The combination of Tarceva and a statin may increase the potential for statin-induced myopathy, including rhabdomyolysis, which was observed rarely.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data for the use of erlotinib in pregnant women. Studies in animals have shown no evidence of teratogenicity or abnormal parturition. However, an adverse effect on the pregnancy can not be excluded as rat and rabbit studies have shown increased embryo/foetal lethality, (see section 5.3). The potential risk for humans is unknown. Women of childbearing potential must be advised to avoid pregnancy while on Tarceva. Adequate contraceptive methods should be used during therapy, and for at least 2 weeks after completing therapy. Treatment should only be continued in pregnant women if the potential benefit to the mother outweighs the risk to the foetus.
Breastfeeding
It is not known whether erlotinib is excreted in human milk. Because of the potential harm to the infant, mothers should be advised against breast-feeding while receiving Tarceva.
Fertility
Studies in animals have shown no evidence of impaired fertility. However, an adverse effect on the fertility can not be excluded as animal studies have shown effects on reproductive parameters (see section 5.3).The potential risk for humans is unknown.
The following adverse reactions have been observed in patients who received Tarceva administered as single agent and patients who received Tarceva concurrently with chemotherapy.
Very common ADR’s from the BR 21 and PA 3 studies are presented in Tables 1 and 2, other ADR’s in other frequency categories including those from other studies are summarized in Table 3.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness
Table 3: Summary of ADRs per frequency category:
Body System
Very common (≥1/10)
Common (≥1/100 to <1/10)
Uncommon (≥1/1,000 to <1/100)
Rare (≥1/10,000
to <1/1000)
Very rare (<1/10,000)
Eye disorders
-Keratitis
-Conjunctivitis1
-Eyelash changes 2
- Corneal perforations
- Corneal ulcerations
Respiratory, thoracic and mediastinal disorders
-Epistaxis
-Serious interstitial lung disease (ILD)3
Gastro-intestinal disorders
-Diarrhoea7
-Gastro-intestinal bleeding4, 7
-Gastro-intestinal perforations7
Hepato biliary disorders
- Liver function test abnormalities 5
- Hepatic failure 6
Skin and subcutaneous tissue disorders
-Alopecia
-Dry skin1
-Paronychia
-Skin fissures
-Hirsutism
-Eyebrow changes
-Brittle and Loose nails
-Mild skin reactions such as hyperpigmentation
-Stevens-Johnson syndrome/Toxic epidermal necrolysis7
1 In clinical study PA.3.2 Including in-growing eyelashes, excessive growth and thickening of the eyelashes.
3 Including fatalities, in patients receiving Tarceva for treatment of NSCLC or other advanced solid tumours (see section 4.4).
4 In clinical studies, some cases have been associated with concomitant warfarin administration and some with concomitant NSAID administration (see section 4.5).
5 Including increased alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin. These were very common in clinical study PA.3 and common in clinical study BR.21. Cases were mainly mild to moderate in severity, transient in nature or associated with liver metastases.
6 Including fatalities. Confounding factors included pre-existing liver disease or concomitant hepatotoxic medications (see section 4.4).
7 Including fatalities (see section 4.4).
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Tarceva in all subsets of the paediatric population in Non Small Cell Lung Cancer and Pancreatic cancer indications (see section 4.2 for information on paediatric use).
Tarceva is indicated as monotherapy for maintenance treatment in patients with locally advanced or metastatic non-small cell lung cancer with stable disease after 4 cycles of standard platinum-based first-line chemotherapy.
Tarceva is also indicated for the treatment of patients with locally advanced or metastatic non‑small cell lung cancer after failure of at least one prior chemotherapy regimen.
Hepatic impairment: Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared with patients with adequate hepatic function, caution should be used when administering Tarceva to patients with hepatic impairment. Dose reduction or interruption of Tarceva should be considered if severe adverse reactions occur. The safety and efficacy of erlotinib has not been studied in patients with severe hepatic impairement dysfunction (AST/SGOT and ALT/SGPT> 5 x ULN). Use of Tarceva in patients with severe hepatic impairement dysfunction is not recommended (see section 5.2).
Rare cases of hepatic failure (including fatalities) have been reported during use of Tarceva. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function testing should be considered. Tarceva dosing should be interrupted if changes in liver function are severe (see section 4.8). Tarceva is not recommended for use in patients with severe hepatic dysfunction.
Non-small cell lung cancer (Tarceva administered as single agent in study BR.21monotherapy):
In a randomized double-blind study (BR.21; Tarceva administered as second line therapy), Rrash (75 %) and diarrhoea (54 %) were the most commonly reported adverse drug reactions (ADRs). Most were Grade 1/2 in severity and manageable without intervention. Grade 3/4 rash and diarrhoea occurred in 9 % and 6 %, respectively in Tarceva‑treated patients and each resulted in study discontinuation in 1 % of patients. Dose reduction for rash and diarrhoea was needed in 6 % and 1 % of patients, respectively. In study BR.21, the median time to onset of rash was 8 days, and the median time to onset of diarrhoea was 12 days.
In another double-blind, randomized, placebo-controlled Phase III study BO18192 (SATURN); Tarceva was administered as maintenance after first-line chemotherapy. SATURN was conducted in 889 patients with advanced, recurrent or metastatic NSCLC following first-line standard platinum-based chemotherapy, no new safety signals were identified.
The most frequent ADRs seen in patients treated with Tarceva in study BO18192 were rash and diarrhoea (any Grade 49% and 20%, respectively), most were Grade 1/2 in severity and manageable without intervention. Grade 3 rash and diarrhoea occurred in 6% and 2% of patients, respectively. No Grade 4 rash or diarrhoea was observed. Rash and diarrhoea resulted in discontinuation of Tarceva in 1% and <1% of patients, respectively. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 8.3% and 3% of patients, respectively.
Pancreatic cancer (Tarceva administered concurrently with gemcitabine in study PA.3):
Other Observations:
Safety evaluation of Tarceva is based on the data from 759more than 1200 patients treated with at least one 150 mg dose of Tarceva monotherapy during Phase III NSCLC study BR.21, Phase II NSCLC study A248‑1007, and three Phase II studies in populations other than NSCLC: 248‑101 (ovarian cancer), A248‑1003 (head and neck cancer), and OSI2288g (metastatic breast cancer) and the and more than 300285 patients who received Tarceva 100 or 150 mg plusin combination with gemcitabine in the phase III pancreatic cancer study PA.3.
Non‑small cell lung cancer (Tarceva administered as single agent in study BR.21monotherapy ):
Maintenance after first-line chemotherapy:
- ITT population results:
The primary PFS analysis in all patients (n=889) showed a PFS hazard ratio (HR) of 0.71 (95 % CI, 0.62 to 0.82; p<0.0001) for the Tarceva group relative to the placebo group. The mean PFS was 22.4 weeks in the Tarceva group compared with 16.0 weeks in the placebo group. PFS results were confirmed by an independent review of the scans. Quality of life data did not suggest a detrimental effect from erlotinib compared with placebo.
A PFS HR of 0.69 (95% CI, 0.58 to 0.82; p < 0.0001) was observed in the coprimary patient population with EGFR IHC positive tumours (n=621). The mean PFS was 22.8 weeks in the Tarceva group (range 0.1 to 78.9 weeks) compared with 16.2 weeks in the placebo group (range 0.1 to 88.1 weeks). The progression free survival rate at 6 months was 27% and 16%, respectively for Tarceva and placebo.
Concerning the secondary endpoint of overall survival, the HR was 0.81 (95% CI, 0.70 to 0.95; p=0.0088). The median overall survival was 12.0 months in the Tarceva group versus 11.0 months in the placebo group.
Patients with EGFR activating mutations had the largest benefit (n= 49, PFS HR=0.10, 95 % CI, 0.04 to 0.25; p<0.0001). In patients with EGFR wild type tumours (n=388), the PFS HR was 0.78 (95% CI, 0.63 to 0.96; p=0.0185) and the overall survival HR was 0.77 (95% CI, 0.61 to 0.97; p=0.0243).
- Patients with Stable Disease after chemotherapy:
Patients with stable disease (SD) (n= 487) had a PFS HR of 0.68 (95% CI, 0.56 to 0.83; p<0.0001; median 12.1 weeks in the Tarceva group and 11.3 weeks in the placebo group) and an overall survival HR of 0.72 (95% CI, 0.59 to 0.89; p= 0.0019; median 11.9 months in the Tarceva group and 9.6 months in the placebo group).
The effect on overall survival was explored across different subsets of patients with SD receiving Tarceva. This did not show major qualitative differences between patients with squamous cell carcinoma (HR 0.67, 95% CI, 0.48-0.92) and non-squamous cell carcinoma (HR 0.76, 95% CI 0.59-1.00) and between patients with EGFR activating mutations (HR 0.48, 95% 0.14-1.62) and without EGFR activating mutations (HR 0.65, 95% CI 0.48-0.87).
Treatment after failure of at least one prior chemotherapy regimen:
The efficacy and safety of Tarceva as second/third-line therapy was demonstrated in a randomised, double‑blind, placebo‑controlled trial (BR.21), in 731 patients with locally advanced or metastatic NSCLC after failure of at least one chemotherapy regimen. Patients were randomised 2:1 to receive Tarceva 150 mg or placebo orally once daily. Study endpoints included overall survival, progression‑free survival (PFS), response rate, duration of response, time to deterioration of lung cancer‑related symptoms (cough, dyspnoea and pain), and safety. The primary endpoint was survival.
27 April 2010.
Underline text = new text Strick through text = deleted text 4.4 Special warnings and precautions for use The following three paragraphs have been added:
Patients receiving Tarceva are at increased risk of developing gastrointestinal perforation, which was observed uncommonly. Patients receiving concomitant anti-angiogenic agents, corticosteroids, NSAIDs, and/or taxane based chemotherapy, or who have prior history of peptic ulceration or diverticular disease are at increased risk. Tarceva should be permanently discontinued in patients who develop gastrointestinal perforation (see section 4.8).
Bullous, blistering and exfoliative skin conditions have been reported, including very rare cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal (see section 4.8). Tarceva treatment should be interrupted or discontinued if the patient develops severe bullous, blistering or exfoliating conditions.
Very rare cases of corneal perforation or ulceration have been reported during use of Tarceva. Other ocular disorders including abnormal eyelash growth, keratoconjunctivitis sicca or keratitis have been observed with Tarceva treatment which are also risk factors for corneal perforation/ulceration. Tarceva therapy should be interrupted or discontinued if patients present with acute/worsening ocular disorders such as eye pain (see section 4.8). 4.8 Undesirable effects In general, rash manifests as a mild or moderate erythematous and papulopustular rash, which may occur or worsen in sun exposed areas. For patients who are exposed to sun, protective clothing, and/or use of sun screen (e.g. mineral-containing) may be advisable. Gastrointestinal disorders: Common: Gastrointestinal bleeding. In clinical studies, some cases have been associated with concomitant warfarin administration (see section 4.5) and some with concomitant NSAID administration. Uncommon: Gastrointestinal perforations. Skin and subcutaneous tissue disorders: Common: Alopecia. Common (in PA.3): Dry skin. Common: Paronychia. Uncommon Hirsutism, eyelash/eyebrow changes and brittle and loose nails. Uncommon Mild skin reactions such as hyperpigmentation. Very rare: Cases suggestive of Stevens-Johnson syndrome/Toxic epidermal necrolysis, which in some cases were fatal. Eye disorders: Common: Keratitis. Common: Conjunctivitis in study PA.3. Uncommon: Eyelash changes (including in-growing eyelashes, excessive growth and thickening of the eyelashes). Very rare: Corneal ulcerations and perforationshave been reported very rarely in patients receiving Tarceva as a complication of mucocutaneous inflammation.
Underlined text has been added, text with strike through deleted:
Smokers: Cigarette smoking has been shown to reduce erlotinib exposure by 50-60%. The maximum tolerated dose of Tarceva in NSCLC patients who currently smoke cigarettes was 300 mg. Efficacy and long term safety of a dose higher than the recommended starting doses have not been established in patients who continue to smoke cigarettes (see sections 4.5 and 5.2). Therefore, current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as compared to non-smokers are reduced.
alveolitis
Erlotinib is characterised by a decrease in solubility at pH above 5. Drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its bioavailability. Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46 % and 61 %, respectively. There was no change to Tmax or half‑life. Concomitant administration of Tarceva with 300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib exposure [AUC] and maximum concentrations [Cmax] by 33% and 54%, respectively. Therefore, drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of Tarceva when co-administered with such agents is not likely to compensate for this loss of exposure. However, when Tarceva was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and maximum concentrations [Cmax] decreased only by 15% and 17%, respectively. The effect of antacids and H2 antagonists on the absorption of erlotinib have not been investigated but absorption may be impaired, leading to lower plasma levels. In summary, the Ccombination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. Therefore, concomitant administration of these combinations should be avoided. If the use of antacids is considered necessary during treatment with Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva. If the use of ranitidine is considered, it should be used in a staggered manner; i.e. Tarceva must be taken at least 2 hours before or 10 hours after ranitidine dosing.
5.2 Pharmacokinetic properties
In the pivotal Phase III NSCLC trial, current smokers achieved erlotinib steady state trough plasma concentration of 0.65 g/mL (n=16) which was approximately 2-fold less than the former smokers or patients who had never smoked (1.28 g/mL, n=108). This effect was accompanied by a 24% increase in apparent erlotinib plasma clearance. In a phase I dose escalation study in NSCLC patients who were current smokers, pharmacokinetic analyses at steady-state indicated a dose proportional increase in erlotinib exposure when the Tarceva dose was increased from 150 mg to the maximum tolerated dose of 300 mg. Steady-state trough plasma concentrations at a 300 mg dose in current smokers in this study was 1.22 g/mL (n=17).
Hepatic impairment: Erlotinib is eliminated by hepatic metabolism and biliary excretion. Although erlotinib exposure was similar in patients with moderately impaired hepatic function (Child-Pugh score 7-9) compared with patients with adequate hepatic function, caution should be used when administering Tarceva to patients with hepatic impairment. Dose reduction or interruption of Tarceva should be considered if severe adverse reactions occur. The safety and efficacy of erlotinib has not been studied in patients with severe hepatic impairment. Therefore caution should be exercised when administering Tarceva to patients with hepatic impairment. Use of Tarceva in patients with severe hepatic impairment is not recommended (see section 5.2).
Skin and subcutaneous tissue disorders:
Common: Alopecia.
Common (in PA.3): Dry skin.
Common: Paronychia.
Uncommon Hirsutism, eyelash/eyebrow changes and brittle and loose nails.
Eye disorders:
Common: Keratitis. One isolated case of corneal ulceration was reported in one patient receiving Tarceva with concurrent chemotherapy, as a complication of mucocutaneous inflammation.
Common: Conjunctivitis in study PA.3.
Very rare: Corneal ulcerations have been reported very rarely in patients receiving Tarceva as a complication of mucocutaneous inflammation.
Hepatic impairment: Erlotinib is primarily cleared by the liver. In patients with solid tumours and with moderately impaired hepatic function (Child-Pugh score 7-9), geometric mean erlotinib AUC0-t and Cmax was 27000 ng•h/mL and 805 ng/mL, respectively, as compared to 29300 ng•h/mL and 1090 ng/mL in patients with adequate hepatic function including patients with primary liver cancer or hepatic metastases. Although the Cmax was statistically significant lower in moderately hepatic impaired patients, this difference is not considered clinically relevant. No data are currently available regarding the influence of severe hepatic dysfunction and/or hepatic metastases on the pharmacokinetics of erlotinib. In population pharmacokinetic analysis, increased serum concentrations of total bilirubin were associated with a slower rate of erlotinib clearance.
Underlined text has been added, text with strike through deleted
Erlotinib is characterised by a decrease in solubility at pH above 5. Drugs that alter the pH of the upper GI tract, like proton pump inhibitors, H2 antagonists and antacids, may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of Tarceva when coadministered with such agents is not likely to compensate for the loss of exposure. Combination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. Therefore, concomitant administration of these combinations should be avoided (see section 4.5). If the use of antacids is considered necessary during treatment with Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva.The effect of antacids, proton pump inhibitors and H2 antagonists on the absorption of erlotinib have not been investigated but absorption may be impaired, leading to lower plasma levels. Caution should be exercised when these medicinal products are combined with erlotinib.
The effects of CYP1A2 inhibitors on the pharmacokinetics of erlotinib have not been investigated and caution should be exercised when these inhibitors are combined with erlotinib.
When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib exposure [AUC] increased significantly by 39 %, while no statistically significant change in Cmax was found. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and Cmax, respectively. The clinical relevance of this increase has not been established. Caution should be exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib. If adverse events related to erlotinib are observed, the dose of erlotinib may be reduced.
Erlotinib is characterised by a decrease in solubility at pH above 5. Co-administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46 % and 61 %, respectively. There was no change to Tmax or half‑life. Therefore, drugs that alter the pH of the upper GI tract may alter the solubility of erlotinib and hence its bioavailability. Increasing the dose of Tarceva when co-administered with such agents is not likely to compensate for this loss of exposure. The effect of antacids, proton pump inhibitors and H2 antagonists on the absorption of erlotinib have not been investigated but absorption may be impaired, leading to lower plasma levels. Caution should be exercised when these medicinal products are combined with erlotinib.Combination of erlotinib with proton pump inhibitors should be avoided. The effects of concomitant administration of erlotinib with H2 antagonists and antacids are unknown; however, reduced bioavailability is likely. Therefore, concomitant administration of these combinations should be avoided. If the use of antacids is considered necessary during treatment with Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva.
Diarrhoea has occurred in approximately 50 % of patients on Tarceva and moderate or severe diarrhoea should be treated with e.g. loperamide. In some cases dose reduction may be necessary. In the clinical studies doses were reduced by 50 mg steps. Dose reductions by 25 mg steps have not been investigated. In the event of severe or persistent diarrhoea, nausea, anorexia, or vomiting associated with dehydration, Tarceva therapy should be interrupted and appropriate measures should be taken to treat the dehydration (see section 4.8). There have been rare reports of hypokalaemia and renal failure (including fatalities). Some cases were secondary to severe dehydration, due to diarrhoea, vomiting and/or anorexia, while others were confounded by mainly in patients receiving concomitant chemotherapy. In more severe or persistent cases of diarrhoea, or cases leading to dehydration, particularly in groups of patients with aggravating risk factors (concomitant medications, symptoms or diseases or other predisposing conditions including advanced age), Tarceva therapy should be interrupted and appropriate measures should be taken to intensively rehydrate the patients intravenously. In addition, renal function and serum electrolytes including potassium should be monitored in patients at risk of dehydration..
Rare cases of hepatic failure (including fatalities) have been reported during use of Tarceva. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications. Therefore, in such patients, periodic liver function testing should be considered. Tarceva dosing should be interrupted if changes in liver function are severe (see section 4.8).
No clinical interaction study with a CYP3A4 substrate has been performed as yet. Based on in vitro data, combination of erlotinib with CYP3A4 substrates should be conducted with caution. If such a combination is considered necessary, a close clinical monitoring should be performed. Pretreatment or coadministration of Tarceva did not alter the clearance of the prototypical CYP3A4 substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability of midazolam by up to 24%. In another clinical study, erlotinib was shown not to affect pharmacokinetics of the concomitantly administered CYP3A4/2C8 substrate paclitaxel. Significant interactions with the clearance of other CYP3A4 substrates are therefore unlikely.
Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg orally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69 % decrease in the median erlotinib AUC. Co-administration of rifampicin with a single 450 mg dose of Tarceva resulted in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg Tarceva dose in the absence of rifampicin treatment. Co-administration of Tarceva with CYP3A4 inducers should therefore be avoided. For patients who require concomitant treatment with Tarceva and a potent CYP3A4 inducer such as rifampicin an increase in dose to 300 mg should be considered while their safety (including renal and liver functions and serum electrolytes) is closely monitored, and if well tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety monitoring. The clinical relevance of this observation is unclear, but efficacy may be reduced. Reduced exposure may also occur with other inducers e.g. phenytoin, carbamazepine, barbiturates or St. Johns Wort (hypericum perforatum). Caution should be observed when these active substances are combined with erlotinib. Alternate treatments lacking potent CYP3A4 inducing activity should be considered when possible.
Erlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with carboplatin and paclitaxel led to an increase of total platinum AUC0-48 of 10.6%. Although statistically significant, the magnitude of this difference is not considered to be clinically relevant. In clinical practice, there may be other co-factors leading to an increased exposure to carboplatin like renal impairment. There were no significant effects of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.
Capecitabine may increase erlotinib concentrations. When erlotinib was given in combination with capecitabine, there was a statistically significant increase in erlotinib AUC and a borderline increase in Cmax when compared with values observed in another study in which erlotinib was given as single agent. There were no significant effects of erlotinib on the pharmacokinetics of capecitabine.
Skin and subcutaneous tissue orders:
Hepato‑biliary disorders:
Very common (in PA.3)
Common (in BR.21): Liver function test abnormalities (including increased alanine aminotransferase [ALT], aspartate aminotransferase [AST], bilirubin). These were mainly mild or moderate in severity, transient in nature or associated with liver metastases.
Rare: Rare cases of hepatic failure (including fatalities) have been reported during use of Tarceva. Confounding factors have included pre-existing liver disease or concomitant hepatotoxic medications (see section 4.4).
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Current smokers should be advised to stop smoking, as plasma concentrations of erlotinib in smokers as compared to non-smokers are reduced. The degree of reduction is likely to be clinically significant could be reduced otherwise (see section 4.5).
Interaction studies have only been performed in adults.
Based on the results of the population pharmacokinetic study, patients who are still smoking should be encouraged to stop smoking while taking Tarceva, as plasma concentrations could be reduced otherwise. Results of a pharmacokinetic interaction study indicated a significant 2.8-, 1.5- and 9-fold reduced AUCinf, Cmax and plasma concentration at 24 hours, respectively, after administration of Tarceva in smokers as compared to non-smokers (see section 5.2). Therefore, patients who are still smoking should be encouraged to stop smoking as early as possible before initiation of treatment with Tarceva, as plasma erlotinib concentrations are reduced otherwise. The clinical effect of the decreased exposure has not been formally assessed but it is likely to be clinically significant.
Respiratory, thoracic and mediastinal disorders:
Common: Epistaxis.
4.9 Overdose
Based on the data from these studies, severe adverse events such as diarrhoea, rash and possibly increased activity of liver aminotransferases may occur above the recommended dose of 150 mg.
Based on population pharmacokinetic analysis, no clinically significant relationship between predicted apparent clearance and patient age, bodyweight, gender and ethnicity were observed. Patient factors, which correlated with erlobinib pharmacokinetics, were serum total bilirubin, AAG and current smoking. Increased serum concentrations of total bilirubin and AAG concentrations were associated with a reduced erlotinib clearance. The clinical relevance of these differences is unclear. However, smokers had an increased rate of erlotinib clearance. This was confirmed in a pharmacokinetic study in non-smoking and currently cigarette smoking healthy subjects receiving a single oral dose of 150 mg erlotinib. The geometric mean of the Cmax was 1056 ng/mL in the non-smokers and 689 ng/mL in the smokers with a mean ratio for smokers to non-smokers of 65.2 % (95 % CI: 44.3 to 95.9, p = 0.031). The geometric mean of the AUC0-inf was 18726 ng·h/mL in the non-smokers and 6718 ng·h/mL in the smokers with a mean ratio of 35.9 % (95 % CI: 23.7 to 54.3, p < 0.0001). The geometric mean of the C24h was 288 ng/mL in the non-smokers and 34.8 ng/mL in the smokers with a mean ratio of 12.1 % (95 % CI: 4.82 to 30.2, p = 0.0001).
Updated to: 23 November 2006