The following is based on the experience of 812 patients treated in Phase II and III clinical trials. The frequency and severity of adverse effects are generally similar between patients receiving paclitaxel for the treatment of ovarian, breast or lung cancer. None of the observed effects were clearly influence by age. Unless stated otherwise, percent figures, where given, are based on observed incidence when using the recommended dosing regimen. If other regimes are used, the incidence of reaction may be higher.
Safety of the paclitaxel/platinum combination has been investigated in a large randomised trial in ovarian cancer and in two Phase III trials in NSCLC. Unless otherwise mentioned, the combination of paclitaxel with platinum agents did not result in any clinically relevant changes to the safety profile of single agent paclitaxel.
Adverse effects reported were those occurring during or following the first course of therapy and have, where possible, been grouped by frequency according to the following criteria. Very common: ≥1/10; Common: ≥1/100 and <1/10; Uncommon: ≥1/1000 and <1/100; Rare: ≥1/10000 and <1/1000; Very rare: <1/10000.
Cardiovascular: Very common: Hypotension.
Common: Bradycardia; ECG abnormalities (non-specific repolarisation and sinus tachycardia).
Uncommon: ECG abnormalities (premature beats), cardiomyopathy.
Rare: Myocardial infarction; congestive heart failure (typically in patients who have received other chemotherapy, notably anthracyclines).
Six severe cardiovascular events possibly related to paclitaxel administration occurred including asymptomatic ventricular tachycardia, tachycardia with bigeminy, atrioventricular block (2 patients), and syncopal episodes (2 patients-in one associated with severe hypotension and coronary stenosis resulting in death). Severe hypotensive reactions have been associated with serious hypersensitivity reactions and have required intervention.
Haematological: Very common: Myelosuppression, thrombocytopenia, leucopoenia, fever, bleeding, anaemia; neutropenia (Overall, 52% of the patients experienced severe Grade IV neutropenia and 56% had Grade III/IV severe neutropenia on their first course. Neutrophil nadirs occurred at a median of 11 days after paclitaxel administration).
Common: Febrile neutropenia (associated with an infectious episode, including UTI and URTI).
Rare: Five septic episodes, which were associated with severe neutropenia attributable to paclitaxel administration had a fatal outcome.
Patients who have received prior radiation or cisplatin therapy exhibit more frequent myelosuppression, which is generally of greater severity (see Precautions and Interactions).
Hepatobiliary: Very common: Elevated alkaline phosphatase; elevated AST; elevated ALT.
Common: Elevated bilirubin.
Rare: Hepatic necrosis (leading to death); hepatic encephalopathy (leading to death).
Hypersensitivity: Very common: Flushing; rash.
Common: Dyspnoea; hypotension; chest pains; tachycardia.
Uncommon: Significant hypersensitivity reactions requiring therapy (e.g. Hypotension, angioneurotic oedema, respiratory distress, generalised urticaria, oedema, back pains, chills.
Infections and Infestation: Very common: Infection.
Uncommon: Septic shock.
Gastrointestinal: Very common: Nausea; vomiting; diarrhoea; mucositis (These manifestations were usually mild to moderate at the recommended dose).
Rare: Bowel perforation (There have been several cases of bowel perforation associated with patients receiving paclitaxel. Patients receiving paclitaxel who complain of abdominal pain with other signs and symptoms, should have bowel perforation excluded).
Neutropenic enterocolitis has been reported.
Vascular Disorders: Very common: Hypotension.
Uncommon: Hypertension, thrombosis, thrombophlebitis.
Musculoskeletal: Very common: Arthralgia; myalgia (The symptoms were usually transient occurring two to three days after paclitaxel administration and resolving within a few days).
Neurological: Very common: Peripheral neuropathy (Peripheral neuropathy occurs and is dose dependent with 60% of patients experiencing Grade I toxicity, 10% Grade II and 2% Grade III at the recommended doses. Neuropathy was present in 87% of patients at higher doses. Severity of symptoms also increased with dose; 4% of patients experienced severe symptoms at the recommended dose versus 10% at higher doses. Neurologic symptoms may occur following the first course and symptoms may worsen with increasing exposure to paclitaxel. Peripheral neuropathy was the cause of paclitaxel discontinuation in 2% of patients. Sensory symptoms have usually improved or resolved within several months of paclitaxel discontinuation).
Rare: Optic nerve and/or visual disturbances (scintillating scotomata) particularly in patients who have received higher doses than recommended; these effects generally have been reversible; motor neuropathy with resultant minor distal weakness and autonomic neuropathy resulting in paralytic ileus and orthostatic hypotension.
Skin and Appendages: Very common: Alopecia.
Rare: Nail and skin changes (mild and transient); radiation-recall dermatitis; recall dermatitis.
Local: Phlebitis following intravenous administration has been reported.
Extravasation leading to oedema, pain, erythema and induration has been reported.
On occasions, extravasation can lead to cellulitis. Skin discolouration may also occur.
General Disorders and Administration Site Conditions: Common: Injection site reactions (including localised oedema, pain, erythema, induration, on occasion extravasation can result in cellulitis).
Injection site reactions, including reactions secondary to extravasation, were usually mild and consistent of erythema, tenderness, skin discolouration, or swelling at the injection site. These reactions have been observed more frequently with the 24-hour infusion than with the 3-hour infusion. 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.
Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis and fibrosis have been received as part of the continuing surveillance of paclitaxel safety. In some cases the onset of the injection site reaction either occurred during a prolonged infusion or was delayed by a week to ten days.
A specific treatment for extravasation reactions is unknown at this time. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.
Radiation pneumonitis has been reported in patients receiving concurrent radiotherapy.
Post-Marketing Experience: The following additional adverse reactions have been identified during post approval use of paclitaxel. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure.
Infections and Infestations: Pneumonia, sepsis.
Cardiac Disorders: Atrial fibrillations, supraventricular tachycardia, reduction of left ventricle ejection fraction, ventricular failure.
Haemotological Disorders: Acute myeloid leukaemia, myelodysplastic syndrome.
Immune System Disorders: Anaphylactic reactions (with fatal outcome), anaphylactic shock, cross-hypersensitivity between Anzatax and other taxanes has been reported.
Metabolism and Nutritional Disorders: Anorexia, tumour lysis syndrome.
Psychiatric Disorders: Confusion state.
Vascular Disorders: Shock.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea, pleural effusion, respiratory failure, interstitial pneumonia, lung fibrosis, pulmonary embolism, cough.
Gastrointestinal Disorders: Bowel obstruction, bowel perforation, ischemic colitis, pancreatitis, mesenteric thrombosis, pseudomembranous colitis, oesophagitis, constipation, ascites.
Neurological Disorders: Autonomic neuropathy (resulting in paralytic ileus and orthostatic hypotension), grand mal seizures, convulsions, encephalopathy, dizziness, headache, ataxia, parasthesia, hyperesthesia.
Eye Disorders: Photopsia, visual floaters.
Ear and Labyrinth Disorders: Hearing loss, tinnitus, vertigo, ototoxicity.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, epidermal necrolysis, erythema multiforme, exfoliative dermatitis, urticaria, onycholysis (patients on therapy should wear sun protection on hands and feet), scleroderma, pruritus, rash, erythema, phlebitis, cellulitis, skin exfoliation, necrosis and fibrosis.
Investigations: Increase in blood creatinine.
General Disorders and Administration Site Conditions: Asthenia, malaise, pyrexia, dehydration, oedema.