Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Pfizer Australia Pty Ltd, Level 17, 151 Clarence Street, Sydney NSW 2000, Toll Free number: 1800 675 229, www.pfizer.com.au
Anzatax Injection Concentrate must not be used in patients who have exhibited hypersensitivity reactions to paclitaxel or other taxanes.
Anzatax Injection Concentrate must not be used in patients who have a history of hypersensitivity reactions to PEG-35 castor oil or drugs formulated in PEG-35 castor oil (e.g., ciclosporin for injection concentrate and teniposide for injection concentrate) or any of the other excipients.
Anzatax Injection Concentrate should not be administered in patients with solid tumours who have a baseline neutrophil counts of <1.5 × 109 cells/L.
Paclitaxel should be administered under the supervision of a physician experienced in the use of chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Paclitaxel should be given before a platinum compound when it is given in combination with a platinum compound.
In order to minimise the possibility of hypersensitivity reactions due to histamine release, patients should be premedicated before every treatment cycle of paclitaxel. Premedication should include corticosteroids (e.g., dexamethasone), antihistamines (e.g., diphenhydramine or promethazine) and an H2-receptor antagonist (e.g., cimetidine or ranitidine) (see section 4.2 Dose and method of administration). The characteristic symptoms of hypersensitivity reactions are dyspnoea and hypotension both requiring treatment, angioedema and widespread urticaria. In clinical trials, 2% of patients treated with paclitaxel experienced severe hypersensitivity. One of these reactions was fatal in a patient treated without premedication. Anzatax Injection Concentrate must not be used in patients who have exhibited hypersensitivity reactions to paclitaxel.
As the dose limiting toxicity of paclitaxel is dose related bone marrow suppression (primarily neutropenia), paclitaxel should not be administered to patients with a pre-treatment neutrophil count of less than 1.5 × 109 cells/L (1,500 cells/mm³) or platelet count of less than 100 × 109 cells/L. Blood counts should be frequently monitored during treatment with paclitaxel. Further cycles of paclitaxel should not be administered until the patient’s neutrophil count is greater than 1.5 × 109 cells/L (1,500 cells/mm³) and the platelet count is greater than 100 × 109 cells/L (100,000 cells/mm³).
If there is severe neutropenia during a course of paclitaxel (i.e., neutrophil count less than 0.5 × 109 cells/L [500 cells/mm³]), the dose of paclitaxel in subsequent cycles should be reduced by 20%. Previous radiation therapy may induce more severe myelosuppression. There is little information available from such patients at doses above 135 mg/m².
Hypotension, hypertension and bradycardia have been observed during paclitaxel administration, but generally do not require treatment. Frequent monitoring of vital signs, particular during the first hours of paclitaxel infusion is recommended (see also section 4.8 Adverse effects (undesirable effects)).
Electrocardiographic monitoring is recommended for patients with serious conduction abnormalities and should be commenced for patients who develop abnormal cardiovascular symptoms or signs during monitoring of vital signs.
Severe cardiac conduction abnormalities have been reported rarely during paclitaxel therapy.
If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered and continuous electrocardiographic monitoring should be commenced and performed during subsequent therapy with paclitaxel (see section 4.8 Adverse effects (undesirable effects)). Severe cardiovascular events were observed more frequently in patients with NSCLC than breast or ovarian cancer.
When paclitaxel is used in combination with trastuzumab or doxorubicin for treatment of metastatic breast cancer, monitoring of cardiac function is recommended. When patients are candidates for treatment with paclitaxel in these combinations, they should undergo baseline cardiac assessment including history, physical examination, ECG, echocardiogram, and/or MUGA scan. Cardiac function should be further monitored during treatment (eg, every 3 months). Monitoring may help to identify patients who develop cardiac dysfunction and treating physicians should carefully assess the cumulative dose (mg/m²) of anthracycline administered when making decisions regarding frequency of ventricular function assessment. When testing indicates deterioration in cardiac function, even asymptomatic, treating physicians should carefully assess the clinical benefits of further therapy against the potential for producing cardiac damage, including potentially irreversible damage. If further treatment is administered, monitoring of cardiac function should be more frequent (eg, every 1-2 cycles).
Severe hypersensitivity (anaphylactoid reactions characterised by dyspnoea and hypotension requiring treatment, angioedema and generalised urticaria have occurred rarely in premedicated patients receiving paclitaxel. Rare fatal reactions have occurred in patients despite pretreatment. Cross-hypersensitivity between ANZATAX and other taxane products has been reported and may include severe reactions such as anaphylaxis. Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of ANZATAX therapy.
Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. Patients receiving paclitaxel should be under continuous observation for at least the first 30 mins following the start of the infusion and frequently thereafter. In case of a severe hypersensitivity reaction, paclitaxel infusion should be discontinued immediately and appropriate treatment given as indicated for anaphylaxis. The patient should not be rechallenged with the drug. Minor hypersensitivity reactions such as flushing, skin reactions etc do not require interruption of therapy (see also section 4.8 Adverse effects (undesirable effects)).
In patients receiving paclitaxel who complain of abdominal pain with other signs and symptoms, bowel perforation should be excluded.
Anzatax Injection Concentrate is administered by intravenous infusion only; it must not be administered by the intracerebral, intrapleural or intraperitoneal routes. Anzatax Injection Concentrate must be diluted before intravenous infusion. Prior to intravenous infusion of paclitaxel, it must be ensured that the indwelling catheter is in the correct position as extravasation, necrosis and/or thrombophlebitis may result with incorrect administration (see section 4.2 Dose and method of administration).
Patients receiving paclitaxel should be under continuous observation for at least the first 30 minutes following the start of the infusion and frequently thereafter. In case of a severe hypersensitivity reaction, paclitaxel infusion should be discontinued immediately and appropriate treatment given as indicated for anaphylaxis. The patient should not be rechallenged with the drug. Minor hypersensitivity reactions such as flushing, skin reactions, etc. do not require interruption of therapy (see also section 4.8 Adverse effects (undesirable effects)).
In some patients, temporary discontinuation of the infusion is sufficient to resolve the symptoms. Other patients may require therapy with bronchodilators, adrenaline, antihistamines and corticosteroids, either alone or in combination.
A specific treatment for extravasation reaction 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.
Patients with pre-existing neuropathy should be carefully monitored. Peripheral neuropathy is frequently reported in patients receiving paclitaxel and the severity is dose dependent. A 20% reduction in paclitaxel dose is recommended for patients who develop peripheral neuropathy during therapy (see section 4.8 Adverse effects (undesirable effects)).
In NSCLC patients, the administration of paclitaxel in combination with cisplatin resulted in a greater incidence of neurotoxicity than usually seen in patients receiving single agent paclitaxel.
Paclitaxel contains ethanol, 396 mg/mL; consideration should be given to possible CNS and other effects of alcohol.
Children may be more sensitive than adults to the effects of ethanol.
Paclitaxel in combination with radiation of the lung, irrespective of their chronological order, may contribute to the development of interstitial pneumonia.
Pseudomembranous colitis has been reported in patients who have not been concomitantly treated with antibiotics. This reaction should be considered in the differential diagnosis of cases of severe or persistent diarrhoea occurring during or shortly after treatment with paclitaxel.
Severe mucositis has been reported which requires dose reduction (see Section 4.2).
There have been reports of reduced visual acuity due to cystoid macular oedema (CMO) during treatment with paclitaxel as well as with other taxanes (see Section 4.8). Patients with visual impairment during paclitaxel treatment should seek a prompt and complete ophthalmologic examination. Paclitaxel should be discontinued if a CMO diagnosis is confirmed.
The effect of hepatic impairment on the pharmacokinetics of paclitaxel has not been established. However, as the liver is thought to be the primary site for metabolism of the drug, paclitaxel should be given cautiously to patients with decreased liver function. Paclitaxel has been shown to cause a dose related elevation of liver enzymes.
When paclitaxel is given as a 24 hour infusion to patients with moderate to severe hepatic impairment, increased myelosuppression may be seen as compared to patients with mildly elevated liver function tests given 24 hour infusions.
The effect of renal impairment on the pharmacokinetics of paclitaxel has not been established.
Of 2228 patients who received paclitaxel in eight clinical studies evaluating its safety and efficacy in the treatment of advanced ovarian cancer, breast carcinoma or NSCLC and 1570 patients who were randomised to receive paclitaxel in the adjuvant breast cancer study, 649 patients (17%) were 65 years or older, including 49 patients (1%) 75 years or older. In most studies, severe myelosuppression was more frequent in elderly patients; in some studies, severe neuropathy was more common in elderly patients. In two clinical studies in NSCLC, the elderly patients treated with paclitaxel had a higher incidence of cardiovascular events. Estimates of efficacy appeared similar in elderly patients and in younger patients; however, comparative efficacy cannot be determined with confidence due to the small number of elderly patients studied. In a study of first line treatment of ovarian cancer, elderly patients had a lower median survival than younger patients, but no other efficacy parameters favoured the younger group.
The safety and effectiveness of paclitaxel in paediatric patients has not been established. There have been reports of central nervous system (CNS) toxicity (rarely associated with death) in a clinical trial in paediatric patients in which paclitaxel was infused intravenously over 3 hours at doses ranging from 350 mg/m² to 420 mg/m². The toxicity is most likely attributable to the high dose of the ethanol component of the paclitaxel vehicle given over a short infusion time. The use of concomitant antihistamines may intensify this effect. Although a direct effect of the paclitaxel itself cannot be discounted, the high doses used in this study (over twice the recommended adult dosage) must be considered in assessing the safety of paclitaxel for use in this population.
No data available.
The recommended regimen of paclitaxel administration for the first-line chemotherapy of ovarian carcinoma is for paclitaxel to be given before cisplatin. When paclitaxel is given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single-agent use. Administration of cisplatin prior to paclitaxel treatment leads to greater myelosuppression than that seen when paclitaxel is given prior to cisplatin. In patients receiving cisplatin prior to paclitaxel, there is about a 33% decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynecological cancers.
Sequence effects characterised by more profound neutropenic and stomatitis episodes have been observed with combination use of paclitaxel and doxorubicin when paclitaxel was administered before doxorubicin and using longer than recommended infusion times (paclitaxel administered over 24 hours; doxorubicin over 48 hours). Plasma levels of doxorubicin (and its active metabolite doxorubicinol) may be increased when paclitaxel and doxorubicin are used in combination and are given closer in time. Paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin (see Section 4.2). However, data from a trial using bolus doxorubicin and 3 hour paclitaxel infusion found no sequence effects on the pattern of toxicity.
Paclitaxel clearance is not affected by cimetidine premedication.
The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and 3A4. Clinical studies have demonstrated that CYP2C8 mediated metabolism of paclitaxel, to 6α-hydroxypaclitaxel, is the major metabolic pathway in humans. Concurrent administration of ketoconazole, a known potent inhibitor of CYP3A4, does not inhibit the elimination of paclitaxel in patients; thus, both medicinal products may be administered together without dosage adjustment. Further data on the potential of drug interactions between paclitaxel and CYP2C8 and 3A4 substrates/inhibitors are limited. Therefore, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g., erythromycin, fluoxetine, gemfibrozil, deferasirox, trimethoprim) or induce (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, efavirenz, nevirapine, St John’s wort) either CYP2C8 or 3A4.
In the clinical trial of paclitaxel in combination with trastuzumab (Herceptin), mean serum trough concentrations of trastuzumab were consistently elevated 1.5 fold as compared with serum concentrations of trastuzumab in combination with anthracycline plus cyclophosphamide (AC).
Arthralgia or myalgia adverse events of paclitaxel appear to be of a higher incidence in patients being treated concurrently with filgrastim (granulocyte colony stimulating factor; G-CSF).
Following treatment with intravenous paclitaxel at a dose of 1 mg/kg (6 mg/m²), rats showed decreased fertility and toxicity in unborn offspring. Paclitaxel administered intravenously to rabbits during organogenesis at a dose of 3 mg/kg (33 mg/m²) was toxic to both mother and foetus.
Based on findings in animal studies, ANZATAX may impair fertility in females and males of reproductive potential.
Category D.
Paclitaxel is a cytotoxic agent that can produce spontaneous abortion, foetal loss and birth defects and may cause foetal harm when administered to a pregnant woman. Studies have shown paclitaxel to be toxic to embryos and foetuses in rabbits at an intravenous dose of 3 mg/kg (33 mg/m²) given during organogenesis. Paclitaxel is toxic to rat foetuses at a dose of 1 mg/kg (6 mg/m²) and produced low fertility and foetal toxicity in rats. Examination revealed that no gross external, soft tissue or skeletal alterations occurred. There are no studies in pregnant women.
Women of childbearing potential should have a pregnancy test prior to starting treatment with ANZATAX. These women should be strongly advised to use effective contraception throughout therapy and for at least six months after the last dose of ANZATAX. If paclitaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard.
Based on findings in genetic toxicity and animal reproduction studies, males should be advised to use effective contraception in order to avoid fathering a child during treatment and for at least three months after the last dose of ANZATAX.
Women of childbearing potential should be advised to use effective contraception in order to avoid becoming pregnant during treatment and for at least six months after the last dose of ANZATAX.
It is not known whether paclitaxel is excreted in human milk. The evidence from many drugs would suggest that paclitaxel could be excreted in breast milk, though this is not known. Because infants receiving the drug could experience serious adverse effects, breastfeeding should be discontinued while the mother is undergoing treatment.
The effects of this medicine on a person’s ability to drive and use machines were not assessed as part of its registration. Patients should refrain from driving or using machines until they know that paclitaxel does not negatively affect these abilities. It should be noted that paclitaxel contains ethanol.
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 influenced by age. Unless stated otherwise, percent figures, where given, are based on observed incidence when using the recommended dosing regime. 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.
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. Cardiac failure and sinus bradycardia have also been observed.
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 section 4.4 Special warnings and precautions for use and section 4.5 Interactions with other medicines and other forms of interactions).
Very common: Elevated alkaline phosphatase; elevated AST; elevated ALT.
Common: Elevated bilirubin.
Rare: Hepatic necrosis (leading to death); hepatic encephalopathy (leading to death).
Very common: Flushing; rash.
Common: Dyspnoea; hypotension; chest pains; tachycardia.
Uncommon: Significant hypersensitivity reactions requiring therapy (eg. Hypotension, angioneurotic oedema, bronchospasm, respiratory distress, generalised urticaria, oedema, back pains, pain in extremities, chills, diaphoresis).
Very Common: Infection
Uncommon: Septic shock
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.
Very common: Hypotension
Uncommon: Hypertension, thrombosis, thrombophlebitis
Very common: Arthralgia; myalgia (The symptoms were usually transient occurring two to three days after paclitaxel administration and resolving within a few days).
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.
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.
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 consisted 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.
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, cystoid macular oedema, macular oedema.
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), pruritus, rash, erythema, phlebitis, cellulitis, skin exfoliation, necrosis, fibrosis, palmar-plantar erythrodysesthesia syndrome.
Musculoskeletal and Connective Tissue Disorders: Systemic lupus erythematosus, scleroderma
Investigations: Increase in blood creatinine.
General Disorders and Administration Site Conditions: Asthenia, malaise, pyrexia, dehydration, oedema.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
