Docetaxel – Non Aqueous Injection 20 mg/0.5 ml, 80 mg/2 ml,120 mg/3 ml.

Composition

Each ml. contains:

Docetaxel Trihydrate         I.P.

equivalent to anhydrous Docetaxel 40 mg.

Polysorbate 80                   I.P.           qs

CLINICAL PHARMACOLOGY

Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting their disassembly. This leads to the production of microtubule bundles without normal function and to the stabilization of microtubules, which results in the inhibition of mitosis in cells. Docetaxel’s binding to microtubules does not alter the number of protofilaments in the bound microtubbules, a feture, which differs from most spindle poisons currently in clinical use.

The Pharmacokinetics ofdocetaxel has been evaluated in cancer patients after administration of 20-115 mg/m2 in phase 1 studies. The area under the curve (AUC) was dose proportional following doses of 70-115 mg/m2 with infusion times of one to two hours. Docetaxel’s pharmacokinetic profile is consistent with a three compartment pharmacokinetic model, with half-lives for the a, b and g phase of 4 min, 36 min, and 11.1 hr, respectively. This initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to relatively slow efflux of docetaxel from the peripheral compartment Mean values for total body clearance and steady state volume of distribution were 21 L/H/m2 and 113 L, respectively. Mean total body clearance for japanese patients dosed at the range of 10-90 mg/m2 was similar to that of European /American populations dosed at 100 mg/m2, suggesting no significant difference in the elimination of docetaxel in the two populations.

A study of “C-docetaxel was conducted in three cancer patients. Docetaxel was eliminated in both the urine and faeces following oxidative metabolism of the tert-butyl ester group, but fecal excretion was the main elimination route within seven days, urinary and fecal excretion accounted for approximately 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 hours as one major and 3 minor metabolites with very small amount (less than 8%) of unchanged drug. Based on in Vitro studies, isoenzymes of the cytochrome P4503A (CYP3A) subfamily appear to be involved in docetaxel metabolism.

A population pharmacokinetic analysis was carried out after docetaxel treatment of 535 patients dosed at 100 mg/m2. Pharmacokinetic prameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of docetaxel were not influenced by age or gender and docetaxel total body clearance was not modified by pretreatment with dexamethasone. In patients with clinical chemistry date suggestive of mild to moderate liver function impairment (SGOT and / or SGPT) 1.5 times the upper limit of normal (ULN) concomitant with alkaline phosphate >2.5 times (ULN), total body clearance was lowered by an average of 27% resulting in a 38% increase in systemic exposure (AUC)

This average, however, includes a substantial range and there is, at present, no measurement that would allow recommendation for dose adjustment in such patients Patients with combined abnormalities of transaminase and alkaline phosphates should, in general not be treated with ZUVITERE

In Vitro Studies showed that docetaxel is about 94% protein bound, mainly to an aud glycoprotein, albumin, and lipo-proteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97% Dexamethasone dose not affect the protein binding of docetaxel.

For treatment of patients with locally advanced or metastatic carcinoma of the breast after progression during anthracycline-based therapy for metastatic disease or relapse during anthracycline-based adjuvant therapy, the recommended dose of ZUVITERE is 60-100 mg/m2 administered intravenously over one hour every three weeks.

duringanthracycline-based adjuvant therapy, the recommended dose of ZUVITERE is 60-100 mg/m2 administered intravenously over one hour every three weeks.

For treatment of patients with advanced or metastatic non-small cell lung cancer after the failure of prior platinum containing therapy , the recommended dose of docetaxel is 75-100 mg/m2 I.V. over one hour every 3 weeks.

Premedication Regimen : All patients should be premedicated with oral corticosteroids such as

Dexamethasone 16 mg. per day (e.g. 8 mg. BD for 5 days starting 1 day prior to ZUVITERE administration in order to reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reaction.

Dosage Adjustments During Treatment : Patients who are dosed initially at 100 mg/m2 and who experience either febrile neutropenia neutrophils < 500 cells/mm3, severe or cumulative cutaneous reactions, or severe peripheral neuropathy during therapy should have the dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions the dosage should either to decreased from 75 mg/m2 to 55 mg/m2 or the treatment should be discontinued, Conversely, patients who are dosed initially at 60 mg/m2 and do not experience febrile neutropenia,neutrophils< 500 /mm2 for more than one week, severe or cummulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy may tolerate higher doses.

Preparation and Reconstitution of Injection:

Preparation of the Premix solution: Docetaxel for Injection Concentrate require dilution prior to use. A Sterile, non-pyrogenic, single dose diluent containing 13% w/v alchol IP in water for Injection is supplied for that purpose, Remove the appropriate number of vials of docetaxel Injection Concentrate from the refrigerator. Allow the vials to stand at room temperature for approximately 5 minutes. Using a syringe fitted with a needle, aseptically withdraw the entire contents of the solvent for Docetaxel Injections concentrate vial and gently transfer it to the corresponding vial of Docetaxel Injection Concentrate (i.e. 9.9 ml +5% for ZUVITERE – 120 ; 7.33 ml, + 5% for ZUVITERE – 80, 1:83 ml. + 5% ZUVITERE – 20) This will assure a minimal extractable volume of 12 ml. (for ZUVITERE-120) or 8 ml. (for ZUVITERE – 80) or 2 ml. (for ZUVITERE -20) of the premix solution containing 10 mg. Docetaxel / ml. for example, a patient requiring a dose of 140 mg. Docetaxel would require 14 ml. premix solution.

Preparation of the infusion solution: Asceptically withdraw the required amount of ZUVITERE premix solution (10 mg. docetaxel /ml) with a calibrated syringe and inject the required volume of premix solution into a 150 ml. Infusion bag or bottle of either sodium chloride intravenous infusion IP or Dextrose Intravenous infusion IP to produce a final concentration of 0.9 mg/ml.

1) If dose greater than 240 mg. of Docetaxel is required use a large volume of the infusion vehicle so that a concentration of 0.9 mg /ml Docetaxel is not exceeded.

2) Thoroughly mix the infusion by manual rotation.

3) As with all products ZUVITERE should be inspected visually for particulate matter or discoloration prior to administration whenever the solution and container permit. If ZUVITERE for Injection premix solution or infusion solution is not clear or appears to have precipition, the solution should be discarded.

ZUVITERE : Infusion solution should be administered intravenously as a one-hour infusion under ambient room temperature and light conditions contact of the undiluted cncentrate with plasticized 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 ZUVITERE solution should be stored in bottle (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethyle-lined administration.

disease has not been established. )

ZUVITERE (docetaxel) for Injection concentrate should be administer under the supervision of a qualified physician experienced in the use of anti neoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

Toxic Deaths: Docetaxel administered at 100mg/m2 was associated with deaths considered possibly or probably related to treatment in 2.4% (34/1435) of patients with normal liver functions and in 11% (6/55) of Patient with abnormal liver function and is 11% (6/55) of Patient with abnormal liver function (SGOT and / or SGPT>1.5 times ULN together with AP > 2.5 times ULN) Among patients dosed at 60mg.m2, mortality related to treatment occured in 0.6% (3/481) of patients with normal liver function and in 3 to 74 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.

Premedication Regimen: Although the optimal premedication regimen is not defined, all patients should be premedicated with oral corticosteroids such as dexamethasone 16mg per day (e.g.), 8 mg BID) for 5 days starting 1 day prior to ZUVITERE to reduce the severity of fluid retentionand hypersensitivity reactions.

Hypersensitivity Reactions: Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions, severe hypersensitivity reactions characterized by hypotension and /or Bronchospasm, or generalized rashierythemaoccured in 0.9% of patients who received the recommended premedication Hypersensitivity reactions requiring discontinuation of the docetaxel infusion were reported in 5 out of 1260 patients who did not receive premedication. Patients with a history of severe hypersensitivity reactions should not be rechallenged with ZUVITERE

Hematologic Effects: Neutropenia (less than 2000 neutrophils /mm2 occur in nearly all patients given

100 mg/m2, and 75-80% of patients given 60-75 mg/m2 Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. ZUVITERE should not be administered to patients with neutrophils <1,500 cell mm2

Three breast cancer patients with severe liver impairment (bilirubin> 1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug -induced thrombocytopenia

Hepatic Impairment : ZUVITERE should generally not be given to patients with bilirubin>upper limit of normal (ULN), or to patients with SGOT and /or SGPT> 15X ULN concomitant with alkaline phosphatase 2.5 XULN Patient with elerations of transaminase concurrent with alkaline Phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.

Patient with isolated elevations of transaminase > 1.5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death, Billrubin SGOT or SGPT, and alkaline phosphatase, values should be obtained prior to each cycle of ZUVITERE therapy and reviewed by the treating physician.

Fluid Retention: Severe fluid retention occured in 6% of patients despite use of a 5-day dexamethasone premedication regimen. It was characterized by one or more of the following events. poorly tolerated peripheral edema, generalized edema, pleural effusion requiring urgent drainage, dyspnea at rest, cardiac tamponade, or pronounced abdominal distention (due to ascites) ,

Pregnancy: Docetaxel can cause fetal harm when administered to pregnancy women, Studies in both rats and rabbits at doses equal to or greater than 0.3 and 0.03 mg/kg/day, respectively (about 1/50 and 1/300 the daily maximum recommended human dose on a mg/m2 basis), administered during the period of organogenesis, have shown that docetaxel is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The dose indicated above also caused matemal toxicity. There are no adequate and well-controlled stuides in pregnant women using docetaxel.

If ZUVITERE is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with ZUVITERE

General: Responding patients may not experience an improvement in performance status on therapy and may experience worsening. The relationship between changes in performance status, response to therapy and treatment – related side effects has been established.

Hemotologic Effects: In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ZUVITERE patients should not be retreated with subsequent cycles of ZUVITERE, until neutrophils recover to a level> 1,500 cells.mm3 and platelets recover to a level > 100,000 cells/mm2

A 25% reduction in the dose of docetaxel is recommended during subsequent cycle following severe neutropenia (<500 cells/mm3) lasting 7 days or more, febrile neutropenia, or grade 4 infections in a docetaxel cycle.

Hypersensitivity Reactions: Hypersensitivity reactions may occur within a few minutes following initiation of an ZUVITERE infusion. If minor reaction such as flushing or localized skin reactions occur, of ZUVITERE and aggressive therapy. All patients shouldbepremedicated with an oral corticosteroid prior to the initiation of the infusion of ZUVITERE

Cutaneous: Localized erythoma of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended (See Dosage and Administration section) Fluid REtention: Severe fluid retenation has been reported following docetaxel therapy. Patients should be premedicated with oral corticosteroids prior to each administration to reduce the incidence and severity of fluid retention (see Dosage and Administration section). Patients with pre-existing effusions should be closedly monitored from the first dose for the possible exacerbation of the effusions. In patients who received the recommended premedication, moderate fluid retention was completely, but sometimes slowly reversible following discontinuation of docetaxel (median of 29 weeks). The median cumulative dose to onset of moderate or severe fluid retention was 7052 mg/m2 in patients receiving premedication. Patients developing peripheral edema may be treated with standard measure, e.g., salt restriction, oral diuretic (S)

Neurologic : Severe neurosensory symptoms (paresthesia, dysesthesia, pain) were observed among 7% of 134 patients with anthracycline-resistant breast cancer. When these occur, dosage must be adjusted. if symptoms persist, treatment should be discontinued (see Dosage Administration section). Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available has spontaneous reversal of symptoms within a median of 9 weeks from onset (range : 0 to 106 weeks) and only about 3.8% of patients required discontinuation due to neurotoxicity. Peripheral motor neuropathy mainly manifested as distal extremity weakness occured in 13.4% ( 7.1% severe) of the 127 anthracycline-resistnat breast cancer patients with normal LFTs. No neuromotor toxicity was reported in the 7 patients with elevated LFTs.

Extremity weakness occured in 13.4% (7.1% severe) of the 127 anthracycline-resistant breast cancer patients with normal LFTs. No neuromotor toxicity was reported in the 7 patients with elevated LFTs.

Asthenia: Severe asthenia has been reported in 111% of the patients but has led to treatment discontinuation in only 2.6% of the patients. Severe asthenia was reported in 23% of 134 patients with anthracycline-resistant breast cancer and 5.5% of the 786 cycles received. Symptoms of fatigue and weakness may last a few days up to several weeks and may be associated with deterioration of performance status in patients with progressive disease.

There have been no formal clinical studies to evaluate the drug interactions of docetaxel with other medications. In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds that induce, inhibit or are metabolized by cytochrome P450 3A4, such as cyclosporine, terfenadine, ketoconazole, erythromycin, and troleandomycin, Caution should be exercised with these drug when treating patients receiving as there is a potential for a significant interaction.

CARCINOGENICITY, MUTAGENICITY, IMPAIRMENT OF FERTILITY: No studies have been conducted to assess the carcinogenic potential of docetaxel. Docetaxel has been shown to be clastogenic in the vitro chromosome aberration, test in CHO-K1 cells and in the in vivo micronucleus test in the mouse, but it did not induce mutagenicity in the Ames test, or the CHO/HGPRT gene mutation assays. Docetaxel produced no impairment of fertility in rats when administered in multiple I.V. dose of up to 3mg./kg (about 1/50 the recommended human dose on a mg/m2 basis), but decreased testicular weight were reported.

This correlates with findings of a 10-cycle toxicity study (during once every 21-days for 6 months) in rats and dogs in which testicular atrophy or degeneration was observed at I.V. doses of 5 mg/kg in rats

and 0.375 mg/kg in dogs (about 1/3 and 1/15 the recommended human dose on a mg/m3 basis, respectively). An increased frequency of dosing in rats produced similar effects at lower dose levels.

Nursing Mothers: It is not known whether ZUVITERE is excreted inhuman milk, and because of the

potential for serious adverse reactions in nursing infants from ZUVITERE, mothers should discontinue nursing prior to taking the drug.

Padiatric use: The safety and effectiveness of ZUVITERE in pediatric patients have been established.

The unopened vials should be stored under refrigeration at a temperature of 2-8°C (36-46°F) and should be protected from light. Freezing dose not adversely affect the product.

Solvent for Docetaxel Injection Concentrate should be stored below 25°C. protected from light. ZUVITERE premix solution (10 mg Docetaxel/ ml. ) and fully prepared ZUVITERE infusion solution (in either sodium chloride intravenous infusion IP or Dextrose intravenous IP ) should be used as soon as possible after preparation . However, the premix solution is stable for 8 hours either at room temperature, 15° to 25° C (59°to 77°F), or stored refrigerated, 2° to 8°c (36° to 46°F)

WARNING:

To be sold by retail on the prescription of a cancer specialist/cancer Hospital and institution only.

Keep out of reach of children.

HANDLING:

ZUVITERE is a cytotoxic anticancer drug and as with other potentially toxic compounds, caution should be exercised when handling and preparing ZUVITERE solutions. The use of gloves is recommended. If ZUVITERE concentrate, premix solution, or infusion come into contact with the skin or mucosa immediately and throughly wash with soap and water.