INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo ANZATAX (CONCENTRATE FOR INJECTION)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

ANZATAX (CONCENTRATE FOR INJECTION)

WARNING
ANZATAX
TM (paclitaxel) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.
Severe hypersensitivity reactions characterised by dyspnoea, flushing, chest pain and tachycardia and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in patients receiving ANZATAX
TM. Patients receiving ANZATAXTM should be pretreated with corticosteroids, promethazine, and H2-antagonists to prevent these reactions (see “DOSAGE AND DIRECTIONS FOR USE”section). Patients who experience severe hypersensitivity reactions to ANZATAXTM should not be rechallenged with the drug.
ANZATAX
TM therapy should not be given to patients with baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ANZATAXTM.
The polyoxyethylated castor oil in ANZATAX
TM can result in phthalate leaching from polyvinyl chloride (PVC) containers, at levels which increase with time and concentration.
Consequently, the preparation, storage and administration of diluted ANZATAX
TM should be carried out by using non-plasticised PVC-containing equipment.

COMPOSITION
Each 1 mL contains:
Paclitaxel 6,00 mg
Ethanol (absolute alcohol) 49,80% - 50,28% v/v

PHARMACOLOGICAL CLASSIFICATION
A 26 Cytostatic agents.

PHARMACOLOGICAL ACTION
Paclitaxel is an antimicrotubular substance, which stimulates the production of a microtubule from tubulin dimers and stabilises the microtubule by preventing depolymerisation. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network, which is crucial to the vital interphase and cellular functions during mitosis.
Moreover, paclitaxel induces the production of abnormal series of microtubule bundles during the entire cell cycle and the production of multiple asters of microtubules during mitosis. After intravenous administration the plasma concentration of paclitaxel decreases biphasically.
In vitro studies of binding to human serum proteins indicated that approximately 89% of paclitaxel is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of paclitaxel.
Pharmacokinetics
The disposition of paclitaxel has not been fully elucidated in humans. After intravenous administration of paclitaxel, mean values of cumulative urinary recovery of unchanged drug ranged from 1,3 to 12,6% of the dose, indicating extensive non-renal clearance. Paclitaxel has been demonstrated to be metabolised in the liver in animals and there is evidence suggesting hepatic metabolism in humans. The effect of renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.

INDICATIONS
ANZATAX
TM is indicated for:
The palliative treatment of stage 3 or 4 advanced local carcinoma of the ovary after surgical resection, in combination with cisplatin.
The palliative management of metastatic carcinoma of the ovary after failure of first line or subsequent chemotherapy.
The treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contra-indicated.
Palliative treatment of advanced non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.

CONTRA-INDICATIONS
ANZATAX
TM is contra-indicated in patients who have a history of severe hypersensitivity reactions to paclitaxel or one of the other ingredients of the product, especially for polyoxyl 35 castor oil.
ANZATAX
TM should not be used in patients who, at the start of the therapy, have a neutrophilic granulocyte count of <1 500/mm3.

Pregnancy and lactation
ANZATAX
TM has been shown to be both foetotoxic and embryotoxic, and to reduce fertility in animal studies. No information is available on the use of ANZATAXTM in pregnant women. ANZATAXTM may damage the foetus if administered to pregnant women.
ANZATAX
TM is contra-indicated during pregnancy. Women should be advised not to fall pregnant during the treatment with ANZATAXTM and they should immediately inform their physician in attendance if this should happen nevertheless.

Use during lactation
It is not known whether ANZATAX
TM is being secreted in the mother's milk. ANZATAXTM is contra-indicated during lactation. Breast-feeding should be stopped during the treatment with ANZATAXTM.

WARNINGS
ANZATAX
TM should be administered under the supervision of a physician who is experienced in the use of oncological chemotherapeutics. As serious hypersensitivity reactions may occur, sufficient supporting equipment should be available.
Patients should be pre-treated with corticosteroids, antihistamines and H
2-antagonists.
Severe hypersensitivity reactions, characterised by dyspnoea and hypotension that should be treated, angioedema and generalised urticaria, have occurred in patients to whom ANZATAX
TM were administered after adequate premedication. These reactions are likely to be related to histamine. In cases in which severe hypersensitivity reactions occur, ANZATAXTM infusion should be stopped immediately and symptomatic therapy should be given. The patient should not again be rechallenged with this medication.
Bone marrow suppression (primary neutropenia) is the dose-limiting toxicity. Frequent monitoring of blood counts should be instituted during ANZATAX
TM treatment. Patients should not be re-treated until neutrophils recover to a level >1 500/mm3 and platelets recover to a level >100 000/mm3.
Serious cardiac conduction abnormalities have been reported. If patients develop serious conduction defects during ANZATAX
TM therapy, the appropriate treatment should be established with continuous cardiac monitoring during the follow-up treatment with ANZATAXTM. For all other patients a frequent check-up of the vital functions, especially during the first hour of the ANZATAXTM infusion, is recommended.
The polyoxyethylated castor oil in ANZATAX
TM can result in phthalate leaching from polyvinyl chloride (PVC) containers, at levels which increase with time and concentration.
Consequently, the preparation, storage and administration of diluted ANZATAX
TM should be carried out by using non-plasticised PVC-containing equipment.

DOSAGE AND DIRECTIONS FOR USE
Primary treatment of ovarian carcinoma
A combination regimen consisting of ANZATAX
TM 135 mg/m2 administered over 24 hours, followed by cisplatin 75 mg/m2, every 3 weeks. ANZATAXTM should be administered before cisplatin.
Secondary treatment of ovarian and breast carcinoma
ANZATAX
TM at a dose of 175 mg/m2, administered intravenously over 3 hours every 3 weeks has been shown to be effective in patients with metastatic carcinoma of the ovary or breast after failure of first line or subsequent chemotherapy.
Palliative treatment of advanced non-small cell lung carcinoma
The recommended dose of ANZATAX
TM is 175 mg/m2 administered over a period of 3 hours; followed by a platinum compound, with a 3 week interval between courses.
ANZATAX
TM should not be re-administered until the neutrophil count is at least 1 500/mm3 and the platelet count is at least 100 000/mm3. Patients who experience severe neutropenia (neutrophil count <500/mm3) or moderate to severe peripheral neuropathy, should receive a dose reduction of 20% for subsequent courses (see "SIDE-EFFECTS AND SPECIAL PRECAUTIONS").
The incidence and severity of neurotoxicity and haematologic toxicity increase with dose.
All patients should be premedicated prior to ANZATAX
TM administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of corticosteroids such as dexamethasone 20 mg orally approximately 12 and 6 hours before ANZATAXTM administration, antihistamines such as promethazine 25 mg intravenous 30 to 60 minutes prior to ANZATAXTM, and H2-antagonists, such as cimetidine 300 mg or ranitidine 50 mg I.V. 30 to 60 minutes before ANZATAXTM.

Handling
ANZATAX
TM should be handled with care. Dilution should be done by trained personnel under aseptic conditions in a specially allocated room. Protective gloves should be worn. Precautions should be taken to avoid contact with the skin and mucous membranes. If contact with the skin has occurred, the skin should be cleansed with water and soap. In case of contact with mucous membranes, flush with plenty of water. Upon inhalation, dyspnoea, chest pain, burning eyes, sore throat and nausea have been reported.

Preparation for IV administration
Before administration ANZATAX
TM must be diluted under aseptic conditions. ANZATAXTM should be diluted with 0,9% Sodium Chloride Injection, or with 5% Dextrose Injection, or 5% Dextrose and 0,9% Sodium chloride Injection or 5% Dextrose in Ringer's Injection to a final concentration of 0,3 to 1,2 mg/mL.
The prepared solutions are physically and chemically stable at room temperature (approx. 25ºC) and artificial light for a period of 27 hours (including preparation and administration). Diluted solutions should not be cooled.
Parenteral products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
After dilution the solutions may show some turbidity, but this is due to the formulation and cannot be corrected by filtration. ANZATAX
TM should be administered through an in-line filter with a microporous membrane with a pore diameter no larger than 0,22 µm. After simulated infusion through an I.V. catheter with in-line filter, no significant loss of effectiveness was observed.
In order to minimise the patient’s exposure to the plasticised DEHP [di-(2-ethylhexyl)phthalate] which can be released from PVC of infusion materials used, the diluted ANZATAX
TM solutions should be stored in non-PVC bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and be administered through polyethylene-lined administration sets. The use of filters (IVEX-2R, for example) which have short PVC inlet and outlet parts, did not result in significant DEHP leakage.

Disposal
All items used for reconstitution, administration or otherwise, coming into contact with ANZATAX
TM, should undergo disposal according to local guidelines for the handling of cytotoxic compounds.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Haematologic
Bone-marrow suppression and peripheral neuropathy are the principal dose-related adverse effects associated with ANZATAX
TM. Compared to 24-hour infusion schedules, neutropenia is less common when ANZATAXTM is given as a 3-hour infusion.
Neutropenia is generally rapidly reversible. Severe neutropenia occurs in some patients.
Neutropenia is no more frequent or severe in patients who receive prior radiation therapy.
Likewise, neutropenia does not appear to be affected by treatment duration or cumulative exposure. Infectious episodes have been reported in some patients but none resulted in fatality.
Thrombocytopenia occurs less frequently. Severe thrombocytopenia is observed only during the first two courses. Bleeding episodes occur in some patients; no patient has required platelet transfusion.
Anaemia has been observed in the majority of the patients. Incidence and severity of anaemia is related to baseline haemoglobin status. Red cell transfusions are required in some patients. ANZATAX
TM therapy should not be administered to patients with baseline neutrophil counts of less than 1 500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ANZATAXTM. Patients should not be retreated with subsequent cycles of ANZATAXTM until neutrophils recover to a level >1 500 cells/mm3 and platelets recover to a level >100 000 cells/mm3.
In the case of severe neutropenia (<500 cells/mm
3 for seven days or more) during a course of ANZATAXTM therapy, a 20% reduction in dose for subsequent courses of therapy is recommended.
Hypersensitivity reactions
Hypersensitivity reactions may occur requiring therapeutic intervention and/or early discontinuation of ANZATAX
TM infusion during the first or second course of treatment despite premedication. Severe symptoms occur within the first hour of ANZATAXTM infusion.
Dyspnoea and hypotension requiring treatment and chest pains were the most frequent manifestations. Besides the few patients with severe hypersensitivity reactions, other patients experienced minor manifestations compatible with hypersensitivity reactions. The most frequent minor manifestations were flushing, rash and dyspnoea. Patients with a history of severe hypersensitivity reactions to products containing polyoxyethylated castor oil (e.g. cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with ANZATAX
TM. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with ANZATAXTM should be pre-medicated with corticosteroids (such as dexamethasone), promethazine and H2-antagonists (such as cimetidine or ranitidine).
Minor symptoms such as flushing, skin reaction, dyspnoea, hypotension or tachycardia do not require interruption of therapy. However, severe reactions, such as hypotension requiring treatment, dyspnoea requiring bronchodilators, angioedema or generalised urticaria require immediate discontinuation of ANZATAX
TM and aggressive symptomatic therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with ANZATAXTM.
Cardiovascular
Hypotension and bradycardia have been observed during administration of ANZATAX
TM, but generally do not require treatment. Frequent vital sign monitoring, particularly during the first hour of ANZATAXTM infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities (see "WARNINGS" section).
Patients may experience severe cardiovascular events possibly related to ANZATAX
TM administration. Included are tachycardia, hypertension and venous thrombosis.
Electrocardiogram alterations were experienced by some patients. The most frequently reported electrocardiogram modifications were non-specific repolarisation abnormalities, sinus tachycardia and premature beats. The relationship between ANZATAX
TM administration and electrocardiogram alterations is not clear.
Neurologic
Peripheral neuropathy occurs and is dose dependent. Neurologic symptoms may occur following the first course and the frequency of symptoms may increase with increasing exposure to ANZATAX
TM. Sensory symptoms have usually improved or resolved within several months of ANZATAXTM discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contra-indication for ANZATAXTM therapy. Although the occurrence of peripheral neuropathy is frequent, the development of severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of ANZATAXTM. Besides peripheral neuropathy, the other neurologic manifestations are grand mal seizure syncope, ataxia and neuroencephalopathy. Reports of motor neuropathy with resultant minor distal weakness and autonomic neuropathy resulting in paralytic ileus and orthostatic hypotension have appeared.
Arthralgia/Myalgia
Arthralgia/myalgia usually consisting of pain in the large joints of the arms and legs occurred, but were usually mild. The symptoms were usually transient occurring two or three days after ANZATAXTM administration and resolving within a few days.
Hepatic
There is no evidence that the toxicity of ANZATAXTM is enhanced in patients with elevated liver enzymes, but no data are available for patients with severe baseline cholestasis. Analysis restricted to patients with normal baseline liver function, showed instances of elevated bilirubin, elevated alkaline phosphate and elevated ALT (SGPT). Hepatic necrosis and hepatic encephalopathy leading to death have been reported.
Other clinical events
Alopecia has been observed in almost all of the patients. Transient and mild nail and skin changes have been observed. Less frequent reports of skin abnormalities related to radiation recall have been received. Gastrointestinal side-effects such as nausea/vomiting, diarrhoea and mucositis were reported. These manifestations were usually mild to moderate at the recommended dose.
Fibrotic phlebitis has been reported.
Extravasation during intravenous administration may lead to oedema, pain, erythema and induration; on occasion, extravasation can result in cellulitis. Skin discolouration may also occur. A specific treatment for extravasation reactions is unknown at this time.
Bowel obstructions/perforations and ischaemic colitis have been reported in patients treated with paclitaxel.
Interactions with other medicaments and other forms of interactions
Medications concomitantly administered with ANZATAX
TM (e.g. corticosteroids, antihistamines, and H2-antagonists) did not appear to interact adversely. However, possible interactions of ANZATAXTM with concomitantly administered medications have not been formally investigated.
In a Phase I trial using escalating doses of paclitaxel (110 to 200 mg/m2) and cisplatin (50 or 75 mg/m2) given as sequential infusions, myelosuppression was more profound when paclitaxel was given after cisplatin than with the alternate sequence (i.e. paclitaxel before cisplatin).
Pharmacokinetic data from these patients demonstrated a decrease in paclitaxel clearance of approximately 33% when paclitaxel was administered following cisplatin.
Based on in vitro data there is the possibility of an inhibition of ANZATAX
TM metabolism in patients treated with ketoconazole. As a result, caution should be exercised when treating patients with ANZATAXTM when they are receiving ketoconazole as concomitant therapy.
Contact of the undiluted concentrate with plasticised polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticiser DEHP [di-(2-ethylhexyl) phthalate], which may leach from PVC infusion bags or sets, diluted ANZATAX
TM solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. ANZATAXTM should be administered through an in-line filter with a microporous membrane not greater that 0,22 microns. Use of filter devices such as IVEX-2 filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
No antidote is known in case of overdosage with ANZATAX
TM. The complications primarily to be expected due to overdosage are bone marrow suppressions, peripheral neurotoxicity and mucositis. See “SIDE-EFFECTS AND SPECIAL PRECAUTIONS”. Treatment is symptomatic and supportive.

IDENTIFICATION
A clear to pale yellow solution, free from visible particulates.

PRESENTATION
5 mL, 16.7 mL, 25 mL and 50 mL clear glass vials with rubber closures and aluminium seals with plastic ‘flip-off’tops packed into carton boxes.

STORAGE INSTRUCTIONS
Store below 25ºC protected from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
ANZATAX
TM: 36/26/0255

NAME AND BUSINESS ADDRESS OF APPLICANT
Pharmaplan (Pty) Ltd
106 16th Road
Midrand

DATE OF PUBLICATION OF THIS PACKAGE INSERT
2 April 2004

New addition to this site: March 2010
Source: Pharmaceutical Industry
Launched: July 2009

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