Adverse reactions : תופעות לוואי

4.8. Undesirable effects
Summary of the safety profile
The overall safety profile of capecitabine is based on data from over 3000 patients treated with capecitabine as monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications. The safety profiles of capecitabine monotherapy for the metastatic breast cancer, metastatic colorectal cancer and adjuvant colon cancer populations are comparable. See section 5.1 for details of major studies, including study designs and major efficacy results.
The most commonly reported and/or clinically relevant treatment-related adverse drug reactions (ADRs) were gastrointestinal disorders (especially diarrhoea, nausea, vomiting, abdominal pain, stomatitis), hand- foot syndrome (palmar-plantar erythrodysesthesia), fatigue, asthenia, anorexia, cardiotoxicity, increased renal dysfunction on those with preexisting compromised renal function, and thrombosis/embolism.

Tabulated list of adverse reactions
ADRs considered by the investigator to be possibly, probably, or remotely related to the administration of capecitabine are listed in table 4 for capecitabine given as monotherapy and in table 5 for capecitabine given in combination with different chemotherapy regimens in multiple indications. The following headings 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, ADRs are presented in order of decreasing seriousness.
Capecitabine Monotherapy:
Table 4 lists ADRs associated with the use of capecitabine monotherapy based on a pooled analysis of safety data from three major studies including over 1900 patients (studies M66001, SO14695, and SO14796). ADRs are added to the appropriate frequency grouping according to the overall incidence from the pooled analysis.

Table 4     Summary of related ADRs reported in patients treated with capecitabine monotherapy Body System           Very             Common                   Uncommon               Rare/Very Rare Common                                                            (Post-Marketing All grades           Severe and/or Life-
Experience)
All grades                           threatening (grade 3-4) or considered medically relevant
Infections and     -                Herpes viral           Sepsis, Urinary tract infestations                        infection,             infection, Cellulitis, Nasopharyngitis,       Tonsillitis, Pharyngitis,
Lower respiratory      Oral candidiasis,
tract infection        Influenza, Gastroenteritis,
Fungal infection,
Infection, Tooth abscess
Neoplasm benign, -                  -                      Lipoma malignant and unspecified


Blood and        -                Neutropenia,           Febrile neutropenia, lymphatic system                  Anaemia                Pancytopenia, disorders                                                Granulocytopenia, Thrombocytopenia,
Leukopenia,
Haemolytic anaemia,
International Normalised
Ratio (INR) increased /
Prothrombin time prolonged

Immune system      -              -                      Hypersensitivity           Angioedema (rare) disorders
Metabolism and     Anorexia       Dehydration,           Diabetes, Hypokalaemia, nutrition                         Weight                 Appetite disorder, disorders                         decreased              Malnutrition, Hypertriglyceridaemia,
Psychiatric        -              Insomnia,              Confusional state, disorders                         Depression             Panic attack, Depressed mood, Libido decreased
Nervous system     -              Headache,              Aphasia, Memory            Toxic disorders                         Lethargy               impairment, Ataxia,        leukoencephalopathy Dizziness,             Syncope,                   (very rare)
Parasthesia            Balance disorder,
Dysgeusia              Sensory disorder,
Neuropathy peripheral
Eye disorders      -              Lacrimation            Visual acuity reduced,     Lacrimal duct increased,             Diplopia                   stenosis (rare),
Conjunctivitis,                                   Corneal disorders
Eye irritation                                    (rare), keratitis (rare), punctate keratitis
(rare)
Ear and labyrinth -               -                      Vertigo, Ear pain disorders
Cardiac            -              -                      Angina unstable, Angina    Ventricular disorders                                                pectoris, Myocardial       fibrillation (rare), ischaemia / infarction,    QT prolongation
Atrial fibrillation,       (rare), Torsade de
Arrhythmia, Tachycardia,   pointes (rare),
Sinus tachycardia,         Bradycardia (rare),
Palpitations               Vasospasm (rare)
Vascular           -              Thrombophlebitis       Deep vein thrombosis, disorders                                                Hypertension, Petechiae, Hypotension, Hot flush,
Peripheral coldness
Respiratory,       -              Dyspnoea,              Pulmonary embolism, thoracic and                      Epistaxis,             Pneumothorax, mediastinal                       Cough,                 Haemoptysis, Asthma, disorders                         Rhinorrhoea            Dyspnoea exertional 

Gastrointestinal    Diarrhoea,     Gastrointestinal         Intestinal obstruction, disorders           Vomiting,      haemorrhage,             Ascites, Enteritis, Nausea,        Constipation, Upper      Gastritis, Dysphagia,
Stomatitis,    abdominal pain,          Abdominal pain lower,
Abdominal      Dyspepsia,               Oesophagitis,
pain           Flatulence,              Abdominal discomfort,
Dry mouth                Gastrooesophageal reflux disease,
Colitis, Blood in stool
Hepatobiliary       -              Hyperbilirubinemia, Jaundice                          Hepatic failure (rare), disorders                          Liver function test                                   Cholestatic hepatitis abnormalities                                         (rare)
Skin and            Palmar-        Rash, Alopecia,          Blister, Skin ulcer,         Cutaneous lupus subcutaneous        plantar        Erythema, Dry skin,      Rash, Urticaria,             erythematosus (rare), tissue disorders    erythro-       Pruritus, Skin           Photosensitivity reaction,   Severe skin reactions dysaesthesia   hyper- pigmentation,     Palmar erythema,             such as Stevens- syndrome**     Rash macular, Skin       Swelling face,               Johnson Syndrome desquamation,            Purpura, Radiation recall    and toxic Epidermal Dermatitis,              syndrome                     Necrolysis (very Pigmentation                                          rare) (see section disorder,                                             4.4.)
Nail disorder
Muskuloskeletal     -              Pain in extremity,       Joint swelling, Bone pain, and connective                     Back pain,               Facial pain, tissue disorders                   Arthralgia               Musculoskeletal stiffness, Muscular weakness
Renal and         -                -                        Hydronephrosis, urinary disorders                                           Urinary incontinence, Haematuria, Nocturia,
Blood creatinine increased
Reproductive      -                -                        Vaginal haemorrhage system and breast disorders
General disorders Fatigue,         Pyrexia,                 Oedema, Chills, and               Asthenia         Oedema peripheral,       Influenza like illness, administration                     Malaise,                 Rigors, Body site conditions                    Chest pain               temperature increased ** Based on the post-marketing experience, persistent or severe palmar-plantar erythrodysaesthesia syndrome can eventually lead to loss of fingerprints (see section 4.4)

Capecitabine in combination therapy:
Table 5 lists ADRs associated with the use of capecitabine in combination with different chemotherapy regimens in multiple indications based on safety data from over 3000 patients. ADRs are added to the appropriate frequency grouping (Very common or Common) according to the highest incidence seen in any of the major clinical trials and are only added when they were seen in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy (see table 4). Uncommon ADRs reported for capecitabine in combination therapy are consistent with the ADRs reported for capecitabine monotherapy or reported for monotherapy with the combination medicinal product (in literature and/or respective summary of product characteristics).
Some of the ADRs are reactions commonly seen with the combination medicinal product (e.g. peripheral sensory neuropathy with docetaxel or oxaliplatin, hypertension seen with bevacizumab); however an exacerbation by capecitabine therapy can not be excluded.

Table 5     Summary of related ADRs reported in patients treated with capecitabine in combination treatment in addition to those seen with capecitabine monotherapy or seen at a higher frequency grouping compared to capecitabine monotherapy
Body System            Very common                     Common                 Rare/Very Rare (Post- Marketing Experience)
All grades                    All grades
Infections and        -                        Herpes zoster, Urinary tract infestations                                   infection, Oral candidiasis, Upper respiratory tract infection, Rhinitis, Influenza,
+
Infection, Oral herpes
+
Blood and               Neutropenia,           Bone marrow depression, +                        + lymphatic system        Leucopenia,              Febrile Neutropenia
+ disorders               Anaemia,
+
Neutropenic fever,
Thrombocytopenia
Immune system       -                          Hypersensitivity disorders
Metabolism and      Appetite decreased         Hypokalaemia,
nutrition disorders                            Hyponatraemia,
Hypomagnesaemia,
Hypocalcaemia,
Hyperglycaemia
Psychiatric           -                        Sleep disorder,
disorders                                      Anxiety
Nervous system        Paraesthesia,            Neurotoxicity,
disorders             Dysaesthesia,            Tremor,
Peripheral neuropathy,   Neuralgia,
Peripheral sensory       Hypersensitivity reaction,
neuropathy,              Hypoaesthesia
Dysgeusia, Headache
Eye disorders         Lacrimation increased Visual disorders, Dry eye, Eye pain, Visual impairment,
Vision blurred
Ear and labyrinth     -                 Tinnitus,
disorders                               Hypoacusis
Cardiac disorders  -                    Atrial fibrillation,
Cardiac ischaemia/infarction
Vascular disorders Lower limb oedema, Flushing, Hypotension,
Hypertension,        Hypertensive crisis,
+
Embolism and       Hot flush,
thrombosis           Phlebitis
Respiratory,       Sore throat,         Hiccups,
thoracic and       Dysaesthesia pharynx Pharyngolaryngeal pain,
mediastinal system                      Dysphonia disorders


Gastrointestinal         Constipation,            Upper gastrointestinal disorders                Dyspepsia                haemorrhage,
Mouth ulceration, Gastritis,
Abdominal distension,
Gastroesophageal reflux disease, Oral pain, Dysphagia,
Rectal haemorrhage,
Abdominal pain lower, Oral dysaesthesia, Paraesthesia oral,
Hypoaesthesia oral,
Abdominal discomfort
Hepatobiliary            -                        Hepatic function abnormal disorders
Skin and            Alopecia,                     Hyperhidrosis,
subcutaneous tissue Nail disorder                 Rash erythematous, Urticaria, disorders                                         Night sweats
Musculoskeletal          Myalgia, Arthralgia,     Pain in jaw,
and connective           Pain in extremity        Muscle spasms, Trismus, tissue disorders                                  Muscular weakness
Renal and urinary        -                        Haematuria, Proteinuria,            Acute renal failure disorder                                          Creatinine renal clearance          secondary to decreased, Dysuria                  dehydration (rare)
General disorders Pyrexia, Weakness,              Mucosal inflammation, Pain in and administration +Lethargy,                     limb, Pain, Chills, Chest pain, site conditions    Temperature                    Influenza-like illness, +Fever, intolerance                    Infusion related reaction,
Injection site reaction, Infusion site pain, Injection site pain
Injury, poisoning        -                        Contusion and procedural complications
+
For each term, the frequency count was based on ADRs of all grades. For terms marked with a "+”, the frequency count was based on grade 3-4 ADRs. ADRs are added according to the highest incidence seen in any of the major combination trials.

Description of selected adverse reactions
Hand-foot syndrome (see section 4.4)
For the capecitabine dose of 1250 mg/m2 twice daily on days 1 to 14 every 3 weeks, a frequency of 53% to 60% of all-grades HFS was observed in capecitabine monotherapy trials (comprising studies in adjuvant therapy in colon cancer, treatment of metastatic colorectal cancer, and treatment of breast cancer) and a frequency of 63% was observed in the capecitabine/docetaxel arm for the treatment of metastatic breast cancer. For the capecitabine dose of 1000 mg/m2 twice daily on days 1 to 14 every 3 weeks, a frequency of 22% to 30% of all-grade HFS was observed in capecitabine combination therapy.
A meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine monotherapy or capecitabine in combination with different chemotherapy regimens in multiple indications (colon, colorectal, gastric and breast cancer) showed that HFS (all grades) occurred in 2066 (43%) patients after a median time of 239 [95% CI 201,288] days after starting treatment with capecitabine. In all studies combined, the following covariates were statistically significantly associated with an increased risk of developing HFS: increasing capecitabine starting dose (gram), decreasing cumulative capecitabine dose (0.1*kg), increasing relative dose intensity in the first six weeks, increasing duration of study treatment (weeks), increasing age (by 10 year increments), female gender, and good ECOG performance status at baseline (0 versus ≥1).

     Diarrhoea (see section 4.4)
Capecitabine can induce the occurrence of diarrhoea, which has been observed in up to 50% of patients.
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, the following covariates were statistically significantly associated with an increased risk of developing diarrhoea: increasing capecitabine starting dose (gram), increasing duration of study treatment (weeks), increasing age (by 10 year increments), and female gender. The following covariates were statistically significantly associated with a decreased risk of developing diarrhoea: increasing cumulative capecitabine dose (0.1*kg) and increasing relative dose intensity in the first six weeks.
Cardiotoxicity (see section 4.4)
In addition to the ADRs described in tables 4 and 5, the following ADRs with an incidence of less than 0.1% were associated with the use of capecitabine monotherapy based on a pooled analysis from clinical safety data from 7 clinical trials including 949 patients (2 phase III and 5 phase II clinical trials in metastatic colorectal cancer and metastatic breast cancer): cardiomyopathy, cardiac failure, sudden death, and ventricular extrasystoles.
Encephalopathy
In addition to the ADRs described in tables 4 and 5, and based on the above pooled analysis from clinical safety data from 7 clinical trials, encephalopathy was also associated with the use of capecitabine monotherapy with an incidence of less than 0.1%.
Exposure to crushed or cut capecitabine tablets
In the instance of exposure to crushed or cut capecitabine tablets, the following adverse drug reactions have been reported: eye irritation, eye swelling, skin rash, headache, paresthesia, diarrhoea, nausea, gastric irritation and vomiting.
Special populations

Elderly patients (see section 4.2)
An analysis of safety data in patients ≥60 years of age treated with capecitabine monotherapy and an analysis of patients treated with capecitabine plus docetaxel combination therapy showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions and treatment-related serious adverse reactions compared to patients <60 years of age. Patients ≥60 years of age treated with capecitabine plus docetaxel also had more early withdrawals from treatment due to adverse reactions compared to patients <60 years of age.
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, increasing age (by 10 year increments) was statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.
Gender
The results of a meta-analysis of 14 clinical trials with data from over 4700 patients treated with capecitabine showed that in all studies combined, female gender was statistically significantly associated with an increased risk of developing HFS and diarrhoea and with a decreased risk of developing neutropenia.
Patients with renal impairment (see section 4.2, 4.4, and 5.2)
An analysis of safety data in patients treated with capecitabine monotherapy (colorectal cancer) with baseline renal impairment showed an increase in the incidence of treatment-related grade 3 and 4 adverse reactions compared to patients with normal renal function (36% in patients without renal impairment n=268, vs. 41% in mild n=257 and 54% in moderate n=59, respectively) (see section 5.2). Patients with moderately impaired renal function show an increased rate of dose reduction (44%) vs. 33% and 32% in patients with no or mild renal impairment and an increase in early withdrawals from treatment (21% withdrawals during the first two cycles) vs. 5% and 8% in patients with no or mild renal impairment.


     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 https://sideeffects.health.gov.il