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 (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1000), 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 Leucopaenia (Neutropaenia 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)
Thrombocytopaenia
Gemcitabine Teva Concentrate for Solution for Infusion, KL05/2024
Anaemia

Common
Febrile neutropaenia

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
Clinical Cerebrovascular accident
Very rare
Posterior reversible encephalopathy syndrome (PRES) (see section 4.4)
Cardiac disorders                                          Uncommon
Arrhythmia, 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)
Gemcitabine Teva Concentrate for Solution for Infusion, KL05/2024
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)
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

Gemcitabine Teva Concentrate for Solution for Infusion, KL05/2024
Renal and urinary disorders                                Very common Haematuria
Mild proteinuria

Uncommon
Renal failure (see section 4.4)
Hemolytic uremic 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 neutropaenia, 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 neutropaenia 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) Neutropaenia                           11 (4.2)             17 (6.6)*   82 (31.3)      45 (17.2)* Non-laboratory
Febrile neutropaenia                   3 (1.2)              0           12 (4.6)       1 (0.4) Gemcitabine Teva Concentrate for Solution for Infusion, KL05/2024
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 neutropaenia 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, doxorubicin      cisplatin arm and cisplatin) arm            (N=200)
(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)         1 (0) 

Combination use in ovarian cancer
Grade 3 and 4 adverse events
Carboplatinversus 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) Neutropaenia                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) Leucopaenia                 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 neutropaenia        0 (0.0)        0 (0.0)      2 (1.1)         (0.0) Infection without           0 (0)          0 (0.0)      (0.0)           1 (0.6) neutropaenia
Sensory neuropathy was also more frequent in the combination arm than with single agent carboplatin.


Gemcitabine Teva Concentrate for Solution for Infusion, KL05/2024
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/.