INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
TAXOL 30
TAXOL 100
TAXOL 300

SCHEDULING STATUS
S4

PROPRIETARY NAME
(and dosage form)

TAXOL 30
TAXOL 100
TAXOL 300
(Concentrate for Infusion)

WARNING

TAXOL (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 TAXOL. Patients receiving TAXOL should be pre-treated with corticosteroids, promethazine, and H2 antagonists to prevent these reactions. (See "DOSAGE AND ADMINISTRATION" section). Patients who experience severe hypersensitivity reactions to TAXOL should not be rechallenged with the drug. TAXOL therapy should not be given to patients with baseline neutrophil counts of less than 1,500 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 TAXOL. The polyoxyethylated castor oil in Taxol 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 TAXOL should be carried out by using non-plasticized PVC-containing equipment.

COMPOSITION
Each 5 mL TAXOL vial contains 30 mg paclitaxel and 49,7% v/v of dehydrated alcohol.
Each vial of TAXOL 100 contains 100 mg paclitaxel and 49,7% v/v of dehydrated alcohol.
Each 50 mL vial of TAXOL 300 contains 300 mg paclitaxel and 49,7% v/v of dehydrated alcohol.

PHARMACOLOGICAL CLASSIFICATION
A 26 Cytostatic Agents

PHARMACOLOGICAL ACTION
Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganisation of the microtubule network that is essential for vital interphase and mitotic cellular functions. In addition, paclitaxel induces abnormal arrays or bundles of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
Following intravenous administration, paclitaxel exhibits a biphasic decline in plasma concentrations. The initial rapid decline represents distribution to the peripheral compartment and elimination; the later phase is due, in part, to a relatively slow efflux of paclitaxel from the peripheral compartment. In patients treated with doses of 135 and 175 mg/m² given as 3 and 24 hour infusions, mean terminal half-life has ranged from 3,0 to 52,7 hours. Mean values for total body clearance ranged from 11.6 to 24 L/h/m². Mean steady state volume of distribution has ranged from 198 to 688 L/m², indicating extensive extravascular distribution and/or tissue binding.
The pharmacokinetics of paclitaxel are non-linear. There is a disproportionately large increase in Cmax and AUC with increasing dose, accompanied by an apparent dose-related decrease in total body clearance. These findings are most readily observed in patients in whom, high plasma concentrations of paclitaxel are achieved. Saturable processes in distribution and elimination/metabolism may account for these findings.
There was no evidence of accumulation of paclitaxel with multiple treatment course.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0,1 to 50 micrograms/mL, indicate that, on average, 89% of drug is bound. The presence of cimetidine, ranitidine, dexamethasone or diphenhydramine did not affect protein binding of paclitaxel.
The disposition of paclitaxel has not been fully elucidated in humans. After intravenous administration of TAXOL, mean values of cumulative urinary recovery of unchanged drug ranged from 1.3 to 12.6% of the dose, indicating extensive non-renal clearance.
Hepatic metabolism and biliary clearance may be the principal mechanism for disposition of paclitaxel. Paclitaxel is metabolized primarily by cytochrome P450 enzymes. Hydroxylated metabolites have been demonstrated to be the principal metabolites. The formation of 6 alpha-hydroxypaclitaxel ,3’-p-hydroxypaclitaxel and 6 alpha,3’-p-dihydroxypaclitaxel is catalysed by CYP2C8, 3A4 and both 2C8 and 3A4 respectively. The effect of the renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated. The clearance of paclitaxel was not affected by cimetidine pre-treatment. Ketoconazole may inhibit the metabolism of paclitaxel. Plasma levels of doxorubicin and doxorubicinol may be increased when paclitaxel and doxorubicin are used in combination.

INDICATIONS
TAXOL is indicated for:

1.	The palliative treatment of stage 3 or 4 advanced local carcinoma of the ovary after surgical resection, in combination with cisplatin.
2.	The palliative management of metastatic carcinoma of the ovary after failure of first line or subsequent chemotherapy.
3.	The treatment of metastatic carcinoma of the breast after failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contra-indicated.
4.	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
TAXOL is contra-indicated in patients who have a history of severe hypersensitivity reactions to TAXOL or other drugs formulated with polyoxyethylated castor oil.
TAXOL should not be used in patients with baseline neutrophils <1 500/mm³.

PREGNANCY AND LACTATION
TAXOL has been shown to be embryotoxic, foetotoxic and to decrease fertility in animal studies.
There is no information on the use of TAXOL in pregnant women. TAXOL may cause foetal harm when administered to pregnant women. TAXOL should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with TAXOL, and to inform the treating physician immediately should this occur.
It is not known whether TAXOL is excreted in human milk. Breast feeding should be discontinued for the duration of TAXOL therapy.

WARNINGS
TAXOL should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Since severe hypersensitivity reactions may occur, appropriate supportive equipment should be available.
TAXOL should be administered as a diluted infusion.
TAXOL should be given before cisplatin when used in combination.
Patients should be pre-treated with corticosteroids, antihistamines and H2 antagonists before receiving TAXOL. Severe hypersensitivity reactions characterised by dyspnoea, flushing, chest pain and tachycardia and hypotension requiring treatment, angioedema and generalised urticaria have occurred in patients receiving TAXOL. These reactions are probably histamine-mediated. In cases of severe hypersensitivity reactions, TAXOL infusion should be immediately discontinued, symptomatic therapy should be initiated and the patient should not be rechallenged with the agent.
Minor hypersensitivity reactions such as flushing, rash, do not require interruption of therapy.
Bone marrow suppression (primary neutropenia) is the principal dose-limiting toxicity. Frequent monitoring of blood counts should be instituted during TAXOL treatment. Patients should not be retreated until neutrophils recover to a level >1 500/mm³ and platelets recover to a level > 100 000/mm³.
Severe cardiac conduction abnormalities have been reported. If patients develop significant conduction abnormalities during TAXOL administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with TAXOL. Severe cardiovascular events were observed more frequently in patients with non-small cell lung carcinoma than breast or ovarian carcinoma.

DOSAGE AND DIRECTIONS FOR USE
Dosage
Indication 1:
Primary treatment of ovarian carcinoma: a combination regimen consisting of TAXOL 135 mg/m² administered over 24 hours, followed by cisplatin 75 mg/m², every 3 weeks. TAXOL should be administered before cisplatin.
Indication 2 and 3:
Secondary treatment of ovarian carcinoma: TAXOL 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 the failure of first line or subsequent chemotherapy.
Indication 4
Palliative treatment of advanced non-small cell lung carcinoma: the recommended dose of Taxol is 175 mg/m²administered over a period of 3 hours; followed by a platinum compound , with a 3 week interval between courses.
TAXOL should not be readministered 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 increases with dose.
All patients must be premedicated with corticosteroids, antihistamines, and H2 antagonists prior to TAXOL administration, e.g. dexamethasone 20 mg orally approximately 12 and 6 hours before TAXOL, promethazine 25 mg IV 30 to 60 minutes prior to TAXOL, and cimetidine 300 mg or ranitidine 50 mg, IV 30 to 60 minutes before TAXOL.
TAXOL should be administered through an in-line filter with a microporous membrane not greater that 0,22 microm.
Directions for Use/Handling
Handling: Caution should be exercised when handling TAXOL. Dilution should be carried out by trained personnel in a designated area. Adequate protective gloves should be worn. Precautions should be taken to avoid contact with the skin, and mucous membranes. Following topical exposure, tingling, burning and redness have been observed. In the event of contact with the skin, the area should be washed with soap and water. In the event of contact with the mucous membranes, these should be flushed thoroughly with water. Upon inhalation, dyspnoea, chest pain, burning eyes, sore throat and nausea have been reported.
Preparation for IV Administration: TAXOL must be diluted prior to infusion. TAXOL should be diluted in 0,9% Sodium Chloride Injection, or 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 for up to 27 hours at ambient temperature (approximately 25°C) and room lighting conditions.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. TAXOL should be administered through an in-line filter with a microporous membrane not greater than 0,22 microm. No significant losses in potency have been noted following delivery of the solution through IV tubing containing an in-line filter.
In order to minimise patient exposure to the plasticiser DEHP [di-(2-ethylexyl)phthalate], which may be leached from plasticised PVC infusion bags or sets, diluted TAXOL solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. Use of filter devices which incorporate short inlet and/or outlet plasticised PVC tubing has not resulted in significant leaching of DEHP.
Disposal: All items used for reconstitution, administration or otherwise coming into contact with TAXOL should undergo disposal according to local guidelines for the handling of cytotoxic compounds.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
Side-Effects
The frequency and severity of adverse events are generally similar between patients receiving Taxol for the treatment of ovarian, breast or lung carcinoma. None of the observed toxicities were clearly influenced by age.
Safety of the TAXOL/platinum combination has been evaluated in a randomised trial in ovarian carcinoma and 2 phase lll trials in non-small cell lung carcinoma. Unless otherwise mentioned the combination of Taxol with platinum agents did not result in clinically relevant changes to the safety profile of single agent Taxol.
Bone marrow suppression and peripheral neuropathy are the principal dose-related adverse effects associated with TAXOL. Myelosuppression is less frequent and less severe with a 3-hour infusion than with a 24 hour infusion schedule. The recommended TAXOL/cisplatin regimen for the primary treatment of ovarian cancer caused more severe myelosuppression than single dose TAXOL using the recommended schedule of 175 mg/m²over 3 hour infusion. There was no increase in clinical sequelae, however.
Haematologic:
Compared to 24-hour infusion schedules, neutropenia is less common when TAXOL is given as a 3-hour infusion. Neutropenia is generally rapidly reversible. Severe neutropenia occurs in some patients. Neutropenia is not 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 have resulted in fatality.
Thrombocytopenia occurs in a few patients. Severe thrombocytopenia is observed only during the first two courses. Although 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.
TAXOL 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 TAXOL. Patients should not be retreated with subsequent cycles of TAXOL 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/mm³ for seven days or more) during a course of TAXOL 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 TAXOL infusion despite premedication. Severe symptoms occur within the first hour of TAXOL infusion. Dyspnoea, flushing, chest pains and tachycardia are the most frequent manifestations.
TAXOL dosage or schedule has no effect on the frequency of hypersensitivity reactions.
Besides the few patients with severe hypersensitivity reactions, other patients experience minor manifestations compatible with hypersensitivity reactions. The most frequent minor manifestations are flushing, rash and hypotension.
Patients with a history of severe hypersensitivity reactions to products containing Cremophor EL (e.g. cyclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with TAXOL. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with TAXOL should be premedicated 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 TAXOL and appropriate emergency therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with TAXOL.
Cardiovascular:
Hypotension and bradycardia have been observed during administration of TAXOL, but generally do not require treatment. Frequent vital sign monitoring, particularly during the first hour of TAXOL infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. (see "WARNINGS" section) Cases of myocardial infarction have been reported. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines.
Patients may experience severe cardiovascular events possibly related to TAXOL administration. Included are hypertension, venous thrombosis, ventricular tachycardia, and atrioventricular conduction block.
ECG alterations are experienced by some patients.
The most frequently reported ECG modifications are non-specific repolarization abnormalities, sinus tachycardia and premature beats. The relationship between TAXOL administration and ECG alterations is not clear.
Neurological:
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 Taxol. Sensory symptoms have usually improved or resolved within several months of TAXOL discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contra-indication for TAXOL therapy.
TAXOL contains dehydrated alcohol, 396 mg/ mL. Consideration should be given to possible CNS and other effects of alcohol.
Although the occurrence of peripheral neuropathy is frequent, the development of moderate to severe symptomatology is unusual and requires a dose reduction of 20% for all subsequent courses of TAXOL.
In non-small cell lung carcinoma patients, the administration of Taxol in combination with cisplatin resulted in a greater incidence of neurotoxicity than usually seen in patients receiving single agent Taxol.
Besides peripheral neuropathy, other rare 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. Optic nerve and/or visual disturbances (scintillating scotomata) have also been reported, particularly in patients who have received higher doses than recommended. These effects generally have been reversible. Ototoxicity has been reported.
Arthralgia/Myalgia:
Arthralgia/myalgia usually consisting of pain in the large joints of the arms and legs occurs but is usually mild. The symptoms are usually transient occurring two or three days after TAXOL administration and resolving within a few days.
Hepatic:
There is no evidence that the toxicity of TAXOL is enhanced when given as a 3-hour infusion in patients with elevated liver enzymes, but no data are available for patients with severe baseline cholestasis.
When TAXOL 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.
Analysis restricted to patients with normal baseline liver function, shows instances of elevated bilirubin elevated alkaline phosphate, and elevated AST (SGOT). 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. Rare reports of skin abnormalities related to radiation recall have been received. Gastrointestinal side effects such as nausea/vomiting, diarrhoea and mucositis have been reported. These manifestations are usually mild to moderate at the recommended dose.
Fibrotic phlebitis has been reported.
Neutropenic enterocolitis has been reported. Radiation pneumonitis has also been reported in patients receiving concurrent radiotherapy.        
Extravasation during intravenous administration may lead to oedema, pain, erythema and induration and ulceration. Extravasation can result in cellulitis. Skin discolouration may also occur. Recurrence of skin reactions at a site of previous extravasation following administration of TAXOL at a different site i.e. "recall reaction" has been reported. A specific treatment for extravasation reactions is unknown at this time.
Bowel obstructions/perforations and ischemic colitis have been reported in patients treated with paclitaxel.
Interaction with other medicaments and other forms of interaction:
The recommended regimen of TAXOL administration for the primary treatment of ovarian carcinoma is for TAXOL to be given before cisplatin. When TAXOL is given before cisplatin, the safety profile of TAXOL is consistent with that reported for single agent use. When TAXOL was given after cisplatin, patients showed a more profound myelosuppression and an approximately 20% decrease in paclitaxel clearance.       
Medications concomitantly administered with TAXOL (e.g., corticosteroids, antihistamines, and H₂ antagonists) did not appear to interact adversely; however, possible interactions of TAXOL with concomitantly administered medications have not been formally investigated.
Based on in vitro data, there is the possibility of an inhibition of TAXOL metabolism in patients treated with ketoconazole. As a result, caution should be exercised when treating patients with TAXOL when they are receiving ketoconazole as concomitant therapy.
Plasma levels of doxorubicin and doxorubicinol may be increased when paclitaxel and doxorubicin are used in combination.
The metabolism of paclitaxel is catalysed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering TAXOL concomitantly with known substrates or inhibitors of these isoenzymes.
Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted TAXOL solutions should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
TAXOL 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.
Paediatric Use
The safety and effectiveness of TAXOL in children have not been established.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There is no antidote for TAXOL overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

IDENTIFICATION
A clear, colourless to slightly yellow viscous solution. It is supplied as a non-aqueous solution intended for dilution with a suitable parenteral fluid prior to intravenous infusion.

PRESENTATION

TAXOL:	30 mg/5 mL multi dose vial individually packaged in a carton.
TAXOL 100:	100 mg multi dose vial individually packaged in a carton.
TAXOL 300:	300 mg multi dose vial individually packaged in a carton.

STORAGE INSTRUCTIONS
Store at room temperature not exceeding 25°C.
After first use any unused concentrate may be stored at room temperature not exceeding 25°C for up to 28 days.
Solutions for infusion prepared as recommended in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets, are stable at ambient temperature (approximately 25°C) and lighting conditions for up to 27 hours.
To be kept in outer container until required. Protect from light.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER

TAXOL:	28/26/157
TAXOL 100:	31/26/107
TAXOL 300:	35/26/0196

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Bristol-Myers Squibb (Pty) Ltd *
47 Van Buuren Road
BEDFORDVIEW
2008

DATE OF PUBLICATION OF THIS PACKAGE INSERT
August 2002

*        Authorised user of the ™ TAXOL.

Updated on this site: November 2005
Source: Pharmaceutical Industry
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