Adverse reactions : תופעות לוואי

4.8 Undesirable effects
The frequency and severity of undesirable effects, unless otherwise mentioned, are generally similar between patients receiving paclitaxel for the treatment of ovarian carcinoma, breast carcinoma, or NSCLC. None of the observed toxicities were clearly influenced by age.


The most frequent significant undesirable effect was bone marrow suppression. Severe neutropenia (< 500 cells/mm³) occurred in 28% of patients, but was not associated with febrile episodes. Only 1% of patients experienced severe neutropenia for 7 days. Thrombocytopenia was reported in 11% of patients. Three percent of patients had a platelet count nadir < 50,000/mm³ at least once while on study. Anaemia was observed in 64% of patients, but was severe (Hb < 5 mmol/l) in only 6% of patients. Incidence and severity of anaemia is related to baseline haemoglobin status.


Neurotoxicity, mainly peripheral neuropathy*, appeared to be more frequent and severe with a 175 mg/m2 3-hour infusion (85% neurotoxicity, 15% severe) than with a 135 mg/m2 24-hour infusion (25% peripheral neuropathy, 3% severe) when paclitaxel was combined with cisplatin. In NSCLC patients and in ovarian cancer patients treated with paclitaxel over three hours followed by cisplatin, there is an apparent increase in the incidence of severe neurotoxicity. Peripheral neuropathy can occur following the first course and can worsen with increasing exposure to paclitaxel. Peripheral neuropathy was the cause of paclitaxel discontinuation in a few cases. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for paclitaxel therapy.

* can persist beyond 6 months of paclitaxel discontinuation.

Arthralgia or myalgia affected 60% of patients and was severe in 13% of patients.


A significant hypersensitivity reaction with possible fatal outcome (defined as hypotension requiring therapy, angioedema, respiratory distress requiring bronchodilator therapy, or generalised urticaria) occurred in two (< 1%) of patients. Thirty-four percent of patients (17% of all courses) experienced minor hypersensitivity reactions. These minor reactions, mainly flushing and rash, did not require therapeutic intervention nor did they prevent continuation of paclitaxel therapy.


Injection site reactions during intravenous administration may lead to localised oedema, pain, erythema, and induration; on occasion, extravasation can result in cellulitis. Skin sloughing and/or peeling has been reported, sometimes related to extravasation. Skin discoloration may also occur.
Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel at a different site, i.e. “recall”, has been reported rarely. A specific treatment for extravasation reactions is unknown at this time.
Disseminated intravascular coagulation (DIC), often in association with sepsis or multi-organ failure, has been reported.

Tabulated summary of undesirable effects
The table below lists undesirable effects regardless of severity associated with the administration of single agent paclitaxel administered as a three hour infusion in the metastatic setting and adverse reactions from post-marketing experience. The latter ones may be attributed to paclitaxel regardless of the treatment regimen..
The frequency of undesirable effects listed below is defined using the following convention:

 very common ( ≥ 1/10); common ( ≥1/100, < 1/10); uncommon ( ≥1/1,000, < 1/100); rare ( ≥1/10,000, < 1/1,000); very rare (< 1/10,000).
Very common : infection (mainly urinary tract and upper respiratory tract infections), with reported cases of fatal
Infections and infestations:               outcome
Uncommon: septic shock
Rare: pneumonia, peritonitis, sepsis
Very common : myelosuppression,
neutropenia, anaemia, thrombocytopenia,
Blood and the               leucopenia, bleeding lymphatic system
Rare: febrile neutropenia disorders:
Very rare: acute myeloid leukaemia,
myelodysplastic syndrome
Very common : minor hypersensitivity reactions (mainly flushing and rash)
Uncommon : significant hypersensitivity reactions requiring therapy (e.g.,
hypotension, angioneurotic oedema,
Immune system               respiratory distress, generalised urticaria, disorders:                  chills, back pain, chest pain, tachycardia, abdominal pain, pain in extremities,
diaphoresis and hypertension)
Rare: anaphylactic reactions
Very rare : anaphylatic shock
Metabolism and nutrition                   Very rare : anorexia disorders:
Psychiatric
Very rare : confusional state disorders:
Very common : neurotoxicity (mainly: peripheral neuropathy)
Rare: motor neuropathy (with resultant
Nervous system              minor distal weakness) disorders:
Very rare : autonomic neuropathy
(resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy,
dizziness, headache, ataxia
Further, it has been demonstrated that peripheral neuropathies can persist beyond 6 months of paclitaxel discontinuation.

Very rare: optic nerve and/or visual disturbances (scintillating scotomata),
Eye disorders: particularly in patients who have received higher doses than recommended
Ear and
Very rare : ototoxicity, hearing loss,
labyrinth tinnitus, vertigo disorders:
Common: bradycardia
Uncommon : cardiomyopathy,
asymptomatic ventricular tachycardia,
Cardiac tachycardia with bigeminy, AV block and disorders: syncope, myocardial infarction
Very rare : atrial fibrillation,
supraventricular tachycardia
Very common : hypotension
Vascular                  Uncommon: hypertension, thrombosis,
disorders:                thrombophlebitis
Very rare: shock

Respiratory,              Rare: dyspnoea, pleural effusion,
thoracic and              interstitial pneumonia, lung fibrosis,
mediastinal               pulmonary embolism, respiratory failure disorders:                Very rare: cough
Very common : nausea, vomiting,
diarrhoea, mucosal inflammation
Rare*: bowel obstruction, bowel
Gastrointestinal perforation, ischaemic colitis, pancreatitis disorders:
Very rare : mesenteric thrombosis,
pseudomembranous colitis, oesophagitis,
constipation, ascites, neutropenic colitis
Very rare: hepatic necrosis, hepatic
Hepato-biliary encephalopathy (both with reported cases disorders: of fatal outcome)
Very common : alopecia : alopecia was
Skin and                  observed in 87% of patients and was subcutaneous              abrupt in onset. Pronounced hair loss of tissue disorders:         ≥50% is expected for the majority of patients who experience alopecia.
Common: transient and mild nail and skin changes
Rare: pruritus, rash, erythema
Very rare : Stevens-Johnson syndrome,
epidermal necrolysis, erythema multiforme, exfoliative dermatitis,
urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet)
Unknown : Palmar-plantar erythrodysesthesia syndrome *
Musculoskeletal,
connective tissue
Very common: arthralgia, myalgia and bone disorders :
Common : injection site reactions
General                     (including localised oedema, pain,
disorders and               erythema, induration, on occasion administration              extravasation can result in cellulitis) site conditions:            Rare: asthenia, pyrexia, dehydration,
oedema, malaise
Common : severe elevation in AST
(SGOT), severe elevation in alkaline
Investigations:             phosphatase
Uncommon: severe elevation in bilirubin
Rare: increase in blood creatinine
* As reported in the post marketing surveillance of paclitaxel
Breast cancer patients who received paclitaxel in the adjuvant setting following AC experienced more neurosensory toxicity, hypersensitivity reactions, arthralgia/myalgia, anaemia, infection, fever, nausea/vomiting and diarrhoea than patients who received AC alone. However, the frequency of these events was consistent with the use of single agent paclitaxel, as reported above.


Combination treatment
When administered as a three hour infusion for the first-line chemotherapy of ovarian cancer, neurotoxicity, arthralgia/myalgia, and hypersensitivity were reported as more frequent and severe by patients treated with paclitaxel followed by cisplatin than patients treated with cyclophosphamide followed by cisplatin. Myelosuppression appeared to be less frequent and severe with paclitaxel as a three hour infusion followed by cisplatin compared with cyclophosphamide followed by cisplatin.
For the first line chemotherapy of metastatic breast cancer, neutropenia, anaemia, peripheral neuropathy, arthralgia/myalgia, asthenia, fever, and diarrhoea were reported more frequently and with greater severity when paclitaxel (220 mg/m²) was administered as a three-hour infusion 24 hours following doxorubicin (50 mg/m²) when compared to standard FAC therapy (5-FU 500 mg/m², doxorubicin 50 mg/m², cyclophosphamide 500 mg/m²). Nausea and vomiting appeared to be less frequent and severe with the paclitaxel (220 mg/m²) / doxorubicin (50 mg/m²) regimen as compared to the standard FAC regimen. The use of corticosteroids may have contributed to the lower frequency and severity of nausea and vomiting in the paclitaxel/doxorubicin arm.

Paclitaxel and trastuzumab

When paclitaxel was administered as a three-hour infusion in combination with trastuzumab for the first line treatment of patients with metastatic breast cancer, the following events (regardless of relationship to paclitaxel or trastuzumab) were reported more frequently than with single agent paclitaxel: heart failure (8% vs 1%), infection (46% vs 27%), chills (42% vs 4%), fever (47% vs 23%), cough (42% vs 22%), rash (39% vs 18%), arthralgia (37% vs 21%), tachycardia (12% vs 4%), diarrhoea (45% vs 30%), hypertonia (11% vs
3%), epistaxis (18% vs 4%), acne (11% vs 3%), herpes simplex (12% vs 3%), accidental injury (13% vs 3%), insomnia (25% vs 13%), rhinitis (22% vs 5%), sinusitis (21% vs 7%), and injection site reaction (7% vs 1%). Some of these frequency differences may be due to the increased number and duration of treatments with paclitaxel /trastuzumab combination vs single agent paclitaxel.
Severe events were reported at similar rates for paclitaxel /trastuzumab and single agent paclitaxel.

Paclitaxel and doxorubicin

When doxorubicin was administered in combination with paclitaxel in metastatic breast cancer, cardiac contraction abnormalities ( 20% reduction of left ventricular ejection fraction) were observed in 15% of patients vs. 10% with standard FAC regimen. Congestive heart failure was observed in < 1% in both paclitaxel /doxorubicin and standard FAC arms.
Administration of trastuzumab in combination with paclitaxel in patients previously treated with anthracyclines resulted in an increased frequency and severity of cardiac dysfunction in comparison with patients treated with paclitaxel single agent (NYHA Class I/II 10% vs. 0%; NYHA Class III/IV 2% vs. 1%) and rarely has been associated with death (see trastuzumab Summary of Product Characteristics). In all but these rare cases, patients responded to appropriate medical treatment.


Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.


AIDS-related Kaposi's sarcoma
Except for haematologic and hepatic undesirable effects (see below), the frequency and severity of undesirable effects are generally similar between KS patients and patients treated with paclitaxel monotherapy for other solid tumours, based on a clinical study including 107 patients.


Blood and the lymphatic system disorders: bone marrow suppression was the major dose-limiting toxicity. Neutropenia is the most important haematological toxicity. During the first course of treatment, severe neutropenia (< 500 cells/mm3) occurred in 20% of patients. During the entire treatment period, severe neutropenia was observed in 39% of patients.
Neutropenia was present for > 7 days in 41% and for 30-35 days in 8% of patients. It resolved within 35 days in all patients who were followed. The incidence of Grade 4 neutropenia lasting 7 days was 22%.


Neutropenic fever related to paclitaxel was reported in 14% of patients and in 1.3% of treatment cycles. There were three septic episodes (2.8%) during paclitaxel administration related to the medicinal product that proved fatal.


Thrombocytopenia was observed in 50% of patients, and was severe (< 50,000 cells/mm3) in 9%. Only 14% experienced a drop in their platelet count < 75,000 cells/mm3, at least once while on treatment. Bleeding episodes related to paclitaxel were reported in < 3% of patients, but the haemorrhagic episodes were localised.


Anaemia (Hb < 11 g/dL) was observed in 61% of patients and was severe (Hb < 8 g/dL) in 10%. Red cell transfusions were required in 21% of patients.


Hepato-biliary disorders : Among patients (> 50% on protease inhibitors) with normal baseline liver function, 28%, 43% and 44% had elevations in bilirubin, alkaline phosphatase and AST (SGOT), respectively. For each of these parameters, the increases were severe in 1% of cases.


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/