DRUGS & SUPPLEMENTS
WARNING:TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA,
HYPERSENSITIVITY REACTIONS, AND FLUID RETENTION
The incidence of treatment-related mortality associated with Trazoteva therapy is increased in patients with abnormal liver function, in patients receiving higher doses, and in patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who receive Trazoteva as a single agent at a dose of 100 mg/m 2 .
Trazoteva Injection should notbe given to patients with bilirubin > upper limit of normal (ULN),or to patients with AST and/or ALT >1.5 × ULN concomitant withalkaline phosphatase >2.5 × ULN. Patients with elevations ofbilirubin or abnormalities of transaminase concurrent with alkalinephosphatase are at increased risk for the development of grade 4 neutropenia,febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis,severe skin toxicity, and toxic death. Patients with isolated elevationsof transaminase >1.5 × ULN also had a higher rate of febrileneutropenia grade 4 but did not have an increased incidence of toxicdeath. Bilirubin, AST or ALT, and alkaline phosphatase values shouldbe obtained prior to each cycle of Trazoteva Injection therapy .
Trazoteva Injection therapy should not be given to patients with neutrophilcounts of <1500 cells/mm 3. In order to monitor the occurrenceof neutropenia, which may be severe and result in infection, frequentblood cell counts should be performed on all patients receiving Trazoteva Injection. .
Severe hypersensitivity reactionscharacterized by generalized rash/erythema, hypotension and/or bronchospasm,or very rarely fatal anaphylaxis, have been reported in patients whoreceived a 3-day dexamethasone premedication. Hypersensitivityreactions require immediate discontinuation of the Trazoteva Injection infusionand administration of appropriate therapy . Trazoteva Injection must not be givento patients who have a history of severe hypersensitivity reactionsto Trazoteva or to other drugs formulated with polysorbate 80 .
Severe fluid retention occurred in 6.5% (6/92) of patients despiteuse of a 3-day dexamethasone premedication regimen. It was characterizedby one or more of the following events: poorly tolerated peripheraledema, generalized edema, pleural effusion requiring urgent drainage,dyspnea at rest, cardiac tamponade, or pronounced abdominal distention(due to ascites) .
WARNING:TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION
See full prescribing information for complete boxed warning
1. INDICATIONS AND USAGE
Trazoteva Injection is a microtubule inhibitor indicated for:
1.1 Breast Cancer
Trazoteva Injection is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy.
Trazoteva Injection in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer.
1.2 Non-Small Cell Lung Cancer
Trazoteva Injection as a single agent is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior platinum based chemotherapy.
Trazoteva Injection in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have not previously received chemotherapy for this condition.
1.3 Prostate Cancer
Trazoteva Injection in combination with prednisone is indicated for the treatment of patients with androgen independent metastatic prostate cancer.
1.4 Gastric Adenocarcinoma
Trazoteva Injection in combination with cisplatin and fluorouracil is indicated for the treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for advanced disease.
1.5 Head and Neck Cancer
Trazoteva Injection in combination with cisplatin and fluorouracil is indicated for the induction treatment of patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
2. DOSAGE AND ADMINISTRATION
For all indications, toxicities may warrant dosage adjustments .
Administer in a facility equipped to manage possible complications (e.g. anaphylaxis).
Administer in a facility equipped to manage possible complications (e.g., anaphylaxis).Administer intravenously over 1 hr every 3 weeks. PVC equipment is not recommended. For One-vial formulation, use only a 21 gauge needle to withdraw Trazoteva Injection from the vial.
For all patients:
2.1 Breast Cancer
2.2 Non-Small Cell Lung Cancer
2.3 Prostate Cancer
2.4 Gastric Adenocarcinoma
2.5 Head and Neck Cancer
Patients must receive premedication with antiemetics, and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. All patients treated on the Trazoteva containing arms of the TAX323 and TAX324 studies received prophylactic antibiotics.
2.6 Premedication Regimen
2.7 Dosage Adjustments During Treatment
Patients who are dosed initially at 100 mg/m 2 and who experienceeither febrile neutropenia, neutrophils <500 cells/mm 3 for more than 1 week, or severe or cumulative cutaneous reactionsduring Trazoteva Injection therapy should have the dosage adjusted from 100 mg/m 2 to 75 mg/m 2. If the patient continues to experiencethese reactions, the dosage should either be decreased from 75 mg/m 2 to 55 mg/m 2 or the treatment should be discontinued. Conversely, patients who are dosed initially at 60 mg/m 2 and who do not experience febrile neutropenia, neutrophils <500cells/mm 3 for more than 1 week, severe or cumulative cutaneousreactions, or severe peripheral neuropathy during Trazoteva Injection therapymay tolerate higher doses. Patients who develop ≥grade 3 peripheralneuropathy should have Trazoteva Injection treatment discontinued entirely.
Combination Therapy with Trazoteva Injection in the Adjuvant Treatmentof Breast Cancer
Trazoteva Injection in combination with doxorubicin and cyclophosphamide should be administered when the neutrophil count is ≥1,500 cells/mm 3. Patients who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their Trazoteva Injection dose reduced to 60 mg/m 2. Patients who experience grade 3 or 4 stomatitis should have their Trazoteva Injection dose decreased to 60 mg/m 2. Patients who experience severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Trazoteva Injection therapy should have their dosage of Trazoteva Injection reduced from 75 mg/m 2 to 60 mg/m 2. If the patient continues to experience these reactions at 60 mg/m , treatment should be discontinued.
Non-Small Cell Lung Cancer
Monotherapy with Trazoteva Injection for NSCLC treatment after failure of prior platinum-based chemotherapy
Patients who are dosed initially at 75 mg/m 2 and who experience either febrile neutropenia, neutrophils <500 cells/mm 3 for more than one week, severe or cumulative cutaneous reactions, or other grade 3/4 non-hematological toxicities during Trazoteva Injection treatment should have treatment withheld until resolution of the toxicity and then resumed at 55 mg/m 2. Patients who develop ≥grade3 peripheral neuropathy should have Trazoteva Injection treatment discontinuedentirely.
Combination therapy with Trazoteva Injection for chemotherapy-naïve NSCLC
For patients who are dosed initially at Trazoteva Injection 75 mg/m 2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is <25,000 cells/mm 3, in patients who experience febrile neutropenia, and in patients with serious non-hematologic toxicities, the Trazoteva Injection dosage in subsequent cycles should be reduced to 65 mg/m 2. In patients who require a further dose reduction, a dose of 50 mg/m 2 is recommended. For cisplatin dosage adjustments, see manufacturers' prescribing information.
Combination therapy with Trazoteva Injection for hormone-refractory metastatic prostate cancer
Trazoteva Injection should be administered when the neutrophil count is ≥1,500 cells/mm 3. Patients who experience either febrile neutropenia, neutrophils < 500 cells/mm 3 for more than one week, severe or cumulative cutaneous reactions or moderate neurosensory signs and/or symptoms during Trazoteva Injection therapy should have the dosage of Trazoteva Injection reduced from 75 mg/m 2 to 60 mg/m 2. If the patient continues to experience these reactions at 60 mg/m 2, the treatment should be discontinued.
Gastric or Head and Neck Cancer
Trazoteva Injection in combination with cisplatin and fluorouracil in gastric cancer or head and neck cancer
Patients treated with Trazoteva Injection in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. In both studies, G-CSF was recommended during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than 7 days. If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the Trazoteva Injection dose should be reduced from 75 mg/m 2 to 60 mg/m 2. If subsequent episodes of complicated neutropenia occur the Trazoteva Injection dose should be reduced from 60 mg/m 2 to 45 mg/m 2. In case of grade 4 thrombocytopenia the Trazoteva Injection dose should be reduced from 75 mg/m 2 to 60 mg/m 2. Patients should not be retreated with subsequent cycles of Trazoteva Injection until neutrophils recover to a level>1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3. Discontinue treatment if these toxicities persist. .
Recommended dose modifications for toxicities in patients treated with Trazoteva Injection in combination with cisplatin and fluorouracil are shown in Table 1.
In case of AST/ALT >2.5 to ≤5 x ULN and AP ≤2.5 x ULN, or AST/ALT >1.5 to ≤5 x ULN and AP >2.5 to ≤5 x ULN, Trazoteva Injection should be reduced by 20%.
In case of AST/ALT >5 x ULN and/or AP >5 x ULN Trazoteva Injection should be stopped.
The dose modifications for cisplatin and fluorouracil in the gastric cancer study are provided below:
Cisplatin dose modifications and delays
Peripheral neuropathy: A neurological examination should be performed before entry into the study, and then at least every 2 cycles and at the end of treatment. In the case of neurological signs or symptoms, more frequent examinations should be performed and the following dose modifications can be made according to NCIC-CTC grade:
- Grade 2: Reduce cisplatin dose by 20%.
- Grade 3: Discontinue treatment.
Ototoxicity: In the case of grade 3 toxicity, discontinue treatment.
Nephrotoxicity: In the event of a rise in serum creatinine ≥grade 2 (>1.5 x normal value) despite adequate rehydration, CrCl should be determined before each subsequent cycle and the following dose reductions should be considered.
For other cisplatin dosage adjustments, also refer to the manufacturers’ prescribing information.
Fluorouracil dose modifications and treatment delays
For diarrhea and stomatitis, see Table 1.
In the event of grade 2 or greater plantar-palmar toxicity, fluorouracil should be stopped until recovery. The fluorouracil dosage should be reduced by 20%.
For other >grade 3 toxicities, except alopecia and anemia, chemotherapy should be delayed (for a maximum of 2 weeks from the planned date of infusion) until resolution to grade ≤1 and then recommenced, if medically appropriate.
For other fluorouracil dosage adjustments, also refer to the manufacturers’ prescribing information.
Combination Therapy with Strong CYP3A4 inhibitors:
Avoid using concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole). There are no clinical data with a dose adjustment in patients receiving strong CYP3A4 inhibitors. Based on extrapolation from a pharmacokinetic study with ketoconazole in 7 patients, consider a 50% Trazoteva Injection dose reduction if patients require co-administration of a strong CYP3A4 inhibitor. .
2.8 Administration Precautions
Trazoteva Injection is a cytotoxic anticancer drug. Follow special handling and disposal procedures when preparing Trazoteva Injection solutions. 1
If Trazoteva Injection, initial diluted solution, or final dilution for infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If Trazoteva Injection, initial diluted solution, or final dilution for infusion should come into contact with mucosa, immediately and thoroughly wash with water.
Contact of the Trazoteva Injection with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP, which may be leached from PVC infusion bags or sets, the final Trazoteva Injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.
Two-vial formulation (Injection with Diluent)
Trazoteva Injection requires two dilutions prior to administration. Please follow thepreparation instructions provided below. Note: Both the Trazoteva Injection and the diluentvials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanyingdiluent, there is an initial diluted solution containing 10 mg/mLdocetaxel.
The table below provides the fill range of the Diluent, the approximate extractable volume of Diluent when the entire contents of the diluent vial are withdrawn, and the concentration of the initial diluted solution for Trazoteva Injection 20 mg and Trazoteva Injection 80 mg.
One-vial formulation (Injection)
Trazoteva Injection requires NO prior dilution with a diluent and is ready to add to the infusion solution.
Please follow the preparation instructions provided below.
2.9 Preparation and Administration
DO NOT use the two-vial formulation (Injection with diluent) with the one-vial formulation.
Two-vial formulation (Injection with Diluent)
A.Initial Diluted Solution
B.Final Dilution for Infusion
One-vial formulation (Injection)
Trazoteva Injection (20 mg/mL) requires NO prior dilution with a diluent and is ready to add to the infusion solution. Use only a 21 gauge needle to withdraw Trazoteva from the vial because larger bore needles (e.g., 18 and 19 gauge) may result in stopper coring and rubber particulates.
The Trazoteva dilution for infusion should be administered intravenously as a 1-hour infusion under ambient room temperature (below 25°C) and lighting conditions.
Trazoteva Injection final dilution for infusion, if stored between 2°C and 25°C (36°F and 77°F) is stable for 4 hours. Trazoteva Injection final dilution for infusion (in either 0.9% Sodium Chloride solution or 5% Dextrose solution) should be used within 4 hours (including the 1 hour intravenous administration).
3. DOSAGE FORMS AND STRENGTHS
Two-vial formulation (Injection with Diluent)
Trazoteva Injection 80 mg/2 mL solution in single dose vial with Diluent for Trazoteva Injection USP 80 mg. Both items are in a blister pack in one carton.
Trazoteva Injection 20 mg/0.5 mL solution in single dose vial with Diluent for Trazoteva Injection USP 20 mg. Both items are in a blister pack in one carton.
One-vial formulation (Injection in Single Dose and Multiple Dose Vials)
Trazoteva Injection: 160 mg/8 mL solution
Trazoteva Injection: 80 mg/4 mL solution
Trazoteva Injection: 20 mg/1 mL solution
5. WARNINGS AND PRECAUTIONS
5.1 Toxic Deaths
Trazoteva administered at 100 mg/m 2 was associated with deaths considered possibly or probably related to treatment in 2.0% (19/965) of metastatic breast cancer patients, both previously treated and untreated, with normal baseline liver function and in 11.5% (7/61) of patients with various tumor types who had abnormal baseline liver function (AST and/or ALT >1.5 times ULN together with AP >2.5 times ULN). Among patients dosed at 60 mg/m 2, mortality related to treatment occurred in 0.6% (3/481) of patients with normal liver function, and in 3 of 7 patients with abnormal liver function. Approximately half of these deaths occurred during the first cycle. Sepsis accounted for the majority of the deaths.
Non-Small Cell Lung Cancer
Trazoteva administered at a dose of 100 mg/m 2 in patients with locally advanced or metastatic non-small cell lung cancer who had a history of prior platinum-based chemotherapy was associated with increased treatment-related mortality (14% and 5% in two randomized, controlled studies). There were 2.8% treatment-related deaths among the 176 patients treated at the 75 mg/m 2 dose in the randomized trials. Among patients who experienced treatment-related mortality at the 75 mg/m 2 dose level, 3 of 5 patients had an ECOG PS of 2 at study entry .
5.2 Hepatic Impairment
Patients with combined abnormalities of transaminases and alkaline phosphatase should not be treated with Trazoteva Injection .
5.3 Hematologic Effects
Perform frequent peripheral blood cell counts on all patients receiving Trazoteva Injection. Patients should not be retreated with subsequent cycles of Trazoteva Injection until neutrophils recover to a level >1500 cells/mm 3 and platelets recover to a level >100,000 cells/mm 3.
A 25% reduction in the dose of Trazoteva Injection is recommended during subsequent cycles following severe neutropenia (<500 cells/mm 3) lasting 7 days or more, febrile neutropenia, or a grade 4 infection in a Trazoteva Injection cycle .
Neutropenia (<2000 neutrophils/mm 3) occurs in virtually all patients given 60 mg/m 2 to 100 mg/m 2 of Trazoteva and grade 4 neutropenia (<500 cells/mm 3) occurs in 85% of patients given 100 mg/m 2 and 75% of patients given 60 mg/m 2. Frequent monitoring of blood counts is, therefore, essential so that dose can be adjusted. Trazoteva Injection should not be administered to patients with neutrophils <1500 cells/mm 3.
Febrile neutropenia occurred in about 12% of patients given 100 mg/m 2 but was very uncommon in patients given 60 mg/m 2. Hematologic responses, febrile reactions and infections, and rates of septic death for different regimens are dose related .
Three breast cancer patients with severe liver impairment (bilirubin >1.7 times ULN) developed fatal gastrointestinal bleeding associated with severe drug-induced thrombocytopenia. In gastric cancer patients treated with Trazoteva in combination with cisplatin and fluorouracil (TCF), febrile neutropenia and/or neutropenic infection occurred in 12% of patients receiving G-CSF compared to 28% who did not. Patients receiving TCF should be closely monitored during the first and subsequent cycles for febrile neutropenia and neutropenic infection
5.4 Hypersensitivity Reactions
Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions characterized by generalized rash/erythema, hypotension and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients premedicated with 3 days of corticosteroids. Severe hypersensitivity reactions require immediate discontinuation of the Trazoteva Injection infusion and aggressive therapy. Patients with a history of severe hypersensitivity reactions should not be rechallenged with Trazoteva Injection.
Hypersensitivity reactions may occur within a few minutes following initiation of a Trazoteva Injection infusion. If minor reactions such as flushing or localized skin reactions occur, interruption of therapy is not required. All patients should be premedicated with an oral corticosteroid prior to the initiation of the infusion of Trazoteva Injection
5.5 Fluid Retention
Severe fluid retention has been reported following Trazoteva therapy. Patients should be premedicated with oral corticosteroids prior to each Trazoteva Injection administration to reduce the incidence and severity of fluid retention . Patients with pre-existing effusions should be closely monitored from the first dose for the possible exacerbation of the effusions.
When fluid retention occurs, peripheral edema usually starts in the lower extremities and may become generalized with a median weight gain of 2 kg.
Among 92 breast cancer patients premedicated with 3-day corticosteroids, moderate fluid retention occurred in 27.2% and severe fluid retention in 6.5%. The median cumulative dose to onset of moderate or severe fluid retention was 819 mg/m 2. Nine of 92 patients (9.8%) of patients discontinued treatment due to fluid retention: 4 patients discontinued with severe fluid retention; the remaining 5 had mild or moderate fluid retention. The median cumulative dose to treatment discontinuation due to fluid retention was 1021 mg/m 2. Fluid retention was completely, but sometimes slowly, reversible with a median of 16 weeks from the last infusion of Trazoteva to resolution (range: 0 to 42+ weeks). Patients developing peripheral edema may be treated with standard measures, e.g., salt restriction, oral diuretic(s).
5.6 Acute Myeloid Leukemia
Treatment-related acute myeloid leukemia or myelodysplasia has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received Trazoteva, doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin and cyclophosphamide . In TAC-treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up.
5.7 Cutaneous Reactions
Localized erythema of the extremities with edema followed by desquamation has been observed. In case of severe skin toxicity, an adjustment in dosage is recommended . The discontinuation rate due to skin toxicity was 1.6% (15/965) for metastatic breast cancer patients. Among 92 breast cancer patients premedicated with 3-day corticosteroids, there were no cases of severe skin toxicity reported and no patient discontinued Trazoteva due to skin toxicity.
5.8 Neurologic Reactions
Severe neurosensory symptoms were observed in 5.5% (53/965) of metastatic breast cancer patients, and resulted in treatment discontinuation in 6.1%. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued . Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event was available had spontaneous reversal of symptoms with a median of 9 weeks from onset (range: 0 to 106 weeks). Severe peripheral motor neuropathy mainly manifested as distal extremity weakness occurred in 4.4% (42/965).
5.9 Eye Disorders
Cystoid macular edema (CME) has been reported in patients treated with Trazoteva Injection. Patients with impaired vision should undergo a prompt and comprehensive ophthalmologic examination. If CME is diagnosed, Trazoteva Injection treatment should be discontinued and appropriate treatment initiated. Alternative non-taxane cancer treatment should be considered.
Severe asthenia has been reported in 14.9% of metastatic breast cancer patients but has led to treatment discontinuation in only 1.8%. 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.
5.11 Alcohol Content
Cases of intoxication have been reported with some formulations of Trazoteva due to the alcohol content. The alcohol content in a dose of Trazoteva Injection may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in Trazoteva Injection on the ability to drive or use machines immediately after the infusion.
For Two-vial formulation (Injection with Diluent)
Each administration of Trazoteva Injection at 100 mg/m 2 delivers 0.15 g/m 2of ethanol. For a patient with a BSA of 2.0 m 2, this would deliver 0.3 grams of ethanol [ see Description (11) ]. Other Trazoteva products may have a different amount of alcohol.
For One-vial formulation (Injection)
Each administration of Trazoteva Injection at 100 mg/m 2 delivers 1.975 g/m 2 of ethanol. For a patient with a BSA of 2.0 m 2, this would deliver 3.95 grams of ethanol [ see Description (11) ]. Other Trazoteva products may have a different amount of alcohol.
5.12 Use in Pregnancy
Trazoteva Injection can cause fetal harm when administered to a pregnant woman. Trazoteva caused embryofetal toxicities including intrauterine mortality when administered to pregnant rats and rabbits during the period of organogenesis. Embryofetal effects in animals occurred at doses as low as 1/50 and 1/300 the recommended human dose on a body surface area basis.
There are no adequate and well-controlled studies in pregnant women using Trazoteva Injection. If Trazoteva Injection 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. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Trazoteva Injection .
6. ADVERSE REACTIONS
The most serious adverse reactions from Trazoteva are:
The most common adverse reactions across all Trazoteva indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.
Adverse reactions are described according to indication. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
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 not been established.
Most common adverse reactions across all Trazoteva indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia( 6)
To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1 Clinical Trial Experience
Monotherapy with Trazoteva for locally advanced or metastatic breast cancer after failure of prior chemotherapy
Trazoteva 100 mg/m 2: Adverse drug reactions occurring in at least 5% of patients are compared for three populations who received Trazoteva administered at 100 mg/m 2 as a 1-hour infusion every 3 weeks: 2045 patients with various tumor types and normal baseline liver function tests; the subset of 965 patients with locally advanced or metastatic breast cancer, both previously treated and untreated with chemotherapy, who had normal baseline liver function tests; and an additional 61 patients with various tumor types who had abnormal liver function tests at baseline. These reactions were described using COSTART terms and were considered possibly or probably related to Trazoteva. At least 95% of these patients did not receive hematopoietic support. The safety profile is generally similar in patients receiving Trazoteva for the treatment of breast cancer and in patients with other tumor types.
Reversible marrow suppression was the major dose-limiting toxicity of Trazoteva . The median time to nadir was 7 days, while the median duration of severe neutropenia (<500 cells/mm 3) was 7 days. Among 2045 patients with solid tumors and normal baseline LFTs, severe neutropenia occurred in 75.4% and lasted for more than 7 days in 2.9% of cycles.
Febrile neutropenia (<500 cells/mm 3 with fever >38°C with intravenous antibiotics and/or hospitalization) occurred in 11% of patients with solid tumors, in 12.3% of patients with metastatic breast cancer, and in 9.8% of 92 breast cancer patients premedicated with 3-day corticosteroids.
Severe infectious episodes occurred in 6.1% of patients with solid tumors, in 6.4% of patients with metastatic breast cancer, and in 5.4% of 92 breast cancer patients premedicated with 3-day corticosteroids. Thrombocytopenia (<100,000 cells/mm3) associated with fatal gastrointestinal hemorrhage has been reported.
Severe hypersensitivity reactions have been reported .Minor events, including flushing, rash with or without pruritus, chest tightness, back pain, dyspnea, drug fever, or chills, have been reported and resolved after discontinuing the infusion and instituting appropriate therapy.
Fluid retention can occur with the use of Trazoteva .
Severe skin toxicity is discussed elsewhere in the label . Reversible cutaneous reactions characterized by a rash including localized eruptions, mainly on the feet and/or hands, but also on the arms, face, or thorax, usually associated with pruritus, have been observed. Eruptions generally occurred within 1 week after Trazoteva infusion, recovered before the next infusion, and were not disabling.
Severe nail disorders were characterized by hypo- or hyperpigmentation, and occasionally by onycholysis (in 0.8% of patients with solid tumors) and pain.
Neurologic reactions are discussed elsewhere in the label [see Warnings and Precautions (5.8) ].
Nausea, vomiting, and diarrhea were generally mild to moderate. Severe reactions occurred in 3 to 5% of patients with solid tumors and to a similar extent among metastatic breast cancer patients. The incidence of severe reactions was 1% or less for the 92 breast cancer patients premedicated with 3-day corticosteroids.
Severe stomatitis occurred in 5.5% of patients with solid tumors, in 7.4% of patients with metastatic breast cancer, and in 1.1% of the 92 breast cancer patients premedicated with 3-day corticosteroids.
Hypotension occurred in 2.8% of patients with solid tumors; 1.2% required treatment. Clinically meaningful events such as heart failure, sinus tachycardia, atrial flutter, dysrhythmia, unstable angina, pulmonary edema, and hypertension occurred rarely. Seven of 86 (8.1%) of metastatic breast cancer patients receiving Trazoteva 100 mg/m 2 in a randomized trial and who had serial left ventricular ejection fractions assessed developed deterioration of LVEF by ≥10% associated with a drop below the institutional lower limit of normal.
Infusion Site Reactions
Infusion site reactions were generally mild and consisted of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis, extravasation, or swelling of the vein.
In patients with normal LFTs at baseline, bilirubin values > the ULN occurred in 8.9% of patients. Increases in AST or ALT >1.5 times the ULN, or alkaline phosphatase >2.5 times ULN, were observed in 18.9% and 7.3% of patients, respectively. While on Trazoteva, increases in AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >2.5 times ULN occurred in 4.3% of patients with normal LFTs at baseline. Whether these changes were related to the drug or underlying disease has not been established.
Hematologic and Other Toxicity: Relation to dose and baseline liver chemistry abnormalities
Hematologic and other toxicity is increased at higher doses and in patients with elevated baseline liver function tests (LFTs). In the following tables, adverse drug reactions are compared for three populations: 730 patients with normal LFTs given Trazoteva at 100 mg/m 2 in the randomized and single arm studies of metastatic breast cancer after failure of previous chemotherapy; 18 patients in these studies who had abnormal baseline LFTs (defined as AST and/or ALT >1.5 times ULN concurrent with alkaline phosphatase >2.5 times ULN); and 174 patients in Japanese studies given Trazoteva at 60 mg/m 2 who had normal LFTs.
In the three-arm monotherapy trial, TAX313, which compared Trazoteva 60 mg/m 2, 75 mg/m 2 and 100 mg/m 2 in advanced breast cancer, grade 3/4 or severe adverse reactions occurred in 49.0% of patients treated with Trazoteva 60 mg/m 2 compared to 55.3% and 65.9% treated with 75 mg/m 2 and 100 mg/m 2 respectively. Discontinuation due to adverse reactions was reported in 5.3% of patients treated with 60 mg/m 2 vs. 6.9% and 16.5% for patients treated at 75 mg/m 2 and 100 mg/m 2 respectively. Deaths within 30 days of last treatment occurred in 4.0% of patients treated with 60 mg/m 2 compared to 5.3% and 1.6% for patients treated at 75 mg/m 2 and 100 mg/m 2 respectively.
The following adverse reactions were associated with increasing Trazoteva doses: fluid retention (26%, 38%, and 46% at 60 mg/m 2, 75 mg/m 2, and 100 mg/m 2 respectively), thrombocytopenia (7%, 11% and 12% respectively), neutropenia (92%, 94%, and 97% respectively), febrile neutropenia (5%, 7%, and 14% respectively), treatment-related grade 3/4 infection (2%, 3%, and 7% respectively) and anemia (87%, 94%, and 97% respectively).
Combination therapy with Trazoteva in the adjuvant treatment of breast cancer
The following table presents treatment emergent adverse reactions observed in 744 patients, who were treated with Trazoteva 75 mg/m 2 every 3 weeks in combination with doxorubicin and cyclophosphamide.
Of the 744 patients treated with TAC, 36.3% experienced severe treatment emergent adverse reactions compared to 26.6% of the 736 patients treated with FAC. Dose reductions due to hematologic toxicity occurred in 1% of cycles in the TAC arm versus 0.1% of cycles in the FAC arm. Six percent of patients treated with TAC discontinued treatment due to adverse reactions, compared to 1.1% treated with FAC; fever in the absence of infection and allergy being the most common reasons for withdrawal among TAC-treated patients. Two patients died in each arm within 30 days of their last study treatment; 1 death per arm was attributed to study drugs.
Fever and Infection
Fever in the absence of infection was seen in 46.5% of TAC-treated patients and in 17.1% of FAC-treated patients. Grade 3/4 fever in the absence of infection was seen in 1.3% and 0% of TAC- and FAC-treated patients respectively. Infection was seen in 39.4% of TAC-treated patients compared to 36.3% of FAC-treated patients. Grade 3/4 infection was seen in 3.9% and 2.2% of TAC-treated and FAC-treated patients respectively. There were no septic deaths in either treatment arm.
In addition to gastrointestinal reactions reflected in the table above, 7 patients in the TAC arm were reported to have colitis/enteritis/large intestine perforation vs. one patient in the FAC arm. Five of the 7 TAC-treated patients required treatment discontinuation; no deaths due to these events occurred.
More cardiovascular reactions were reported in the TAC arm vs. the FAC arm; dysrhythmias, all grades (7.9% vs. 6.0%), hypotension, all grades (2.6% vs. 1.1%) and CHF (2.3% vs. 0.9%, at 70 months median follow-up). One patient in each arm died due to heart failure.
Acute Myeloid Leukemia (AML)
Treatment-related acute myeloid leukemia or myelodysplasia is known to occur in patients treated with anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. AML occurs at a higher frequency when these agents are given in combination with radiation therapy. AML occurred in the adjuvant breast cancer trial (TAX316). The cumulative risk of developing treatment-related AML at 5 years in TAX316 was 0.4% for TAC treated patients and 0.1% for FAC-treated patients. This risk of AML is comparable to the risk observed for other anthracyclines/cyclophosphamide containing adjuvant breast chemotherapy regimens.
Monotherapy with Trazoteva for unresectable, locally advanced or metastatic NSCLC previously treated with platinum-based chemotherapy
Treatment emergent adverse drug reactions are shown in Table 8. Included in this table are safety data for a total of 176 patients with non-small cell lung carcinoma and a history of prior treatment with platinum-based chemotherapy who were treated in two randomized, controlled trials. These reactions were described using NCI Common Toxicity Criteria regardless of relationship to study treatment, except for the hematologic toxicities or where otherwise noted.
Combination therapy with Trazoteva in chemotherapy-naïve advanced unresectable or metastatic NSCLC
Table 9 presents safety data from two arms of an open label, randomized controlled trial (TAX326) that enrolled patients with unresectable stage IIIB or IV non-small cell lung cancer and no history of prior chemotherapy. Adverse reactions were described using the NCI Common Toxicity Criteria except where otherwise noted.
Deaths within 30 days of last study treatment occurred in 31 patients (7.6%) in the docetaxel+cisplatin arm and 37 patients (9.3%) in the vinorelbine+cisplatin arm. Deaths within 30 days of last study treatment attributed to study drug occurred in 9 patients (2.2%) in the docetaxel+cisplatin arm and 8 patients (2.0%) in the vinorelbine+cisplatin arm.
The second comparison in the study, vinorelbine+cisplatin versus Trazoteva + carboplatin (which did not demonstrate a superior survival associated with Trazoteva ) demonstrated a higher incidence of thrombocytopenia, diarrhea, fluid retention, hypersensitivity reactions, skin toxicity, alopecia and nail changes on the Trazoteva + carboplatin arm, while a higher incidence of anemia, neurosensory toxicity, nausea, vomiting, anorexia and asthenia was observed on the vinorelbine+cisplatin arm.
Combination therapy with Trazoteva in patients with prostate cancer
The following data are based on the experience of 332 patients, who were treated with Trazoteva 75 mg/m 2 every 3 weeks in combination with prednisone 5 mg orally twice daily.
Combination therapy with Trazoteva in gastric adenocarcinoma
Data in the following table are based on the experience of 221 patients with advanced gastric adenocarcinoma and no history of prior chemotherapy for advanced disease, who were treated with Trazoteva 75 mg/m 2 in combination with cisplatin and fluorouracil.
Head and Neck Cancer
Combination therapy with Trazoteva in head and neck cancer
Table 12 summarizes the safety data obtained from patients that received induction chemotherapy with Trazoteva 75 mg/m 2 in combination with cisplatin and fluorouracil followed by radiotherapy (TAX323; 174 patients) or chemoradiotherapy (TAX324; 251 patients). The treatment regimens are described in Section 14.6.
6.2 Post-Marketing Experiences
The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made.
Body as a whole: diffuse pain, chest pain, radiation recall phenomenon.
Cardiovascular: atrial fibrillation, deep vein thrombosis, ECG abnormalities, thrombophlebitis, pulmonary embolism, syncope, tachycardia, myocardial infarction.
Cutaneous: very rare cases of cutaneous lupus erythematosus and rare cases of bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and Scleroderma-like changes usually preceded by peripheral lymphedema. In some cases multiple factors may have contributed to the development of these effects. Severe hand and foot syndrome has been reported. Cases of permanent alopecia have been reported.
Gastrointestinal: abdominal pain, anorexia, constipation, duodenal ulcer, esophagitis, gastrointestinal hemorrhage, gastrointestinal perforation, ischemic colitis, colitis, intestinal obstruction, ileus, neutropenic enterocolitis and dehydration as a consequence to gastrointestinal events have been reported.
Hematologic: bleeding episodes. Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported. Cases of acute myeloid leukemia and myelodysplasic syndrome have been reported in association with Trazoteva when used in combination with other chemotherapy agents and/or radiotherapy.
Hypersensitivity: rare cases of anaphylactic shock have been reported. Very rarely these cases resulted in a fatal outcome in patients who received premedication.
Hepatic: rare cases of hepatitis, sometimes fatal primarily in patients with pre-existing liver disorders, have been reported.
Neurologic: confusion, rare cases of seizures or transient loss of consciousness have been observed, sometimes appearing during the infusion of the drug.
Ophthalmologic:conjunctivitis, lacrimation or lacrimation with or without conjunctivitis. Excessive tearing which may be attributable to lacrimal duct obstruction has been reported. Rare cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity reactions have been reported. These were reversible upon discontinuation of the infusion. Cases of cystoid macular edema (CME) have been reported in patients treated with Trazoteva.
Hearing: rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.
Respiratory: dyspnea, acute pulmonary edema, acute respiratory distress syndrome/pneumonitis, interstitial lung disease, interstitial pneumonia, respiratory failure, and pulmonary fibrosis have rarely been reported and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy.
Renal: renal insufficiency and renal failure have been reported, the majority of these cases were associated with concomitant nephrotoxic drugs.
Metabolism and nutrition disorders: cases of hyponatremia have been reported.
7. DRUG INTERACTIONS
Trazoteva is a CYP3A4 substrate. In vitro studies have shown that the metabolism of Trazoteva may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.
In vivo studies showed that the exposure of Trazoteva increased 2.2-fold when it was coadministered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of Trazoteva. Concomitant use of Trazoteva Injection and drugs that inhibit CYP3A4 may increase exposure to Trazoteva and should be avoided. In patients receiving treatment with Trazoteva Injection, close monitoring for toxicity and a Trazoteva Injection dose reduction could be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided .
8. USE IN SPECIFIC POPULATIONS
Pregnancy Category D.
Based on its mechanism of action and findings in animals, Trazoteva Injection can cause fetal harm when administered to a pregnant woman. If Trazoteva Injection 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. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with Trazoteva Injection.
Trazoteva Injection can cause fetal harm when administered to a pregnant woman. Studies in both rats and rabbits at doses ≥0.3 and 0.03 mg/kg/day, respectively, administered during the period of organogenesis, have shown that Trazoteva is embryotoxic and fetotoxic (characterized by intrauterine mortality, increased resorption, reduced fetal weight, and fetal ossification delay). The doses indicated above also caused maternal toxicity.
8.3 Nursing Mothers
It is not known whether Trazoteva is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Trazoteva Injection, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
The safety and effectiveness of Trazoteva Injection in pediatric patients have not been established. The alcohol content of Trazoteva Injection should be taken into account when given to pediatric patients [ see Warnings and Precautions ].
8.5 Geriatric Use
In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy in elderly patients.
Non-Small Cell Lung Cancer
In a study conducted in chemotherapy-naïve patients with NSCLC (TAX326), 148 patients (36%) in the docetaxel+cisplatin group were 65 years of age or greater. There were 128 patients (32%) in the vinorelbine+cisplatin group 65 years of age or greater. In the docetaxel+cisplatin group, patients < 65 years of age had a median survival of 10.3 months (95% CI: 9.1 months, 11.8 months) and patients 65 years or older had a median survival of 12.1 months (95% CI: 9.3 months, 14 months). In patients 65 years of age or greater treated with docetaxel+cisplatin, diarrhea (55%), peripheral edema (39%) and stomatitis (28%) were observed more frequently than in the vinorelbine+cisplatin group (diarrhea 24%, peripheral edema 20%, stomatitis 20%). Patients treated with docetaxel+cisplatin who were 65 years of age or greater were more likely to experience diarrhea (55%), infections (42%), peripheral edema (39%) and stomatitis (28%) compared to patients < the age of 65 administered the same treatment(43%, 31%, 31% and 21%, respectively).
When Trazoteva was combined with carboplatin for the treatment of chemotherapy-naïve, advanced non-small cell lung carcinoma, patients 65 years of age or greater (28%) experienced higher frequency of infection compared to similar patients treated with docetaxel+cisplatin, and a higher frequency of diarrhea, infection and peripheral edema than elderly patients treated with vinorelbine+cisplatin.
Of the 333 patients treated with Trazoteva every three weeks plus prednisone in the prostate cancer study (TAX327), 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with Trazoteva every three weeks, the following treatment emergent adverse reactions occurred at rates ≥10% higher in patients 65 years of age or greater compared to younger patients: anemia (71% vs. 59%), infection (37% vs. 24%), nail changes (34% vs. 23%), anorexia (21% vs. 10%), weight loss (15% vs. 5%) respectively.
In the adjuvant breast cancer trial (TAX316), Trazoteva in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.
Among the 221 patients treated with Trazoteva in combination with cisplatin and fluorouracil in the gastric cancer study, 54 were 65 years of age or older and 2 patients were older than 75 years. In this study, the number of patients who were 65 years of age or older was insufficient to determine whether they respond differently from younger patients. However, the incidence of serious adverse reactions was higher in the elderly patients compared to younger patients. The incidence of the following adverse reactions (all grades, regardless of relationship): lethargy, stomatitis, diarrhea, dizziness, edema, febrile neutropenia/neutropenic infection occurred at rates ≥ 10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.
Head and Neck Cancer
Among the 174 and 251 patients who received the induction treatment with Trazoteva in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX323 and TAX324 studies, 18 (10%) and 32 (13%) of the patients were 65 years of age or older, respectively.
These clinical studies of Trazoteva in combination with cisplatin and fluorouracil in patients with SCCHN did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience with this treatment regimen has not identified differences in responses between elderly and younger patients.
8.6 Hepatic Impairment
Patients with bilirubin >ULN should not receive Trazoteva Injection. Also, patients with AST and/or ALT >1.5 x ULN concomitant with alkaline phosphatase >2.5 x ULN should not receive Trazoteva Injection. .
The alcohol content of Trazoteva Injection should be taken into account when given to patients with hepatic impairment [ see Warnings and Precautions (5.11) ].
There is no known antidote for Trazoteva Injection overdosage. In case of overdosage, the patient should be kept in a specialized unit where vital functions can be closely monitored. Anticipated complications of overdosage include: bone marrow suppression, peripheral neurotoxicity, and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.
In two reports of overdose, one patient received 150 mg/m 2 and the other received 200 mg/m 2 as 1-hour infusions. Both patients experienced severe neutropenia, mild asthenia, cutaneous reactions, and mild paresthesia, and recovered without incident.
In mice, lethality was observed following single intravenous doses that were ≥154 mg/kg (about 4.5 times the human dose of 100 mg/m 2 on a mg/m 2 basis); neurotoxicity associated with paralysis, non-extension of hind limbs, and myelin degeneration was observed in mice at 48 mg/kg (about 1.5 times the human dose of 100 mg/m 2 basis). In male and female rats, lethality was observed at a dose of 20 mg/kg (comparable to the human dose of 100 mg/m 2 on a mg/m 2 basis) and was associated with abnormal mitosis and necrosis of multipleorgans.
Trazoteva is an antineoplasticagent belonging to the taxoid family. It is prepared by semisynthesisbeginning with a precursor extracted from the renewable needle biomassof yew plants. The chemical name for Trazoteva is (2R,3S)-N-carboxy-3-phenylisoserine,N- tert-butyl ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate. Trazoteva has the following structuralformula:
Trazoteva is a white to off-white powder with an empirical formulaof C 43H 53NO 14 and a molecular weight of 807.88. It is highly lipophilic and practicallyinsoluble in water.
Two-vial formulation (Injection with Diluent)
Trazoteva Injection USP is a clear yellow to brownish-yellow viscous solution. Trazoteva Injection USP is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (0.5 mL) or 80 mg (2 mL) Trazoteva anhydrous USP. Each mL contains 40 mg Trazoteva anhydrous USP, 60 mg dehydrated alcohol and 1040 mg polysorbate 80. Citric acid (anhydrous) may be used to adjust the pH.
Trazoteva Injection USP requires dilution with Diluent prior to addition to the infusion bag. A sterile, non-pyrogenic, single-dose diluent is supplied for that purpose. The diluent for Trazoteva Injection USP contains 13% polyethylene glycol 400 in water for injection, and is supplied in vials.
One-vial formulation (Injection)
Trazoteva Injection USP is a sterile, non-pyrogenic, pale yellow to brownish-yellow solution at 20 mg/mL concentration.
Each mL contains 20 mg Trazoteva anhydrous USP, 4 mg anhydrous citric acid, 520 mg polysorbate 80 and 395 mg dehydrated alcohol solution.
Trazoteva Injection USP is available in single dose and multiple dose vials containing 20 mg (1 mL), 80 mg (4 mL) or 160 mg (8 mL) Trazoteva anhydrous USP.
Trazoteva Injection USP requires NO prior dilution with a diluent and is ready to add to the infusion solution.
12. CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Trazoteva is an antineoplastic agent that acts by disrupting the microtubular network in cells that is essential for mitotic and interphase cellular functions. Trazoteva 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 microtubules, a feature which differs from most spindle poisons currently in clinical use.
12.3 Human Pharmacokinetics
Absorption: The pharmacokineticsof Trazoteva have been evaluated in cancer patients after administrationof 20 mg/m 2 to 115 mg/m 2 in phase 1 studies. The area underthe curve (AUC) was dose proportional following doses of 70 mg/m 2 to 115mg/m 2 with infusion times of 1 to 2 hours. Docetaxel'spharmacokinetic profile is consistent with a three-compartment pharmacokineticmodel, with half-lives for the α, β, and γ phasesof 4 min, 36 min, and 11.1 hr, respectively. Mean total body clearancewas 21 L/h/m 2
Distribution: The initial rapid decline represents distribution to the peripheral compartments and the late (terminal) phase is due, in part, to a relatively slow efflux of Trazoteva from the peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies showed that Trazoteva is about 94% protein bound, mainly to α 1-acid glycoprotein, albumin, and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to be approximately 97%. Dexamethasone does not affect the protein binding of Trazoteva.
Metabolism: In vitro drug interaction studies revealed that Trazoteva is metabolized by the CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4 .
Elimination: A study of 14C-docetaxel was conducted in three cancerpatients. Trazoteva was eliminated in both the urine and feces followingoxidative metabolism of the tert-butyl ester group, but fecal excretion was the main eliminationroute. Within 7 days, urinary and fecal excretion accounted for approximately6% and 75% of the administered radioactivity, respectively. About80% of the radioactivity recovered in feces is excreted during thefirst 48 hours as 1 major and 3 minor metabolites with very smallamounts (< 8%) of unchanged drug.
Effect of Age: A population pharmacokinetic analysis was carried out after Trazoteva treatment of 535 patients dosed at 100 mg/m 2. Pharmacokinetic parameters estimated by this analysis were very close to those estimated from phase 1 studies. The pharmacokinetics of Trazoteva were not influenced by age.
Effect of Gender: The population pharmacokinetics analysis described above also indicated that gender did not influence the pharmacokinetics of Trazoteva.
Hepatic Impairment: The population pharmacokinetic analysis described above indicated that in patients with clinical chemistry data suggestive of mild to moderate liver impairment(AST and/or ALT >1.5 times ULN concomitant with alkaline phosphatase >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 phosphatase should not be treated with Trazoteva Injection. Patients with severe hepatic impairment have not been studied.
Effect of Race: Mean total body clearance for Japanese patients dosed at the range of 10 mg/m 2 to 90 mg/m 2 was similar to that of European/American populations dosed at 100 mg/m 2, suggesting no significant difference in the elimination of Trazoteva in the two populations.
Effect of Ketoconazole: The effect of ketoconazole (a strong CYP3A4 inhibitor) on the pharmacokinetics of Trazoteva was investigated in 7 cancer patients. Patients were randomized to receive either Trazoteva (100 mg/m 2 intravenous) alone or Trazoteva (10 mg/m 2 intravenous) in combination with ketoconazole (200 mg orally once daily for 3 days) in a crossover design with a 3-week washout period. The results of this study indicated that the mean dose-normalized AUC of Trazoteva was increased 2.2-fold and its clearance was reduced by 49% when Trazoteva was co-administration with ketoconazole
Effect of Combination Therapies:
13. NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with Trazoteva have not been performed.
Trazoteva was clastogenic in the in vitro chromosome aberration testin CHO-K 1 cells and in the in vivo micronucleus test in mice administered doses of0.39 to 1.56 mg/kg (about 1/60 th to 1/15 th therecommended human dose on a mg/m 2 basis).Docetaxel was not mutagenic in the Ames test or the CHO/HGPRT gene mutationassays.
Trazoteva did not reduce fertility in rats when administered in multiple intravenous doses of up to 0.3 mg/kg (about 1/50 th the recommended human dose on a mg/m 2 basis),but decreased testicular weights were reported. This correlates with findings of a 10-cycle toxicity study (dosing once every 21 days for6 months) in rats and dogs in which testicular atrophy or degenerationwas observed at intravenous doses of 5 mg/kg in rats and 0.375 mg/kg in dogs(about 1/3 rd and 1/15 th the recommended human dose on a mg/m 2 basis, respectively). An increased frequencyof dosing in rats produced similar effects at lower dose levels.
14. CLINICAL STUDIES
14.1 Locally Advanced or Metastatic Breast Cancer
The efficacy and safety of another formulation of Trazoteva have been evaluated in locally advanced or metastatic breast cancer after failure of previous chemotherapy.
In one randomized trial, patients with a history of prior treatment with an anthracycline containing regimen were assigned to treatment with Trazoteva (100 mg/m 2 every 3 weeks) or the combination of mitomycin (12 mg/m 2 every 6 weeks) and vinblastine (6 mg/m 2 every 3 weeks). Two hundred three patients were randomized to Trazoteva and 189 to the comparator arm. Most patients had received prior chemotherapy for metastatic disease; only 27 patients on the Trazoteva arm and 33 patients on the comparator arm entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The following table summarizes the study results.
In a second randomized trial, patients previously treated with an alkylating-containing regimen were assigned to treatment with Trazoteva (100 mg/m 2) or doxorubicin (75 mg/m 2) every 3 weeks. One hundred sixty-one patients were randomized to Trazoteva and 165 patients to doxorubicin. Approximately one-half of patients had received prior chemotherapy for metastatic disease, and one-half entered the study following relapse after adjuvant therapy. Three-quarters of patients had measurable, visceral metastases. The primary endpoint was time to progression. The study results are summarized below.
In another multicenter open-label, randomized trial (TAX313), in the treatment of patients with advanced breast cancer who progressed or relapsed after one prior chemotherapy regimen, 527 patients were randomized to receive Trazoteva monotherapy 60 mg/m 2 (n=151), 75 mg/m 2 (n=188) or 100 mg/m 2 (n=188). In this trial, 94% of patients had metastatic disease and 79% had received prior anthracycline therapy. Response rate was the primary endpoint. Response rates increased with Trazoteva dose: 19.9% for the 60 mg/m 2 group compared to 22.3% for the 75 mg/m 2 and 29.8% for the 100 mg/m 2 group; pair-wise comparison between the 60 mg/m 2 and 100 mg/m 2 groups was statistically significant (p=0.037).
Single Arm Studies
Trazoteva at a dose of 100 mg/m 2 was studied in six single arm studies involving a total of 309 patients with metastatic breast cancer in whom previous chemotherapy had failed. Among these, 190 patients had anthracycline-resistant breast cancer, defined as progression during an anthracycline-containing chemotherapy regimen for metastatic disease, or relapse during an anthracycline-containing adjuvant regimen. In anthracycline-resistant patients, the overall response rate was 37.9% (72/190; 95% C.I.: 31.0 to 44.8) and the complete response rate was 2.1%.
Trazoteva was also studied in three single arm Japanese studies ata dose of 60 mg/m 2, in 174 patients who had received prior chemotherapy for locally advanced or metastatic breast cancer. Among 26 patients whose best response to an anthracycline had been progression, the response rate was 34.6% (95% C.I.: 17.2 to 55.7), similar to the response rate in single arm studies of 100 mg/m 2.
14.2 Adjuvant Treatment of Breast Cancer
A multicenter, open-label, randomized trial (TAX316) evaluated the efficacy and safety of another formulation of Trazoteva for the adjuvant treatment of patients with axillary-node-positive breast cancer and no evidence of distant metastatic disease. After stratification according to the number of positive lymph nodes (1 to 3, 4+), 1491 patients were randomized to receive either Trazoteva 75 mg/m 2 administered 1-hour after doxorubicin 50 mg/m 2 and cyclophosphamide 500 mg/m 2 (TAC arm), or doxorubicin 50 mg/m 2 followed by fluorouracil 500 mg/m 2 and cyclosphosphamide 500 mg/m 2 (FAC arm). Both regimens were administered every 3 weeks for 6 cycles.
Trazoteva was administered as a 1-hour infusion; all other drugs were given as intravenous bolus on day 1. In both arms, after the last cycle of chemotherapy, patients with positive estrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 5 years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.
Results from a second interim analysis (median follow-up 55 months) are as follows: In study TAX316, the docetaxel-containing combination regimen TAC showed significantly longer disease-free survival (DFS) than FAC (hazard ratio=0.74; 2-sided 95% CI=0.60, 0.92, stratified log rank p=0.0047). The primary endpoint, disease-free survival, included local and distant recurrences, contralateral breast cancer and deaths from any cause. The overall reduction in risk of relapse was 25.7% for TAC-treated patients..
At the time of this interim analysis, based on 219 deaths, overall survival was longer for TAC than FAC (hazard ratio=0.69, 2-sided 95% CI=0.53, 0.90).. There will be further analysis at the time survival data mature.
Figure 1 - TAX316 Disease Free Survival K-M curve
Figure 2 - TAX316 Overall Survival K-Mcurve
The following table describes the results of subgroup analyses for DFS and OS.
14.3 Non-Small Cell Lung Cancer
The efficacy and safety of another formulation of Trazoteva has been evaluated in patients with unresectable, locally advanced or metastatic non-small cell lung cancer whose disease has failed prior platinum-based chemotherapy or in patients who are chemotherapy-naïve.
Monotherapy with Trazoteva for NSCLC Previously Treated with Platinum Based Chemotherapy
Two randomized, controlled trials established that a Trazoteva dose of 75 mg/m 2 was tolerable and yielded a favorable outcome in patients previously treated with platinum-based chemotherapy. Trazoteva at a dose of 100 mg/m 2, however, was associated with unacceptable hematologic toxicity, infections, and treatment-related mortality and this dose should not be used .
One trial (TAX317), randomized patients with locally advanced or metastatic non-small cell lung cancer, a history of prior platinum-based chemotherapy, no history of taxane exposure, and an ECOG performance status ≤2 to Trazoteva or best supportive care. The primary endpoint of the study was survival. Patients were initially randomized to Trazoteva 100 mg/m 2 or best supportive care, but early toxic deaths at this dose led to a dose reduction to Trazoteva 75 mg/m 2. A total of 104 patients were randomized in this amended study to either Trazoteva 75 mg/m 2 or best supportive care.
In a second randomized trial (TAX320), 373 patients with locally advanced or metastatic non small cell lung cancer, a history of prior platinum-based chemotherapy, and an ECOG performance status ≤2 were randomized to Trazoteva 75 mg/m 2, Trazoteva 100 mg/m 2 and a treatment in which the investigator chose either vinorelbine 30 mg/m 2 days 1, 8, and 15 repeated every 3 weeks or ifosfamide 2 g/m 2 days 1 to 3 repeated every 3 weeks. Forty percent of the patients in this study had a history of prior paclitaxel exposure. The primary endpoint was survival in both trials. The efficacy data for the Trazoteva 75 mg/m 2 arm and the comparator arms are summarized in Table 16 and Figures 3 and 4 showing the survival curves for the two studies.
Only one of the two trials (TAX317) showed a clear effect on survival, the primary endpoint; that trial also showed an increased rate of survival to one year. In the second study (TAX320) the rate of survival at one year favored Trazoteva 75 mg/m 2.
Figure 3 - TAX317 Survival K-M Curves - Trazoteva 75 mg/m 2 vs. Best Supportive Care
Figure 4 - TAX320 Survival K-M Curves - Trazoteva 75 mg/m 2 vs. Vinorelbine or Ifosfamide Control
Patients treated with Trazoteva at a dose of 75 mg/m 2 experienced no deterioration in performance status and body weight relative to the comparator arms used in these trials.
Combination Therapy with Trazoteva for Chemotherapy-Naïve NSCLC
In a randomized controlled trial (TAX326), 1218 patients with unresectable stage IIIB or IV NSCLC and no prior chemotherapy were randomized to receive one of three treatments: Trazoteva 75 mg/m 2 as a 1 hour infusion immediately followed by cisplatin 75 mg/m 2 over 30 to 60 minutes every 3 weeks; vinorelbine 25 mg/m 2 administered over 6 to 10 minutes on days 1, 8, 15, 22 followed by cisplatin 100 mg/m 2 administered on day 1 of cycles repeated every 4 weeks; or a combination of Trazoteva and carboplatin.
The primary efficacy endpoint was overall survival. Treatment with docetaxel+cisplatin did not result in a statistically significantly superior survival compared to vinorelbine+cisplatin. The 95% confidence interval of the hazard ratio (adjusted for interim analysis and multiple comparisons) shows that the addition of Trazoteva to cisplatin results in an outcome ranging from a 6% inferior to a 26% superior survival compared to the addition of vinorelbine to cisplatin. The results of a further statistical analysis showed that at least (the lower bound of the 95% confidence interval) 62% of the known survival effect of vinorelbine when added to cisplatin (about a 2-month increase in median survival; Wozniak et al. JCO, 1998) was maintained. The efficacy data for the docetaxel+cisplatin arm and the comparator arm are summarized in Table 17.
The second comparison in the same three-arm study, vinorelbine+cisplatin versus docetaxel+carboplatin, did not demonstrate superior survival associated with the Trazoteva arm (Kaplan-Meier estimate of median survival was 9.1 months for Trazoteva +carboplatin compared to 10.0 months on the vinorelbine+cisplatin arm) and the docetaxel+carboplatin arm did not demonstrate preservation of at least 50% of the survival effect of vinorelbine added to cisplatin. Secondary endpoints evaluated in the trial included objective response and time to progression. There was no statistically significant difference between docetaxel+cisplatin and vinorelbine+cisplatin with respect to objective response and time to progression.
14.4 Hormone Refractory Prostate Cancer
The safety and efficacy of another formulation of Trazoteva in combination with prednisone in patients with androgen independent metastatic prostate cancer were evaluated in a randomized multicenter active control trial. A total of 1006 patients with Karnofsky Performance Status (KPS) ≥60 were randomized to the following treatment groups:
All 3 regimens were administered in combination with prednisone 5 mg twice daily, continuously.
In the Trazoteva every three week arm, a statistically significant overall survival advantage was demonstrated compared to mitoxantrone. In the Trazoteva weekly arm, no overall survival advantage was demonstrated compared to the mitoxantrone control arm. Efficacy results for the Trazoteva every 3 week arm versus the control arm are summarized in Table 19 and Figure 5.
14.5 Gastric Adenocarcinoma
A multicenter, open-label,randomized trial was conducted to evaluate the safety and efficacy of another formulation of Trazoteva for the treatment of patients with advanced gastric adenocarcinoma,including adenocarcinoma of the gastroesophageal junction, who hadnot received prior chemotherapy for advanced disease. A total of445 patients with KPS >70 were treated with either Trazoteva (T) (75mg/m 2 on day 1) in combination with cisplatin (C) (75 mg/m 2 on day 1) and fluorouracil (F) (750 mg/m 2 perday for 5 days) or cisplatin (100 mg/m 2 on day 1) and fluorouracil(1000 mg/m 2 per day for 5 days). The length of a treatmentcycle was 3 weeks for the TCF arm and 4 weeks for the CF arm. Thedemographic characteristics were balanced between the two treatmentarms. The median age was 55 years, 71% were male, 71% were Caucasian,24% were 65 years of age or older, 19% had a prior curative surgeryand 12% had palliative surgery. The median number of cycles administeredper patient was 6 (with a range of 1 to 16) for the TCF arm comparedto 4 (with a range of 1 to 12) for the CF arm. Time to progression(TTP) was the primary endpoint and was defined as time from randomizationto disease progression or death from any cause within 12 weeks ofthe last evaluable tumor assessment or within 12 weeks of the firstinfusion of study drugs for patients with no evaluable tumor assessmentafter randomization. The hazard ratio (HR) for TTP was 1.47 (CF/TCF,95% CI: 1.19 to 1.83) with a significantly longer TTP (p=0.0004)in the TCF arm. Approximately 75% of patients had died at the timeof this analysis. Overall survival was significantly longer (p=0.0201)in the TCF arm with a HR of 1.29 (95% CI: 1.04 to 1.61). Efficacyresults are summarized in Table 20 and Figures 6 and 7.
Subgroup analyses were consistent with the overall results across age, gender and race.
Figure 6 - Gastric Cancer Study (TAX325) Time to Progression K-M Curve
Figure 7 - Gastric Cancer Study (TAX325) Survival K-M Curve
14.6 Head and Neck Cancer
Induction chemotherapy followed by radiotherapy (TAX323)
The safetyand efficacy of another formulation of Trazoteva in the induction treatment of patients withsquamous cell carcinoma of the head and neck (SCCHN) was evaluatedin a multicenter, open-label, randomized trial (TAX323). In thisstudy, 358 patients with inoperable locally advanced SCCHN, and WHOperformance status 0 or 1, were randomized to one of two treatmentarms. Patients on the Trazoteva arm received Trazoteva (T) 75 mg/m 2 followed by cisplatin (P) 75 mg/m 2 on Day 1, followedby fluorouracil (F) 750 mg/m 2 per day as a continuous infusionon Days 1 to 5. The cycles were repeated every three weeks for4 cycles. Patients whose disease did not progress received radiotherapy(RT) according to institutional guidelines (TPF/RT). Patients onthe comparator arm received cisplatin (P) 100 mg/m 2 onDay 1, followed by fluorouracil (F) 1000 mg/m 2/day as acontinuous infusion on Days 1 to 5. The cycles were repeated everythree weeks for 4 cycles. Patients whose disease did not progressreceived RT according to institutional guidelines (PF/RT). At theend of chemotherapy, with a minimal interval of 4 weeks and a maximalinterval of 7 weeks, patients whose disease did not progress receivedradiotherapy (RT) according to institutional guidelines. Locoregionaltherapy with radiation was delivered either with a conventional fractionregimen (1.8 Gy to 2.0 Gy once a day, 5 days per week for a totaldose of 66 to 70 Gy) or with an accelerated/hyperfractionated regimen(twice a day, with a minimum interfraction interval of 6 hours, 5days per week, for a total dose of 70 to 74 Gy, respectively). Surgicalresection was allowed following chemotherapy, before or after radiotherapy.
The primary endpoint in this study, progression-free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p=0.0077 (median PFS: 11.4 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival with a median follow-up of 51.2 months was also significantly longer in favor of the TPF arm compared to the PF arm (median OS: 18.6 vs. 14.2 months respectively). Efficacy results are presented in Table 21 and Figures 8 and 9.
Figure 9 - TAX323 Overall Survival K-M Curve
Trazoteva Injection Trazoteva Injection
Induction chemotherapy followed by chemoradiotherapy (TAX324)
The safety and efficacy of another formulation of Trazoteva in the induction treatment of patients with locally advanced (unresectable, low surgical cure, or organ preservation) SCCHN was evaluated in a randomized, multicenter open-label trial (TAX324). In this study, 501 patients, with locally advanced SCCHN, and a WHO performance status of 0 or 1, were randomized to one of two treatment arms. Patients on the Trazoteva arm received Trazoteva (T) 75 mg/m 2 by intravenous infusion on day 1 followed by cisplatin (P) 100 mg/m 2 administered as a 30-minute to three-hour intravenous infusion, followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 cycles. Patients on the comparator arm received cisplatin (P) 100 mg/m 2 as a 30-minute to three-hour intravenous infusion on day 1 followed by the continuous intravenous infusion of fluorouracil (F) 1000 mg/m 2/dayfrom day 1 to day 5. The cycles were repeated every 3 weeks for 3 cycles.
All patients in both treatment arms who did not have progressive disease were to receive 7 weeks of chemoradiotherapy (CRT) following induction chemotherapy 3 to 8 weeks after the start of the last cycle. During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour intravenous infusion for a maximum of 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks for a total dose of 70 to 72 Gy). Surgery on the primary site of disease and/or neck could be considered at anytime following completion of CRT.
The primary efficacy endpoint, overall survival (OS), was significantly longer (log-rank test, p=0.0058) with the docetaxel-containing regimen compared to PF [median OS: 70.6 versus 30.1 months respectively, hazard ratio (HR)=0.70, 95% confidence interval (CI)= 0.54 to 0.90]. Overall survival results are presented in Table 22 and Figure 10.
16. HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
Trazoteva Injection is supplied in single dose vials for 80 mg/mL and 20 mg/mL as a sterile, pyrogen-free, non-aqueous, viscous solution with an accompanying sterile, non-pyrogenic, diluent vial.
Trazoteva Injection 80 mg/2 mL with Diluent for Trazoteva Injection USP 80 mg: Both items are in a blister pack in one carton. NDC 16729-228-50
Trazoteva Injection 20 mg/0.5 mL with Diluent for Trazoteva Injection USP 20 mg: Both items are in a blister pack in one carton. NDC 16729-120-49
One-vial formulation (Injection)
Trazoteva Injection is supplied in single dose and multiple dose vials as a sterile, pyrogen-free, non-aqueous solution.
Trazoteva Injection Single Dose Vials
Trazoteva Injection 160 mg/8 mL: The vial is in one carton. NDC 16729-231-65
Trazoteva Injection 80 mg/4 mL: The vial is in one carton. NDC 16729-231-64
Trazoteva Injection 20 mg/1 mL: The vial is in one carton. NDC 16729-231-63
Trazoteva Injection Multiple Dose Vials
Trazoteva Injection 160 mg/8 mL: The vial is in one carton. NDC 16729-267-65
Trazoteva Injection 80 mg/4 mL: The vial is in one carton. NDC 16729-267-64
Trazoteva Injection 20 mg/1 mL: The vial is in one carton. NDC 16729-267-63
Two-vial formulation (Injection with Diluent)
Store at 25°C (77°F); excursions permitted from 15°C - 30°C (59°-86°F). Protect from light.
One-vial formulation (Injection)
Store between 15°C and 25°C (59°F and 77°F); Retain in the original package to protect from light. Freezing does not adversely affect the product.
After initial puncture, Trazoteva Injection multiple dose vials are stable for 28 days when stored at room temperature, with protection from light.
16.3 Handling and Disposal
Follow procedures for proper handling and disposal of anticancer drugs. 1
17. PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling
Accord Healthcare, Inc.,
1009, Slater Road,
Durham, NC 27703,
Intas Pharmaceuticals Limited,
Ahmedabad – 380 009, India.
10 0739 0 667819
Issued July 2016
NDC 16729- 120-33
80 mg/2 mL
Before Initial Dilution
80 mg/2 mL Trazoteva in
FOR INTRAVENOUS INFUSION
ONLY AFTER FINAL DILUTION
NDC 16729- 121-33
Trazoteva Injection USP
(13% polyethylene glycol 400
in water for injection)
NDC 16729- 120-31
Before Initial Dilution
20 mg/0.5 mL Trazoteva in
FOR INTRAVENOUS INFUSION
ONLY AFTER FINAL DILUTION
NDC 16729- 121-31
Trazoteva Injection USP
(13% polyethylene glycol 400
in water for injection)
Two-vial formulation (Injection Concentrate and Diluent)
Trazoteva Injection USP 80 mg/2 mL (NDC 16729-228-50)
Trazoteva Injection USP 20 mg/0.5 mL (NDC 16729-120-49)
One-vial formulation (Injection Concentrate)- Single Dose
Trazoteva Injection USP 160 mg/8 mL (NDC 16729-231-65)
One-vial formulation - Multiple Dose
Trazoteva Injection USP 160 mg/8 mL (NDC 16729-267-65)
Trazoteva pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Trazoteva available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Trazoteva destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Trazoteva Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Trazoteva pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Trazoteva?
Depending on the reaction of the Trazoteva after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Trazoteva not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Trazoteva addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Trazoteva, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Trazoteva consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
The information was verified by Dr. Arunabha Ray, MD Pharmacology