Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Safety evaluation of erlotinib is based on the data from more than 1500 patients treated with at least one 150 mg dose of erlotinib monotherapy and more than 300 patients who received erlotinib 100 or 150 mg in combination with gemcitabine.
The incidence of adverse drug reactions (ADRs) from clinical trials reported with erlotinib alone or in combination with chemotherapy are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 1. The listed ADRs were those reported in at least 10% (in the erlotinib group) of patients and occurred more frequently (≥3%) in patients treated with erlotinib than in the comparator arm. Other ADRs including those from other studies are summarized in Table 2.
Adverse drug reactions from clinical trials (Table 1) and other ADRs (Table 2) are listed by MedDRA system organ class.
The corresponding frequency category for each adverse drug reaction is based on the following convention: 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).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Non-small cell lung cancer (erlotinib administered as monotherapy)
First-Line Treatment of Patients with EGFR Mutations
In an open-label, randomised phase III study, ML20650 conducted in 154 patients, the safety of erlotinib 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 erlotinib in study ML20650 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 erlotinib in 1% of patients. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 11% and 7% of patients, respectively.
Maintenance treatment
In two other double-blind, randomised, placebo-controlled Phase III studies BO18192 (SATURN) and BO25460 (IUNO); erlotinib was administered as maintenance after first-line chemotherapy. These studies were conducted in a total of 1532 patients with advanced, recurrent or metastatic NSCLC following first-line standard platinum-based chemotherapy, no new safety signals were identified.
https://www.medicines.org.uk/emc/product/8846/smpc/print                                                                          6/18 The most frequent ADRs seen in patients treated with erlotinib in studies BO18192 and BO25460 were rash (BO18192: all grades 49.2%, grade 3: 6.0%; BO25460: all grades 39.4%, grade 3: 5.0%) and diarrhoea (BO18192: all grades      20.3%, grade 3: 1.8%; BO25460: all grades 24.2%, grade 3: 2.5%). No Grade 4 rash or diarrhoea was observed in either study. Rash and diarrhoea resulted in discontinuation of erlotinib in 1% and <1% of patients, respectively, in study BO18192, while no patients discontinued for rash or diarrhoea in BO25460. Dose modifications (interruptions or reductions) for rash and diarrhoea were needed in 8.3% and 3% of patients, respectively, in study BO18192 and 5.6% and 2.8% of patients, respectively, in study BO25460.
Second and Further Line Treatment
In a randomised double-blind study (BR.21; erlotinib administered as second line therapy), rash (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 erlotinib -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 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 sunscreen (e.g. mineral- containing) may be advisable.
Pancreatic cancer (erlotinib administered concurrently with gemcitabine) The most common adverse reactions in pivotal study PA.3 in pancreatic cancer patients receiving erlotinib 100 mg plus gemcitabine were fatigue, rash and diarrhoea. In the erlotinib plus gemcitabine arm, Grade 3/4 rash and diarrhoea were each reported in 5% of patients. The median time to onset of rash and diarrhoea was 10 days and 15 days, respectively.
Rash and diarrhoea each resulted in dose reductions in 2% of patients, and resulted in study discontinuation in up to 1% of patients receiving erlotinib plus gemcitabine.
Table 1: ADRs occurring in ≥ 10% of patients in BR.21 (treated with erlotinib ) and PA.3 (treated with erlotinib plus gemcitabine) studies and ADRs occurring more frequently (≥ 3%) than placebo in BR.21 (treated with erlotinib ) and PA.3 (treated with erlotinib plus gemcitabine) studies
 erlotinib (BR.21)             erlotinib (PA.3)                      Frequency category
N = 485                      N = 259 of highest
Any                             Any                                        incidence NCI-CTC Grade                    Grade          3            4   Grade         3          4 
MedDRA Preferred Term               %          %             %    %            %          % 
Infections and infestations
31           3          <1                    very
Infection*                          24          4            0                                                common 
Metabolism and nutrition very disorders                                                          -           -          -                   common Anorexia                            52          8            1
39           2          0                     very
Weight decreased                     -          -            -                                                common  very
Eye disorders
-           -          -                   common
Keratoconjunctivitis sicca          12          0            0
-           -          -                     very
Conjunctivitis                      12         <1            0                                                common 
Psychiatric disorders
-          -            -    19           2          0                     very Depression                                                                                                    common 
Nervous system disorders
Neuropathy                           -          -            -    13           1          <1                    very Headache                             -          -            -    15           <1         0                   common very common

Respiratory, thoracic and very mediastinal disorders
-           -          -                   common https://www.medicines.org.uk/emc/product/8846/smpc/print                                                                    7/18 Dyspnoea                            41         17           11
16            0        0                            very
Cough                               33          4           0                                                             common  very common very common very
Gastrointestinal disorders                                                                                                common Diarrhoea**                         54          6           <1          48            5        <1                           very Nausea                              33          3           0            -            -         -                         common 
Vomiting                            23          2           <1           -            -         -                           very common
Stomatitis                          17         <1           0           22            <1       0 very
Abdominal pain                      11          2           <1           -            -         -                         common Dyspepsia                            -          -           -           17            <1       0                            very Flatulence                           -          -           -           13            0        0                          common 
Skin and subcutaneous               75          8           <1 tissue disorders                                                                                                            very 13         <1           0 common
Rash***
12          0           0 very
Pruritus                                                                69            5        0 -          -           -                                                             common Dry skin                                                                 -            -         - 
Alopecia                                                                 -            -         -                           very common
14            0        0 very common


General disorders and                                                                                                       very administration site common conditions very
Fatigue                             52         14           4           73            14       2                          common Pyrexia                              -          -           -           36            3        0                            very Rigors                               -          -           -           12            0        0                          common 
* Severe infections, with or without neutropenia, have included pneumonia, sepsis, and cellulitis.
** Can lead to dehydration, hypokalemia and renal failure.
*** Rash included dermatitis acneiform.
- corresponds to percentage below threshold.
Table 2: Summary of ADRs per frequency category:

Body System           Very               Common (≥1/100 Uncommon                           Rare           Very rare      Not common             to <1/10)      (≥1/1,000 to                       (≥1/10,000     (<1/10,000)    known8 (≥1/10)                           <1/100) to <1/1,000)

Eye disorders                            -Keratitis              -Eyelash changes                         -Corneal 2                                        perforations
-Conjunctivitis1
-Corneal ulcerations
-Uveitis

Respiratory,                             -Epistaxis              -Interstitial lung thoracic and                                                     disease (ILD)3 mediastinal disorders https://www.medicines.org.uk/emc/product/8846/smpc/print                                                                                 8/18 Gastrointestinal    -Diarrhoea7       -Gastrointestinal   -Gastrointestinal    -Pneumatosis disorders                             bleeding4, 7        perforations7        intestinalis 
Hepato biliary      -Liver function                                            -Hepatic failure                    -Acute disorders           test                                                       6                                   hepatitis abnormalities
5                                                          -Hepatitis 
Skin and            -Rash             -Alopecia           -Hirsutism           -Palmar            -Stevens- subcutaneous                                                                   plantar            Johnson tissue disorders                      -Dry skin1          -Eyebrow erythrodys-        syndrome/Toxic changes
-Paronychia                              aesthesia          epidermal -Brittle and Loose   syndrome           necrolysis7
-Folliculitis       nails
-Acne/ Dermatitis   -Mild skin acneiform           reactions such as
-Skin fissures      hyperpigmentation


Renal and                             -Renal              -Nephritis1 urinary disorders                     insufficiency1
-Proteinuria1

1
In clinical study PA.3.
2
Including in-growing eyelashes, excessive growth and thickening of the eyelashes.
3
Including fatalities, in patients receiving erlotinib for treatment of NSCLC or other advanced solid tumours (see section      4.4). A higher incidence has been observed in patients in Japan (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. Risk factors may include pre-existing liver disease or concomitant hepatotoxic medications (see section 4.4).
7
Including fatalities (see section 4.4).
8
Cannot be estimated from the available data
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form http://sideeffects.health.gov.il