Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Safety evaluation of Tarceva is based on the data from more than 1500 patients treated with at least one 150 mg dose of Tarceva monotherapy and more than 300 patients who received Tarceva 100 or 150 mg in combination with gemcitabine.

The incidence of adverse drug reactions (ADRs) from clinical trials reported with Tarceva 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 Tarceva group) of patients and occurred more frequently (3%) in patients treated with Tarceva 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) 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).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Non-small cell lung cancer (Tarceva 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 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 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 Tarceva 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); Tarceva 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.
The most frequent ADRs seen in patients treated with Tarceva 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 Tarceva 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; Tarceva 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 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 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.

Pancreatic cancer (Tarceva administered concurrently with gemcitabine) The most common adverse reactions in pivotal study PA.3 in pancreatic cancer patients receiving Tarceva 100 mg plus gemcitabine were fatigue, rash and diarrhoea. In the Tarceva 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 Tarceva plus gemcitabine.


Table 1:     ADRs occurring in  10% of patients in BR.21 (treated with Tarceva) and PA.3 (treated with Tarceva plus gemcitabine) studies and ADRs occurring more frequently (≥ 3%) than placebo in BR.21 (treated with Tarceva) and PA.3 (treated with Tarceva plus gemcitabine) studies 

Tarceva (BR.21)                  Tarceva (PA.3)          Frequency
N = 485                          N=259               category of highest
Any                              Any                            incidence NCI-CTC Grade                    Grade        3           4       Grade         3         4 MedDRA Preferred Term              %         %            %         %          %          % Infections and infestations
Infection*                      24         4           0         31          3         <1   Very common 
Metabolism and nutrition disorders
Anorexia                        52         8           1         --          --        --   Very common Weight decreased                --         --          --        39          2         0    Very common Eye disorders
Keratoconjunctivitis sicca       12        0            0         --          --        --   Very common Conjunctivitis                   12        <1           0         --          --        --   Very common Psychiatric disorders
Depression                         --         --          --        19          2         0    Very common Nervous system disorders
Neuropathy                         --         --          --        13          1         <1   Very common Headache                           --         --          --        15         <1         0    Very common 
Respiratory, thoracic and mediastinal disorders
Dyspnoea                         41        17           11        --          --        --   Very common Cough                            33        4            0         16          0         0    Very common Gastrointestinal disorders
Diarrhoea**                      54        6            <1        48          5         <1   Very common Nausea                           33        3            0          -          -          -   Very common Vomiting                         23        2            <1         -          -          -   Very common Stomatitis                       17        <1           0         22         <1         0    Very common Abdominal pain                   11        2            <1         -          -          -   Very common Dyspepsia                         -         -            -        17         <1         0    Very common Flatulence                        -         -            -        13          0         0    Very common 
Skin and subcutaneous tissue disorders
Rash***                         75        8            <1        69          5         0    Very common Pruritus                        13        <1           0         --          --        --   Very common Dry skin                        12        0            0         --          --        --   Very common Alopecia                        --        --           --        14          0         0    Very common 
General disorders and administration site conditions
Fatigue                         52        14           4        73         14         2        Very common Pyrexia                          --        --          --       36          3         0        Very common Rigors                           --        --          --       12          0         0        Very 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                  Uncommon        Rare           Very rare common           (≥1/100 to              (≥1/1,000 to    (≥1/10,000     (<1/10,000) (≥1/10)          <1/10)                  <1/100)         to
<1/1,000)
Eye disorders                       -Keratitis              -Eyelash                       -Corneal -Conjunctivitis1        changes 2                      perforations
-Corneal ulcerations
-Uveitis
Respiratory,                        -Epistaxis              -Interstitial thoracic and                                                lung disease mediastinal                                                 (ILD)3 disorders
Gastro-            -Diarrhoea7      -Gastro-                -Gastro- intestinal                          intestinal              intestinal disorders                           bleeding4, 7            perforations7 Hepato biliary     -Liver                                                   -Hepatic disorders          function test                                            failure 6 abnormalities
5

Skin and           -Rash            -Alopecia               -Hirsutism      -Palmar        -Stevens-Johnson subcutaneous                        -Dry skin1              -Eyebrow        plantar        syndrome/Toxic tissue disorders                    -Paronychia             changes         erythrodys-    epidermal -Folliculitis           -Brittle and    aesthesia      necrolysis7
-Acne/                  Loose nails     syndrome
Dermatitis              -Mild skin acneiform               reactions
-Skin fissures          such as hyperpigmen tation
Renal and                           -Renal                  -Nephritis1 urinary                             insufficiency1          -Proteinuria1 disorders
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). 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. Confounding factors included pre-existing liver disease or concomitant hepatotoxic medications (see section 4.4).
7
Including fatalities (see section 4.4).

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