1.INDICATIONS AND USAGE

JEVTANA® is a microtubule inhibitor indicated in combination with prednisone for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

2.DOSAGE AND ADMINISTRATION

2.1 General Dosing Information

• The individual dosage of JEVTANA is based on calculation of the Body Surface Area (BSA) and is 25 mg/m2 administered as a one-hour intravenous infusion every three weeks in combination with oral prednisone 10 mg administered daily throughout JEVTANA treatment.
• Premedication is recommended prior to treatment [see Dosage and Administration (2.3)].
• JEVTANA should be administered under the supervision of a qualified physician experienced in the use of antineoplastic medicinal products. Appropriate management of complications is possible only when the adequate diagnostic and treatment facilities are readily available.
• JEVTANA Injection single-use vial requires two dilutions prior to administration [see Dosage and Administration (2.5)].
• Do not use PVC infusion containers and polyurethane infusions sets for preparation and administration of JEVTANA infusion solution [see Dosage and Administration (2.5)].
• Both the JEVTANA Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation.

2.2 Dose Modifications

The JEVTANA dose should be reduced to 20 mg/m2 if patients experience the following adverse reactions.

Discontinue JEVTANA treatment if a patient continues to experience any of these reactions at 20 mg/m2.

2.3 Premedication

Premedicate at least 30 minutes prior to each dose of JEVTANA with the following intravenous medications to reduce the risk and/or severity of hypersensitivity:

• antihistamine (dexchlorpheniramine 5 mg, or diphenhydramine 25 mg or equivalent antihistamine),
• corticosteroid (dexamethasone 8 mg or equivalent steroid),
• H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist).

Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed.

2.4 Administration Precautions

JEVTANA is a cytotoxic anticancer drug and caution should be exercised when handling and preparing JEVTANA solutions, taking into account the use of containment devices, personal protective equipment (e.g., gloves), and preparation procedures. Please refer to Handling and Disposal (16.3).

If JEVTANA Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with the skin, immediately and thoroughly wash with soap and water. If JEVTANA Injection, first diluted solution, or second (final) dilution for intravenous infusion should come into contact with mucosa, immediately and thoroughly wash with water.

2.5 Instructions for Preparation

Do not use PVC infusion containers or polyurethane infusions sets for preparation and administration of JEVTANA infusion solution.

Read this entire section carefully before mixing and diluting. JEVTANA requires two dilutions prior to administration. Please follow the preparation instructions provided below. Note: Both the JEVTANA Injection and the diluent vials contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the entire contents of the accompanying diluent, there is an initial diluted solution containing 10 mg/mL JEVTANA.

The following two-step dilution process must be carried out under aseptic conditions to prepare the second (final) infusion solution.

Set aside the JEVTANA Injection and supplied diluent vials. The JEVTANA Injection is a clear yellow to brownish-yellow viscous solution, if appropriately stored.

Step 1 – First Dilution

Each vial of JEVTANA (cabazitaxel) 60 mg/1.5 mL must first be mixed with the entire contents of supplied diluent. Once reconstituted, the resultant solution contains 10 mg/mL of JEVTANA.

When transferring the diluent, direct the needle onto the inside wall of JEVTANA vial and inject slowly to limit foaming. Remove the syringe and needle and gently mix the initial diluted solution by repeated inversions for at least 45 seconds to assure full mixing of the drug and diluent. Do not shake.

Let the solution stand for a few minutes to allow any foam to dissipate, and check that the solution is homogeneous and contains no visible particulate matter. It is not required that all foam dissipate prior to continuing the preparation process.

The resulting initial diluted JEVTANA solution (cabazitaxel 10 mg/mL) requires further dilution before administration. The second dilution should be done immediately (within 30 minutes) to obtain the final infusion as detailed in Step 2.

Step 2 – Second (Final) Dilution

Withdraw the recommended dose from the JEVTANA solution containing 10 mg/mL as prepared in Step 1 using a calibrated syringe and further dilute into a sterile 250 mL PVC-free container of either 0.9% sodium chloride solution or 5% dextrose solution for infusion. If a dose greater than 65 mg of JEVTANA is required, use a larger volume of the infusion vehicle so that a concentration of 0.26 mg/mL JEVTANA is not exceeded. The concentration of the JEVTANA final infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.

JEVTANA should not be mixed with any other drugs.

Remove the syringe and thoroughly mix the final infusion solution by gently inverting the bag or bottle.

JEVTANA final infusion solution (in either 0.9% sodium chloride solution or 5% dextrose solution) should be used within 8 hours at ambient temperature (including the one-hour infusion) or within a total of 24 hours if refrigerated (including the one-hour infusion).

As the final infusion solution is supersaturated, it may crystallize over time. Do not use if this occurs and discard.

Inspect visually for particulate matter, any crystals and discoloration prior to administration. If the JEVTANA first diluted solution or second (final) infusion solution is not clear or appears to have precipitation, it should be discarded.

Discard any unused portion.

2.6 Administration

The final JEVTANA infusion solution should be administered intravenously as a one-hour infusion at room temperature.

Use an in-line filter of 0.22 micrometer nominal pore size during administration.

The final JEVTANA infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions, i.e. 8 hours under ambient conditions (including the one-hour infusion) or for a total of 24 hours if refrigerated (including the one-hour infusion) [see Dosage and Administration (2.5)].

3.DOSAGE FORMS AND STRENGTHS

JEVTANA (cabazitaxel) Injection 60 mg/1.5 mL is supplied as a kit consisting of the following:

–

JEVTANA Injection 60 mg/1.5 mL: contains 60 mg cabazitaxel in 1.5 mL polysorbate 80,

–

Diluent for JEVTANA Injection 60 mg/1.5 mL: contains approximately 5.7 mL of 13% (w/w) ethanol in water for injection.

4.CONTRAINDICATIONS

JEVTANA should not be used in patients with neutrophil counts of ≤ 1,500/mm3.

JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80.

5.WARNINGS AND PRECAUTIONS

5.1 Neutropenia

Five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient's death was attributed to neutropenia without a documented infection.

G-CSF may be administered to reduce the risks of neutropenia complications associated with JEVTANA use. Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia. Therapeutic use of G-CSF and secondary prophylaxis should be considered in all patients considered to be at increased risk for neutropenia complications.

Monitoring of complete blood counts is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed [see Dosage and Administration (2.2)].

JEVTANA should not be administered to patients with neutrophils ≤ 1,500/mm3 [see Contraindications (4)].

If a patient experiences febrile neutropenia or prolonged neutropenia (greater than one week) despite appropriate medication (e.g., G-CSF), the dose of JEVTANA should be reduced [see Dosage and Administration (2.2)]. Patients can restart treatment with JEVTANA only when neutrophil counts recover to a level > 1,500/mm3 [see Contraindications (4)].

5.2 Hypersensitivity Reactions

All patients should be premedicated prior to the initiation of the infusion of JEVTANA [see Dosage and Administration (2.3)]. Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of JEVTANA, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe hypersensitivity reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of the JEVTANA infusion and appropriate therapy. Patients with a history of severe hypersensitivity reactions should not be re-challenged with JEVTANA [see Contraindications (4)].

5.3 Gastrointestinal Symptoms

Nausea, vomiting and severe diarrhea, at times, may occur. Death related to diarrhea and electrolyte imbalance occurred in the randomized clinical trial. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Patients should be treated with rehydration, anti-diarrheal or anti-emetic medications as needed. Treatment delay or dosage reduction may be necessary if patients experience Grade ≥ 3 diarrhea [see Dosage and Administration (2.2)].

5.4 Renal Failure

Renal failure, including four cases with fatal outcome, was reported in the randomized clinical trial. Most cases occurred in association with sepsis, dehydration, or obstructive uropathy [see Adverse Reactions (6.1)]. Some deaths due to renal failure did not have a clear etiology. Appropriate measures should be taken to identify causes of renal failure and treat aggressively.

5.5 Elderly Patients

In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) ≥ 65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose. Patients ≥ 65 years of age are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia [see Adverse Reactions (6) and Use in Specific Populations (8.5)].

5.6Hepatic Impairment

No dedicated hepatic impairment trial for JEVTANA has been conducted. Patients with impaired hepatic function (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN) were excluded from the randomized clinical trial.

Cabazitaxel is extensively metabolized in the liver, and hepatic impairment is likely to increase cabazitaxel concentrations.

Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs belonging to the same class as JEVTANA. JEVTANA should not be given to patients with hepatic impairment (total bilirubin ≥ ULN, or AST and/or ALT ≥ 1.5 × ULN).

5.7 Pregnancy

Pregnancy category D.

JEVTANA can cause fetal harm when administered to a pregnant woman. In non-clinical studies in rats and rabbits, cabazitaxel was embryotoxic, fetotoxic, and abortifacient at exposures significantly lower than those expected at the recommended human dose level.

There are no adequate and well-controlled studies in pregnant women using JEVTANA. If this drug is used during pregnancy, or if the patient becomes pregnant while taking 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 treatment with JEVTANA [see Use in Specific Populations (8.1)].

6.ADVERSE REACTIONS

The following serious adverse reactions are discussed in greater detail in another section of the label:

• Neutropenia [see Warnings and Precautions (5.1)].
• Hypersensitivity Reactions [see Warnings and Precautions (5.2)].
• Gastrointestinal Symptoms [see Warnings and Precautions (5.3)].
• Renal Failure [see Warnings and Precautions (5.4)].

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

The safety of JEVTANA in combination with prednisone was eva luated in 371 patients with hormone-refractory metastatic prostate cancer treated in a single randomized trial, compared to mitoxantrone plus prednisone.

Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (5%) JEVTANA-treated patients and 3 (< 1%) mitoxantrone-treated patients. The most common fatal adverse reactions in JEVTANA-treated patients were infections (n=5) and renal failure (n=4). The majority (4 of 5 patients) of fatal infection-related adverse reactions occurred after a single dose of JEVTANA. Other fatal adverse reactions in JEVTANA-treated patients included ventricular fibrillation, cerebral hemorrhage, and dyspnea.

The most common (≥ 10%) grade 1–4 adverse reactions were anemia, leukopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysguesia, cough, arthralgia, and alopecia.

The most common (≥ 5%) grade 3–4 adverse reactions in patients who received JEVTANA were neutropenia, leukopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia.

Treatment discontinuations due to adverse drug reactions occurred in 18% of patients who received JEVTANA and 8% of patients who received mitoxantrone. The most common adverse reactions leading to treatment discontinuation in the JEVTANA group were neutropenia and renal failure. Dose reductions were reported in 12% of JEVTANA-treated patients and 4% of mitoxantrone-treated patients. Dose delays were reported in 28% of JEVTANA-treated patients and 15% of mitoxantrone-treated patients.

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