Injectable

DOLECTRAN
DOCETAXEL 80 mg/ 2ml
DOCETAXEL 20 mg/ 0,5ml
INJECTABLE
CONCENTRATE FOR INTRAVENOUS INFUSION
Made In Argentina - Under Prescription Only CUALIQUANTITATIVE FORMULA

Each 0,5 ml DOLECTRAN vial of 20 mg contains:
Docetaxel.20,0
Polysorbate 80 csp.0,5 mg Each sterile diluent vial contains: Ethanol (95% v/v) .……….13% Sterile Distillate water.……….87% For a final volume of .….…….1,5 ml Each 2 ml DOLECTRAN vial of 80 mg contains: Docetaxel.80,0 Polysorbate 80 csp.2,0 mg Each sterile diluent vial contains: Ethanol (95% v/v) .……….13% Sterile Distillate water.……….87% For a final volume of .…….….6 ml Each 80 mg and 20 mg DOLECTRAN vial contains per ml of solution:
Docetaxel.40,0 mg
Polysorbate 80 csp.1,0 mg
THERAPEUTIC ACTION:
Docetaxel is an antineoplastic agent that acts by means of disrupting the microtubular
network in cells that is essential for mitotic and interphase cellular functions. Docetaxel
promotes the assembly of tubulin into stable microtubules while simultaneously inhibiting the critical intracellular concentration of tubulin. The stimulated polimerization of the microtubules 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 microtubules, a feature which differs from most spindle poisons. In in vitro clonogenic assays, it has been found that Docetaxel is citotoxic for several tumoural murine and human cellular lines and against human tumour cells which have been recently excised in clonogenic assays. It has also been found that Docetaxel acts on several cell lines overexpressing the p-gliprotein which codifies the resitant gen to multiple drugs. In 70-115 mg/m2 doses, the Docetaxel´s kinetic profile is independent of the dosage and responds to a three-compartment pharmacokinetic pattern with a medium shelf life for the phases a, β and γ of 4 and 36 minutes and 11,1 hours, respectively. The average values for the total body clearance and distribution volume in the balance state have been respectively of 21 L/h/m2 and 113 L, respectively. A pharmacokinetic analysis has been carried out in a group of patients who were under Docetaxel administration. The estimated pharmacokinetic parameters by the pattern were very close to those estimated from the Phase 1 studies. Pharmacokinetic alterations for Docetaxel have not been seen, depending on the patient´s age or sex. A reduction of 27% of clearance (as an average) has been seen in a reduced amount of patients with clinical chemical data, which suggested an insufficiency in the hepatic function between mild to slight (ALT, AST ≥ 1, 5 times the superior normal limit related to alkaline phosphatase ≥ 2, 5 times the superior normal limit). (see Section: “Dosage Based on in vitro studies, it seems that the isoenzimes corresponding to the sub-family of P450-3A cytochrome are involved in Docetaxel´s metabolism. Docetaxel binds to the proteins in a proportion that goes beyond 95%. Dexamethasone
does not affect the Docetaxel´s protein binding.
INDICATIONS
Breast cancer: DOLECTRAN (Docetaxel) has been indicated for the treatment of
patients with locally advanced or metastatic breast carcinoma, for those who the previous treatment has not been successful. The previous treatment should have included anthracyclines, unless this has been clinically contraindicated.
Non-Small Cell Lung Cancer: DOLECTRAN (Docetaxel) has been indicated for the
treatment of patients with locally advanced or metastatic non-small cell lung cancer, for those who the chemotherapy based on platinum has not been successful. The previous treatment should have included anthracyclines, unless this has been clinically contraindicated.

DOSAGE AND ADMINISTRATION
The recommended DOLECTRAN dosage is 100mg/m2 administered as an one-hour-
infusion each three weeks. In order to reduce the incidence and severity of fluid retention, all the patients should be pre-treated with oral corticosteroids. The recommended pre-medication should only consist of oral corticosteriods, such as Dexamethasone 16mg each day, during 5 days before each DOLECTRAN administration. The anti-histaminic´s utility in the control of fluid retention has not been verified.
Dosage adjustement: Patients with neutropenia, cutaneous reactions or peripheral
neuropathy: As it happens with many other chemotherapeutic, an essential part of the
DOLECTRAN´s therapy is a careful screening of the neutrophil counts. DOLECTRAN should not be administered until the neutrophil counts is at least 1500 cells/ mm3. Patients who experience either febrile neutropenia, severe neutropenia (neutrophils <500 for more than one week), severe or cumulative cutaneous reaction or severe peripheral neuropathy during the treatment with Doxetacel should have their DOLECTRAN dosage adjusted from 100 mg/m2 to 75 mg/m2. If the patient continues to experience these reactions, the dosage should be decreased from 75 mg/m2 to 55 mg/ m2.
Patients with mild Hepatic Impairment: Based on pharmacokinetic information,
the recommended Doxetacel dosage for patients who have increased transaminase values (ALT and/ or AST) in greater amount than 1,5 times the superior limit of the normal range and increases in the alkaline phosphatase greater than 2,5 times the superior limit of the normal range is 75 mg/ m2. ADMINISTRATION PRECAUTIONS
DOLECTRAN should be administered intravenously. It´s extremely important that the intravenous needle or catheter are properly placed before Docetaxel is injected. Dispersion to the surrounding tissue during intravenously DOLECTRAN administration may lead to a significant irritation, local tissue necrosis and/ or thrombophlebitis. If extravasation occurs, the injection should be discontinued immediately and any portion remaining should be inserted in another vein. CONTRAINDICATIONS
DOLECTRAN is contraindicated in patients who have a history of severe
hypersensitivity reactions to DOLECTRAN or to other drugs formulated with polysorbate 80. DOLECTRAN should not be used in patients with neutrophil counts 1500 cells/ mm3.
DOLECTRAN is contraindicated in patients with severe hepatic impairment.
WARNINGS
DOLECTRAN (Docetaxel) for Injection Concentrate should be administered under the
supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are available. DOLECTRAN treatment should not be used in patients with neuthrophil counts less than 1500 cells/ mm3. In order to monitor the appearance of neutropenia, which could be severe and lead to infection, it is recommended that all patients receiving DOLECTRAN proceed to frequent blood counts. In 0,5% of the patients (4 of 837) severe hypersensitivity reactions were observed which lead to an immediate discontinuation. DOLECTRAN should not be administered in patients who have a history of severe hypersensitivity reactions to Docetaxel or to other drugs formulated with Polysorbate 80. The adverse reaction most commonly reported is neutropenia. Neutrophil nadirs occur within an average of 8 days.during the treatment with DOLECTRAN, frequent monitorings of blood counts should be carried out. These patients should not be administered once again with DOLECTRAN unitl the neutrophil count is back to >1500 cells/ mm3 (see DOSAGE AND ADMINISTRATION). Severe hypersensitivity reactions characterized by hypotension and/ or bronchospasm, or generalized rash/ erythema have been observed. These reactions lead to an immediate discontinuation of the treatment in 0,5% of the patients (4 of 837). Severe symtomps are resolved after the discontinuation of the infusion and the administration of an appropriate treatment. Patients who have a history of severe hypersensitivity reactions should not be given extra doses of DOLECTRAN. DOLECTRAN can cause fetal harm when administered to pregnant women. There have not been studies carried out in pregnant women. There have not been evidences regarding the teratogenic effect when Docetaxel was administered 1,8 or 1,2 mg/ m2/ day in rats or rabbits, respectively. However, these studies have shown that Docetaxel is also embryo-fetotoxic, characterized by intrauterine mortality, reduced fetal weight and ossification delay. These effects are coherent, taking into account the maternal toxicity. If Docetaxel is used during pregnancy or if the patient becomes pregnant while receiving this drug, the patient should be apprised and the potential risk to the fetus should be assessed.
PRECAUTIONS:
Hematology: DOLECTRAN treatment should not be re-administered until neutrophils
recover to a level >1500 cells/ mm3. In order to monitor the occurrence of
myelotoxicity, it is recommended that frequent blood cell counts in all patients receiving DOLECTRAN (see “Dosage and Administration” section). Patients should not be retreated with subsequent DOLECTRAN cycles until neutrophils recover to a level >1500 cells/ mm3. A reduction in the dose is recommended for subsequent treatments cycles in cases where severe neutropenia (>500 cells/ mm3) lasting 7 days or more during the DOLECTRAN treatment is present (See “Dosage and Administration” section).
Hypersensitivity reactions: Hypersensitivity reactions may occur within a few
minutes following initiation of a DOLECTRAN infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of the therapy is not required. However, more severe reactions, such as an hypotension which needs treatment, or bronchospasm or generalized erythema, require the immediate discontinuation of DOLECTRAN. Patients who have developed severe hypersensitivity reactions should not
be retreated with DOLECTRAN.
Cutaneous: Localized erythema of the extremities (hands and feet´s sole) with
edema followed by desquamation has been observed. In case of severe skin toxicity during the period of the DOLECTRAN treatment, a reduction in the dosage is recommended for post cycles corresponding to subsequent treatments (see “Dosage and Administration” section). Fluid retention: Fluid retention has been reported following Docetaxel treatment. Therefore, patients should be premedicated with oral corticosteroids, prior to each DOLECTRAN administration in order to reduce the incidence and severity of fluid
retention (see “Dosage and Administration” section).
Neurologic: Severe peripheral neurotoxicity´s development is rare and when it
occurs, the doses should be reduced. (see “Dosage and Administration” section).
Carcinogenicity, mutagenicity- Impairment of Fertility: No studies have been
conducted to assess the Docetaxel carcinogenic potential. Docetaxel has been shown to be mutagenic in the in vitro chromosome aberration test in CHO-K1 cells and in the in vivo micronucleous test in mice. However, it did not induce mutagenicity in the Ames test or the CHO/HGPRT gene mutation assays. These results are coherent with Docetaxel´s farmacological activity.
Nursing mothers: It has not been determined whether Docetaxel is excreted in the
maternal milk. Due to the fact that many drugs are excreted in human milk and
because of the potential for serious adverse reactions in nursing infants, it´s recommended to advise women who are nursing their babies to not to breastfeed during the DOLECTRAN treatment.
Pediatric Use: Docetaxel´s safety and effectiveness have not been established in
children.
Geriatric Use: Based on the population´s pharmacokinetis, there are no special
instructions for its use in the elderly age.
Drug´s interactions: There have been not carried out formal clinical studies in order
to assess Docetaxel´s interaction with other drugs. In vitro studies have shown that
Ketoconazol inhibits Docetaxel´s metabolism significantly, therefore, care should be taken when DOLECTRAN and Ketoconazol are administered concomitantly.
ADVERSE REACTIONS
837 patients took part in 24 studies corresponding to Phase II which were carried out in North America and Europe (breast carcinoma n= 228; non-small cell lung cancer n= 248, various tumor types n= 361). 95% of these patients did not receive hematopoietic support. The following chart includes information about adverse reactions in 833 assessed patients. These reactions were considered to be possible or probably related to Docetaxel. The profile´s security is generally similar in all patients, whether they have been treated because of breast carcinoma or non-small cell lung cancer.
Summary of Adverse Events in 833 Patients (1) Receiving Docetaxel at 100
Hematologic
Infections
Hypersensitivity Reactions (n= 837)
Fluid Retention
Neurosensory
Neuromotor
Cutaneous
Gastrointestinal
Alopecia
Asthenia
Mucositis
Infusion Site Reactions
(1) The four (4) patients who experienced hypersensitivity reactions, together with immediate discontinuation of the treatment, were not included in the general security assessment. (2) Patients did not receive hematopoietic support. Hematologic: Neutropenia is the most frequent adverse reaction related to Docetaxel
with characteristics such as reversible and non-cumulative.
The median time to nadir was eight days, while the median duration of severe neutropenia (<500 cells/ mm3) was seven days. Severe neutropenia occurred in 75% of the patients treated with Docetaxel and lasted for more than 7 days in 3% of the calculable cycles. Feber related to neutropenia (<1000 cells/ mm3) occurred in 22% of the patients (7% of the cycles). Infections incidence, related to neutrophil counts (<1000 cells/ mm3) was 6% in patients and 3% of the cycles. Infectious episodes took place, including sepsis and pneumonia in 19% of the patients (5% of the cycles) and in approximately 2% of the patients treated with Docetaxel were fatal. Thrombocytopenia (<1000 cells/ mm3) has been reported in 8% of the patients. There were hemorrhage episodes in 2% of the patients and this has been related to severe thrombocytopenia (<50000 cells/ mm3) in just two patients. A fatal gastrointestinal hemorrhage has also been reported to be caused by thrombocytopenia in a patient. Anemia (11 g/dl) has been reported in 89% of the patients and has been severe (<8 g/dl) in 10% of the cases. Hypersensitivity reactions: Hypersensitivity reactions occurred in 31% of the
patients (14% of the cycles). 19% of the patients experienced minor events,
compatible with hypersensitivity reactions. The most frequent minor events included: flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever or chills. Severe hypersensitivity reactions, characterized byhypotension, bronchospasm or generalized rash/ erythema a few minutes after the beginning of Docetaxel infusion. Severe symptoms have been reported in 7% of the patients. However, only in 0,5% (4 of 837) there was immediate discontinuation of the treatment. All hypersensitivity reactions were solved after the discontinuation of the infusion and together with an appropriate treatment.
Fluid Retention: 47% of the patients reported fluid retention, including edema, and
less frequent the following events have been reported: pleural effusion, ascites, pericardial effusion and weight gain. Fluid retention usually begins in the lower extremities and could become generalized with weight gain of around 3 kg or more. This reaction appears generally after 4 cycles of treatment or with a cumulative dosages of ≥ 400 mg/m2. 9% of patients discontinued the treatment due to fluid retention, after having received more than 13 cycles and a cumulative average dosage of 1300 mg/m2. Fluid retention´s incidence in the general population was 47%, 9% of this percentage was severe. In patients who have been pre-medicated up to 4 to 5 days with oral corticosteroids, fluid retention´s incidence was of 33% and among this percentage, 2% was severe. There follows a chart which describes the effect on the fluid retention with pre-medication with corticosteroids (see “Dosage and Administration” section).
Pre-medication´s effect with corticosteroids on the fluid retention´s
incidence


Acute dehydration, oliguria or hypotension events did not occurr while on the fluid´s
retention and this situation could be slowly reverted after interrupting the Docetaxel
treatment.
Cutaneous: Cutaneous reaction have been reported by 64% the patients treated with
Docetaxel. These reactions are characterized by rash including localized eruptions mainly on the feet and/ or hands but also in the arms, face and thorax, usually related to pruritus. Eruptions generally occurred within a week after the Docetaxel´s infusion and were recovered before the next infusion and were not disabling. Less frequently (2%), there were also severe symptoms such as: rash, followed by desquamation. Rarely there occurred an interruption or discontinuation of the treatment with Docetaxel. As a reaction, 26% of the patients experienced discomfort in nails. These reactions were characterized by hypo or hyperpigmentation and ocassionally, by onycholysis and pain (2%). Neurologic: 48% of all patients reported to have experienced neurosensitive
symptoms characterized by paresthesia, dystenia or pain (including burning
sensation). Less than 4% of the patients reported severe reactions. 14% of patients reported reported neuro-motor events and these reactions were severe in 4% of the patients.
Gastrointestinal: Gastrointestinal reactions such as nausea (45%), diarrhea (43%)
and vomiting (28%) were observed in patients under Docetaxel treatment. Generally,
these reactions were mild to moderate. Gastrointestinal severe reactions occurred only in less than 5% of the patients. Cardiovascular: 5% of the patients reported to have experienced hypotension and
0,5% of these patients needed treatment. Less than 2% of patients evidenced clinically
meaningful events, among them: heart failure (2 patients), auricular paroxysmal tachycardia, auricular flutter, dysrhytmia and hypertension. Infusion Site Reactions: In 6% of the patients under Docetaxel administration, the
following infusion site reactions were generally mild and consisted of:
hyperpigmentation, inflammation, local erythema, dryness of the skin and swelling of
the vein. Less frequently there occured: phlebitis or extravasation.
Hepatic: 10% of the patients reported increased values in Alanine Transferase,
Aspartate Transferase, alkaline phosphatase which exceeded 2,5 the normal superior limit. Other: Alopecia was reported by 83% of the patients, although it was severe in few
occasions.
Asthenia was also reported by 68% of the patients and this event was considered to be severe in 11% of the patients. 43% of the patients reported mucositis. Arthralgias (10%) and myalgias (22%) were also reported, but they were generally
considered to be mild and moderate.
SYMPTOMS AND OVERDOSAGE TREATMENT
In case of an overdose, go to the nearest hospital or medical centre or contact the toxicology centres. Reference in Argentina: Hospital de Pediatría Ricardo Gutierrez: (011) 4962-6666 / 2247 Hospital A. Posadas: (011) 4654-6648 / 4658-7777 There is no known antidote for Docetaxel overdosage. In case of an overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored and, in case it is necessary, the patient can be administered a support treatment. Anticipated overdosage´s complications include: bone marrow supression, peripheral neurotoxicity and mucositis. In two reports of overdose, one patient received a 150 mg/m2 and the other one received 200 mg/m2 as one-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions and mild paresthesia and recovered without incident.
CONSERVATION:
Stability: If refrigerated between 2°C and 8°C and kept away from bright light, the
unopened DOLECTRAN vials will stay stable until the expiration date indicated in the
container. Freezing does not adversely affect the product.
Storage: Store the unopened vials in the refrigerator at a temperature between 2°C
and 8°C. Retain in the original package in order to protect from bright light. Fully prepared DOLECTRAN pre-mixture solution (10mg Docetaxel/ml) and DOLECTRAN infusion solution (whether as in 0,9% Sodium Chloride solution or as in 5% Dextrose Solution) should be rapidly used after the preparation. However, they will stay stable for 8 hours in the refrigerator between 2°C and 8°C. PREPARATION AND ADMINISTRATION PRECAUTIONS
DOLECTRAN for Injection Concentrate requires to be diluted prior administration.
Please, follow the preparation instructions provided below.
A. Preparation of the Initial Diluted Solution.
1. Remove the appropriate amount of vials of DOLECTRAN for Injection Concentrate from the refrigerator. Allow the vials to stand at room temperature for approximately 5 minutes. 2. Aseptically withdraw the contents of the diluent vial into a syringe and transfer the content to the DOLECTRAN vial for Injection Concentrate. 3. Gently shake each vial initial diluted Solution for approximately 15 seconds in order to assure full mixture of the concentrate and diluent. 4. The initial diluted DOLECTRAN solution (10mg of Docetaxel/ml) should be clear. Allow the solution to stand for a few minutes to allow any foam to dissipate. It is not
required that all foam dissipates prior to continuing the preparation process.
B. Preparation of the Infusion Solution
1. Aseptically withdraw the required amount of the DOLECTRAN initial diluted with a calibrated syringe and inject the solution´s required amount into a 250ml infusion bag or bottle of either 0,9 Sodium Chloride, or 5% Dextrose solution in order to produce a final concentration of 0,3 to 0,9 mg/ml. 2. Thoroughly mix the infusion by manual rotation. 3. As with all parenteral products, DOLECTRAN should be inspected visually in order to verify the presence of material particles or change of colloration prior to administration whenever the solution and container allow. If DOLECTRAN initial diluted solution for Injection or the Solution is not clear or appears to have precipitation, these should be discarded. Infusion DOLECTRAN Infusion Solution should be administered intravenously under room temperature and lightning conditions. DOLECTRAN Infusion is compatible with the administration groups that are usually available, even the PVC groups.
Special instructions:
Docetaxel is a cytotoxic anticancer drug and, as with other potentially toxic compounds, caution should be exercised when handling and preparing Docetaxel´s solutions. The use of gloves is recommended. Please refer to Handling and Disposal section.
In case DOLECTRAN concentrate, initial diluted solution or infusion solution come into
contact with the skin, immediately and thoroughly wash with soap and water. In case DOLECTRAN concentrate, initial diluted solution or infusion solution come into contact with the mucosa, immediately and thoroughly wash with soap and water.
Handling and Disposal: Procedures for proper handling and disposalof anticancer
drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
HOW SUPPLIED:
DOLECTRAN (Doectaxel) Injection Concentrate is supplied in a single-dose vial as a sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, diluent (13% ethanol (95% v/v) in Water for Injection) vial. This drug is available in the following concentrations: 80 mg DOLECTRAN in 2 ml single-dose vial and 6ml single-dose vial of diluent. Both items come in a blister pack in one carton. 20 mg DOLECTRAN in 0,5 ml single-dose vial and 1,5 ml single-dose vial of diluent. Both items come in a blister pack in one carton. “ This drug should be administered exclusively under medical prescription and
cannot be repeated without a new prescription”.
“ This drug has only been prescribed for your current medical condition; do
not recommend it to other people”.
ANY DOUBT ARISING, CONSULT YOUR DOCTOR
PHARMACEUTICAL PRODUCT AUTHORIZED BY THE DEPARTMENT OF HEALTH. LABORATORIO KAMPEL MARTIAN
Av. Córdoba 4694 - Buenos Aires.
Technical Director: Raúl González - Pharmacist. Filled at: Palpa 2870- Buenos Aires

Source: http://www.kampelmartian.com.ar/lkm/prospectos/dolectran_engl.pdf?PHPSESSID=9c3ed356e0d1f5095e5299b070a47a57