Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The types of adverse reactions (ADRs) were generally associated with the EGFR inhibitory mode of action of afatinib. The summary of all ADRs is shown in Table 2. The most frequent ADRs were diarrhoea and skin related adverse events (see section 4.4) as well as stomatitis and paronychia (see also Table 3, 4 and 5).
Overall, dose reduction (see section 4.2) 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 in the LUX-Lung 3 trial and in 25% of the patients in the LUX-Lung 8 trial. Discontinuation due to ADRs diarrhoea and rash/acne was 1.3% and 0% in LUX-Lung 3 and 3.8% and 2.0% in LUX-Lung 8, respectively.

ILD-like adverse reactions were reported in 0.7% of afatinib treated patients. Bullous, blistering and exfoliative skin conditions have been reported including rare cases suggestive of Stevens-Johnson syndrome and toxic epidermal necrolysis although in these cases there were potential alternative aetiologies (see section 4.4).

Tabulated list of adverse reactions
Table 2 summarises the frequencies of ADRs from all NSCLC trials and from post-marketing experience with daily GIOTRIF doses of 40 mg or 50 mg as monotherapy. The following terms are used to rank the ADRs by frequency: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.



Giotrif                                                                                 Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                              December 2019 Table 2: Summary of ADRs per frequency category

Body System             Very common             Common                Uncommon                    Rare 

Infections and infestations                Paronychia1         Cystitis

Metabolism and              Decreased           Dehydration nutrition disorders         appetite            Hypokalaemia
Nervous system disorders                                       Dysgeusia
Eye disorders                                   Conjunctivitis           Keratitis Dry eye
Respiratory, thoracic                                                    Interstitial lung and mediastinal             Epistaxis           Rhinorrhoea              disease disorders
Gastrointestinal            Diarrhoea                                    Pancreatitis disorders                   Stomatitis2         Dyspepsia
Nausea              Cheilitis                Gastrointestinal
Vomiting                                     perforation
Hepatobiliary disorders                         Alanine aminotransferase increased

Aspartate aminotransferase increased
Skin and subcutaneous       Rash3                                                                Stevens-Johnson tissue disorders                                Palmar-plantar                                   syndrome7 Dermatitis erythrodysaesthesia                              Toxic epidermal acneiform4 syndrome                                         necrolysis7
Pruritus5
Nail disorders8
Dry skin6
Musculoskeletal and
Muscle spasms connective tissue disorders
Renal and urinary                               Renal impairment/ disorders                                       Renal failure
General disorders and administration site                             Pyrexia conditions
Investigations
Weight decreased
1
Includes Paronychia, Nail infection, Nail bed infection
2
Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, Mucosal erosion, Mucosal ulceration
3
Includes group of rash preferred terms
4
Includes Acne, Acne pustular, Dermatitis acneiform
5
Includes Pruritus, Pruritus generalised
6
Includes Dry skin, Skin chapped
7
Based on post-marketing experience
8
Includes Nail disorder, Onycholysis, Nail toxicity, Onychoclasis, Ingrowing nail, Nail pitting, Onychomadesis, Nail discoloration, Nail dystrophy, Nail ridging, and Onychogryphosis

Giotrif                                                                             Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                           December 2019 

Description of selected adverse reactions
Very common ADRs in GIOTRIF-treated patients occurring in at least 10% of patients in trial LUX-Lung 3 and LUX-Lung 7 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Tables 3 and 4.

Table 3: Very common ADRs in trial LUX-Lung 3

GIOTRIF                     Pemetrexed/
(40 mg/day)                    Cisplatin
N=229                         N=111
NCI-CTC Grade                                        Any        3            4       Any      3    4 Grade                          Grade
MedDRA Preferred Term                                 %         %            %        %      %     % Infections and infestations
Paronychia1                                           57.6     11.4       0         0         0       0 Metabolism and nutrition disorders
Decreased appetite                                    20.5      3.1       0       53.2       2.7      0 Respiratory, thoracic and mediastinal disorders
Epistaxis                                             13.1       0        0        0.9       0.9      0 Gastrointestinal disorders
Diarrhoea                                             95.2     14.4       0       15.3        0       0 Stomatitis2                                           69.9     8.3       0.4      13.5       0.9      0 Cheilitis                                             12.2      0         0       0.9         0       0 Skin and subcutaneous tissue disorders
Rash3                                                 70.3      14        0        6.3        0       0 Dermatitis acneiform4                                 34.9      2.6       0         0         0       0 Dry skin5                                             29.7      0.4       0        1.8        0       0 Pruritus6                                             19.2      0.4       0        0.9        0       0 Investigations
Weight decreased                                       10.5       0        0        9.0        0       0 1
Includes Paronychia, Nail infection, Nail bed infection
2
Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, Mucosal erosion, Mucosal ulceration
3
Includes group of rash preferred terms
4
Includes Acne, Acne pustular, Dermatitis acneiform
5
Includes Dry skin, Skin chapped
6
Includes Pruritus, Pruritus generalised



Giotrif                                                                            Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                          December 2019 Table 4: Very common ADRs in trial LUX-Lung 7

GIOTRIF                       Gefitinib
(40 mg/day)
N=160                         N=159
NCI-CTC Grade                                       Any      3          4         Any         3        4 Grade                         Grade
MedDRA Preferred Term                               %        %          %         %           %        % Infections and infestations
Paronychia1                                   57.5        1.9       0         17.0        0.6      0 2
Cystitis                                      11.3        1.3       0         7.5         1.3      0.6 Metabolism and nutrition disorders
Decreased appetite                            27.5        1.3       0         24.5        1.9      0 3
Hypokalaemia                                  10.6        2.5       1.3       5.7         1.3      0 Respiratory, thoracic and mediastinal disorders
Rhinorrhoea4                                  19.4        0         0         7.5         0        0 Epistaxis                                     18.1        0         0         8.8         0        0 Gastrointestinal disorders
Diarrhoea                                     90.6        13.8      0.6       64.2        3.1      0 Stomatitis5                                   64.4        4.4       0         27.0        0        0 Nausea                                        25.6        1.3       0         27.7        1.3      0 Vomiting                                      19.4        0.6       0         13.8        2.5      0 Dyspepsia                                     10.0        0         0         8.2         0        0 Hepatobiliary disorders
Alanine aminotransferase increased            11.3        0         0         27.7        8.8      0.6 Skin and subcutaneous tissue disorders
Rash6                                         80.0        7.5       0         67.9        3.1      0 Dry skin                                      32.5        0         0         39.6        0        0 Pruritus7                                     25.6        0         0         25.2        0        0 Dermatitis acneiform8                         23.8        1.9       0         32.1        0.6      0 General disorders and administration site conditions
Pyrexia                                       13.8        0         0         6.3         0        0 Investigations
Weight decreased                              10.0        0.6       0         5.7         0.6      0 1
Includes Paronychia, Nail infection, Nail bed infection
2
Includes Cystitis, Urinary tract infection
3
Includes Hypokalaemia, Blood potassium decreased
4
Includes Rhinorrhoea, Nasal inflammation
5
Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Mucosal erosion 6
Includes group of rash preferred terms
7
Includes Pruritus, Pruritus generalised
8
Includes Dermatitis acneiform, Acne


Liver function test abnormalities
Liver function test abnormalities (including elevated ALT and AST) were observed in patients receiving GIOTRIF 40 mg. These elevations were mainly transient and did not lead to discontinuation. Grade 2 (> 2.5 to 5.0 times upper limit of normal (ULN)) ALT elevations occurred in < 8% of patients treated with this medicinal product. Grade 3 (> 5.0 to 20.0 times ULN) elevations occurred in <4% of patients treated with GIOTRIF (see section 4.4).

You can report side effects to the Ministry of Health by following the link ‘Reporting Side Effects of Drug Treatment' on the Ministry of Health home page (www.health.gov.il) which links to an online form for reporting side effects. You can also use this link: https://sideeffects.health.gov.il
Giotrif                                                                                Updated Prescribing Information Film coated tablets 20mg, 30mg, 40mg, 50mg                                                               December 2019 

Description of selected adverse reactions
Very common ADRs in GIOTRIF-treated patients occurring in at least 10% of patients in trial LUX-Lung 8 are summarised by National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade in Table 5.

Table 5: Very common ADRs in trial LUX-Lung 8*
GIOTRIF                                  Erlotinib
(40 mg/day)                              N=395
N=392
NCI-CTC Grade                                Any        3                      4      Any          3        4 Grade                                    Grade
MedDRA Preferred Term                        %          %                      %      %            %        % Infections and infestations
Paronychia1                               11.0       0.5                    0      5.1          0.3      0 Metabolism and nutrition disorders
Decreased appetite                        24.7       3.1                    0      26.1         2.0      0 Gastrointestinal disorders
Diarrhoea                                          74.7          9.9        0.8    41.3         3.0      0.3 Stomatitis2                                        30.1          4.1        0      10.6         0.5      0 Nausea                                             20.7          1.5        0      16.2         1.0      0.3 Skin and subcutaneous tissue disorders
Rash3                                                 60.7      5.4         0       56.7       8.1       0 Dermatitis acneiform4                                 14.0      1.3         0       18.0       2.5       0 *
Reporting the frequency of patients with all causality AEs
1
Includes Paronychia, Nail infection, Nail bed infection
2
Includes Stomatitis, Aphthous stomatitis, Mucosal inflammation, Mouth ulceration, Oral mucosa erosion, Mucosal erosion, Mucosal ulceration
3
Includes group of rash preferred terms
4
Includes Acne, Acne pustular, Dermatitis acneiform

Liver function test abnormalities
Liver function test abnormalities (including elevated ALT and AST) were observed in patients receiving GIOTRIF 40 mg. These elevations were mainly transient and did not lead to discontinuation. Grade 2 ALT elevations occurred in 1% and Grade 3 elevations occurred in 0.8% of patients treated with GIOTRIF (see section 4.4).