Adverse reactions : תופעות לוואי

4.8 Undesirable Effects

Results from clinical trials reveal that, when used at the recommended dosage and treatment regimen, paclitaxel is generally well tolerated.
Frequency and severity of adverse effects were shown to correlate with the administered dosage and depended on the patients’ baseline condition, but were generally equal in patients with ovarian cancer, breast cancer or non-small cell lung cancer (NSCLC). No association has been established between the age of the patients and any occurring adverse effects.

The following safety data relate to patients with ovarian or breast cancer, who in phase III trials received 175 mg/m2 of paclitaxel as a single dose over three hours.

Data on the paclitaxel-plus-platinum chemotherapy were generally derived from a large randomised study of ovarian cancer therapy (24-hour infusion, GOG-111) and phase III trials in non-small cell lung cancer (three-hour infusion). Neither the combination of paclitaxel and platinum components nor the infusion of paclitaxel over 24 hours showed a clinically relevant difference with respect to the safety profile of paclitaxel for single-agent use.

The following adverse effects were described:

Infections and infestations
Very common: One quarter of the patients presented symptoms of infection; two of these cases with recommended dosage and infusion regimen had a fatal outcome in the phase III trials.

The most common infections related to neutropenia are urinary tract infections, respiratory infections and sepsis.

Blood and lymphatic system disorders
Very common:
• Haematopoietic system: Myelosuppression is the most common serious adverse reaction of paclitaxel therapy. Neutropenia (values <2,000/mm3) occurred in 28% of patients, but has not been associated with fever; severe neutropenia occurred in only 1% of the cases for seven days or longer. Neutropenia was in general rapidly reversible.

• Thrombocytopenia occurred in 11% of patients, 3% had a nadir of <50,000/mm3 at least once during the trial.

• Anaemia was observed in 64%, severe anaemia (Hb<5 mmol/l) occurred in only 6% of patients. Frequency and severity depended on baseline haemoglobin status.

• Myelosuppression was less common and less severe if paclitaxel was administered as an infusion over three hours instead of 24 hours. In first-line chemotherapy of ovarian cancer the recommended paclitaxel/cisplatin regimen resulted in greater myelosuppression than the use of paclitaxel as a single agent (175 mg/m2/3h), but without causing an increase in clinical reactions.

Very rare: Acute myeloid leukaemia and myelodysplastic syndrome were very rarely reported.
Benign and malignant tumours (including cysts and polyps)
Very rare: One case of acute myeloid leukaemia and one case of myelodysplastic syndrome were reported.

Hypersensitivity reactions
Very common: One third of patients exhibited mild hypersensitivity reactions (especially flush and skin rash), which did not necessitate therapeutic treatment nor discontinuation of paclitaxel therapy.

Common: With adequate premedication, severe hypersensitivity reactions (hypotension requiring treatment, angioedema, severe dyspnoea, or generalised urticaria) are expected to occur in only 2% of the cases.

Nervous system disorders
Very common: Mild peripheral neuropathy (in particular paraesthesia) occurred in two thirds of patients.

Common: 5% of patients experienced severe peripheral neuropathy. This was slightly more common (6%) in patients with non-small cell lung cancer. More frequent use of paclitaxel may result in greater peripheral neuropathy, and in some cases a discontinuation of the therapy may be strongly recommended. Pre-existing neuropathy resulting from earlier treatment courses does not constitute a contraindication, yet existing symptoms may be intensified as a result of cumulative toxicity.

Neuropathic symptoms improved and/or disappeared only a few months after discontinuation of paclitaxel therapy.

Very rare: Grand mal attacks, encephalopathy, neuropathy (autonomous, resulting in paralytic ileus) and orthostatic hypotension were exhibited in the course of non- randomised clinical trials.

Optical nerve disorders and/or visual impairment (scintillating scotoma) were observed in patients receiving a higher than the recommended dosage. Such symptoms were generally reversible.

Ototoxicity (hearing loss, tinnitus) occurred very rarely and may have been associated with neuropathy, the underlying disease, or the patient’s previous medical condition.

Cardiac disorders
Very common: Hypotension and bradycardia have been commonly observed (in 22% and 5% of patients, respectively). However, therapeutic treatment was not necessary.

Uncommon: ECG changes of no or minor clinical relevance were reported, but were not safely associated with paclitaxel.

Very rare: Hypertension, hypotension with aseptic shock and severe thrombotic events (thrombophlebitis and thrombosis of the upper extremities) were very rarely reported.

The following cardiovascular events may occur during paclitaxel therapy, especially in the case of prior anthracycline exposure or non-small cell lung cancer: junctional ventricular tachycardia with bigeminal beats, AV block, syncope, cardiomyopathy, cardiac insufficiency, myocardial infarction and hypotension.

Gastrointestinal disorders
Very common: Adverse gastrointestinal reactions (anorexia, nausea, vomiting, diarrhoea) were mild and occurred in approximately half of patients; nausea and vomiting in approx. 40%, diarrhoea in approx. 30% and mucositis in approx. 20%.

Rare: Intestinal obstruction (ileus), perforation and thrombosis of the mesentery including ischaemic colitis have been reported.

In case of concomitant radiotherapy: neutropenic enterocolitis and pneumonitis.

Hepato-biliary disorders
Common: Significant increase in AST (SGOT) levels (up to five times the normal values) in 5% of patients, and of alkaline phosphatase in 4%.

Uncommon: Increased bilirubin levels were observed in less than 1% of patients.

Very rare: Hepatic necrosis, hepatic encephalopathy and peripheral oedema were reported.

Skin and subcutaneous tissue disorders
Very common: Alopecia was observed in nearly all patients.

Very rare: Exfoliative dermatitis was reported. Stevens-Johnson syndrome, epidermal necrolysis and erythema multiforme were reported, but it is unknown whether these effects may have been the result of other concomitant circumstances.

Musculoskeletal, connective tissue and bone manifestations
Very common: Arthralgia and myalgia were very common (60%). Pain normally occurred 2-3 days following therapy and disappeared within five days.

General disorders and administration site conditions
Very common: Injection site reactions (oedema, pain, erythema, hardening) occurred in 13% of patients.

Rare: In rare cases a "recall” phenomenon was observed, i.e. a recurring local skin reaction at sites of previous extravasation following paclitaxel infusion at a different site. Extravasation may result in cellulitis or discoloration of the skin.

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.