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),and 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
System Organ Class                     Frequency grouping


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


System Organ Class                      Frequency grouping
Metabolism and nutrition disorders      Common
Anorexia
Nervous system disorders                Common
Headache, insomnia, somnolence
Uncommon
Clinical Cerebrovascular accident

Very rare
Posterior reversible encephalopathy syndrome(PRES) (see section 4.4)

Cardiac disorders                       Uncommon
Arrhythmias, predominantly supraventricular in nature, heart failure
Rare
Myocardial infarct


Vascular disorders                      Rare
Hypotension, Clinical signs of peripheral vasculitis and gangrene,
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)


System Organ Class                        Frequency grouping
Gastrointestinal disorders                  Very common
Vomiting, nausea

Common
Diarrhoea, stomatitis and ulceration of the mouth, constipation
Very rare lschaemic 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)


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, Acute generalized exanthematous pustulosis
Musculoskeletal and connective tissue     Common disorders                                 Back pain, myalgia


System Organ Class                          Frequency grouping
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.
lt 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/