Adverse reactions : תופעות לוואי

4.8   Undesirable effects

The most commonly reported adverse drug reactions associated with gemcitabine treatment include: nausea with or without vomiting, raised liver transaminases (AST/ALT) and alkaline phosphatase, reported in approximately 60% of patients; proteinuria and haematuria reported in approximately 50 % of patients; dyspnoea reported in 10 - 40% of patients (highest incidence in lung cancer patients); allergic skin rashes occur in approximately 25% of patients and are associated with itching in 10% of patients.

The frequency and severity of the adverse reactions are affected by the dose, infusion rate and intervals between doses (see section 4.4). Dose-limiting adverse reactions are reductions in thrombocyte, leucocyte and granulocyte counts (see section 4.2).

Clinical trial data
Frequencies are defined as: 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).


The following table of undesirable effects and frequencies is based on data from clinical trials. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Class                               Frequency grouping
Infections and infestations                      Common
Infections

Not known
Sepsis
Blood and lymphatic system disorders             Very common
Leucopenia (neutropenia grade 3 = 19.3 %;
Grade 4 = 6 %). Bone-marrow suppression is usually mild to moderate and mostly affects the granulocyte count (see section 4.2).
Thrombocytopenia, anaemia

Common
Febrile neutropenia

Very rare
Thrombocytosis, thrombotic microangiopathy
Immune system disorders                          Very rare
Anaphylactoid reaction
Metabolism and nutrition disorders               Common
Anorexia
Nervous system disorders                         Common
Headache, insomnia, somnolence
Uncommon
Cerebrovascular accident

Very rare
Posterior reversible encephalopathy syndrome
(see section 4.4.)
Cardiac disorders                                Uncommon
Arrhythmias, predominantly supraventricular in nature, heart failure

Rare
Myocardial infarct
Vascular disorders                               Rare
Clinical signs of peripheral vasculitis and gangrene, hypotension
System Organ Class                             Frequency grouping

Very rare
Capillary leak syndrome (see section 4.4.)
Respiratory,    thoracic     and   mediastinal Very common disorders                                      Dyspnoea – usually mild and passes rapidly without treatment.

Common
Cough, rhinitis

Uncommon
Interstitial pneumonitis (see section 4.4),
bronchospasm – usually mild and transient but may require parenteral treatment.
Rare
Pulmonary oedema, adult respiratory distress syndrome (see section 4.4)
Gastrointestinal disorders                     Very common
Vomiting, nausea

Common
Diarrhoea, stomatitis and ulceration of the mouth, constipation

Very rare
Ischaemic colitis
Hepatobiliary disorders                        Very common
Elevation of liver transaminases (AST and
ALT) and alkaline phosphatase
Common
Increased bilirubin

Uncommon
Serious hepatotoxicity, including liver failure and death

Rare
Increased gamma-glutamyl transferase (GGT)


System Organ Class                              Frequency grouping
Skin and subcutaneous tissue disorders          Very common
Allergic skin rash frequently associated with pruritus, alopecia

Common
Itching, sweating

Rare
Severe skin reactions, including desquamation and bullous skin eruptions, ulceration, vesicle and sore formation, scaling
Very rare
Toxic epidermal necrolysis, Stevens-Johnson syndrome

Not known
Pseudocellulitis
Musculoskeletal and connective           tissue Common disorders                                       Back pain, myalgia
Renal and urinary disorders                     Very common
Haematuria, mild proteinuria

Uncommon
Renal failure (see section 4.4), haemolytic uraemic syndrome (see section 4.4)
General disorders and administration site Very common conditions                                Influenza-like symptoms – the most common symptoms are fever, headache, chills,
myalgia, asthenia and anorexia. Cough,
rhinitis, malaise, perspiration and sleeping difficulties have also been reported.
Oedema/peripheral oedema –including facial oedema. Oedema is usually reversible after stopping treatment

Common
Fever, asthenia, chills

Rare
Injection site reactions, mainly mild in nature
Injury,    poisoning,      and     procedural Rare complications                                 Radiation toxicity (see section 4.5), radiation recall

Combination use in breast cancer
The frequency of Grade 3 and 4 haematological toxicities, particularly neutropenia, increases when gemcitabine is used in combination with paclitaxel. However, the increase in these adverse reactions is not associated with an increased incidence of infections or haemorrhagic events. Fatigue and febrile neutropenia occur more frequently when gemcitabine is used in combination with paclitaxel. Fatigue, which is not associated with anaemia, usually resolves after the first cycle.



Grade 3 and 4 adverse events
Paclitaxel versus gemcitabine plus paclitaxel

Number (%) of patients
Paclitaxel         arm Gemcitabine          plus
(N = 259)              paclitaxel arm (N =262)
Grade 3    Grade 4     Grade 3       Grade 4
Laboratory
Anaemia                        5 (1.9)    1 (0.4)      15 (5.7)      3 (1.1) Thrombocytopenia               0          0            14 (5.3)      1 (0.4) Neutropenia                    11 (4.2)   17 (6.6)*    82 (31.3)     45 (17.2)* Non-laboratory
Febrile neutropenia            3 (1.2)    0            12 (4.6)      1(0.4) Fatigue                        3 (1.2)    1 (0.4)      15 (5.7)      2 (0.8) Diarrhoea                      5 (1.9)    0            8 (3.1)       0 Motor neuropathy               2 (0.8)    0            6 (2.3)       1 (0.4) Sensory neuropathy             9 (3.5)    0            14( 5.3)      1 (0.4) *Grade 4 neutropenia lasting for more than 7 days occurred in 12.6 % of patients in the combination arm and 5.0 % of patients in the paclitaxel arm.

Combination use in bladder cancer

Grade 3 and 4 adverse events
MVAC versus gemcitabine plus cisplatin
Number (%) of patients
MVAC (methotrexate,       Gemcitabine               plus vinblastine,              cisplatin arm doxorubicin        and    (N = 200) cisplatin)         arm
(N = 196)
Grade 3      Grade 4      Grade 3         Grade 4
Laboratory
Anaemia                     30 (16)      4 (2)        47 (24)         7 (4) Thrombocytopenia            15 (8)       25 (13)      57 (29)         57 (29) Non-laboratory
Nausea and vomiting          37 (19)      3 (2)        44 (22)         0 (0) Diarrhoea                    15 (8)       1 (1)        6 (3)           0 (0) Infection                    19 (10)      10 (5)       4 (2)           1 (1) Stomatitis                   34 (18)      8 (4)        2 (1)           0 (0) 


Combination use in ovarian cancer

Grade 3 and 4 adverse events
Carboplatin versus gemcitabine plus carboplatin
Number (%) of patients
Carboplatin arm             Gemcitabine          plus
(N = 174)                   carboplatin arm
(N = 175)
Grade 3       Grade 4      Grade 3       Grade 4
Laboratory
Anaemia                      10 (5.7)      4 (2.3)      39 (22.3)      9 (5.1) Neutropenia                  19(10.9)      2(1.1)       73(41.7)       50(28.6) Thrombocytopenia             18(10.3)      2(1.1)       53(30.3)       8(4.6) Leucopenia                   11(6.3)       1(0.6)       84(48.0)       9(5.1) Non-laboratory
Haemorrhage                  0(0.0)        0(0.0)       3(1.8)         (0.0) Febrile neutropenia                0(0.0)        0(0.0)       2(1.1)         (0.0) Infection without            0(0)          0(0.0)       (0.0)          1(0.6) neutropenia

Sensory neuropathy was also more frequent in the combination arm than with single agent carboplatin 

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/