Jevtana

Dosage Forms & Strengths

injectable solution

• 60mg/1.5mL

Prostate Cancer

Indicated in combination with prednisone for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen

25 mg/sq.meter IV q3Weeks; infuse IV over 1 hr  

Give with prednisone 10 mg PO qDay (ie, administer prednisone every day throughout course of treatment with cabazitaxel)

Dose modification

• Reduce dose to 20 mg/m² with following reactions
• Febrile neutropenia or prolonged (>1 week) neutropenia grade 3 or greater: Delay until neutrophil count is >1500/mm³, and then reinitiate at reduced dose; consider G-CSF for secondary prophylaxis
• Persistent diarrhea or diarrhea grade 3 or greater: Delay until improvement, and then reinitiate at reduced dose of 20 mg/m²
• Grade 2 peripheral neuropathy: Delay treatment until improvement or resolution; then reduce dose to 20 mg/m²
• Grade 3 peripheral neuropathy: Discontinue therapy
• Discontinue if reactions persist despite reduced dose

Hepatic Impairment

Mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x upper limit of normal (ULN) or AST >1.5 x ULN): Reduce dose to 20 mg/m²  

Moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 x ULN and AST = any): 15 mg/m²

Severe hepatic impairment (total bilirubine >3 x ULN): Contraindicated

Administration

Vial contents require 2 dilutions prior to administration

Use entire contents of accompanying diluent to achieve a concentration of 10 mg/mL

Antiemetic prophylaxis recommended as needed

Premedication regimen

• Initiate premedication 30 minutes before each dose Antihistamine (eg, diphenhydramine 25 mg IV) Corticosteroid (dexamethasone 8 mg IV or equivalent) H2-antagonist (eg, ranitidine 50 mg IV)

Other Information

Use cytotoxic precautions for handling, administration, and disposal

Safety and efficacy not established

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• ketoconazole
• itraconazole
• clarithromycin
• atazanavir
• indinavir
• nefazodone
• nelfinavir
• ritonavir
• saquinavir
• telithromycin
• voriconazole
• phenytoin
• carbamazepine
• rifampin
• rifabutin
• rifapentin
• phenobarbital

This is not a complete list of Jevtana drug interactions. Ask your doctor or pharmacist for more information.

Many drugs can interact with cabazitaxel. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with cabazitaxel. Give a list of all your medicines to any healthcare provider who treats you.

Prostate Cancer

Used in combination with prednisone for the treatment of hormone-refractory metastatic prostate cancer in patients whose disease has progressed following prior treatment with docetaxel-based therapy.1 2 3 4 Regimen improved overall survival compared with mitoxantrone and prednisone.1 2

No formal drug interaction studies to date.1

Metabolized principally by CYP3A4/5 and to a lesser extent by CYP2C8.1 4

Cabazitaxel does not induce CYP isoenzymes in vitro.1 In vitro data indicate low potential for inhibition of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5.1

Substrate of P-glycoprotein (P-gp), but not a substrate of multidrug resistance proteins MRP1 and MRP2 or breast cancer resistance protein (BCRP).1

Cabazitaxel 25 mg/m2 is unlikely to inhibit MRP1, MRP2, P-gp, or BCRP in vivo.1 Does not inhibit MRP1 or MRP2 in vitro; inhibition of P-gp transport and BCRP observed in vitro, but at concentrations at least 38 times those achieved clinically.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Potential pharmacokinetic interaction (increased plasma cabazitaxel concentrations).1 4 Avoid concomitant use.1

Moderate CYP3A inhibitors: Use concomitantly with caution.1

Potent CYP3A inducers: Potential pharmacokinetic interaction (decreased plasma cabazitaxel concentrations).1 4 Avoid concomitant use.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Unlikely to inhibit metabolism of drugs that are substrates of CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5.1

Specific Drugs

Distribution

Extent

Not known whether cabazitaxel is distributed into human milk.1 (See Lactation under Cautions.) Crosses placenta and distributes into milk in rats.1

Plasma Protein Binding

89–92% (mainly albumin and lipoproteins).1

Elimination

Metabolism

Extensively (>95%) metabolized in the liver, mainly by CYP3A4/5 and to a lesser extent by CYP2C8.1

Elimination Route

Eliminated in feces (76%) as metabolites and in urine (3.7%) as unchanged drug or metabolites; about 20 metabolites have been identified in urine or feces.1

Half-life

Terminal half-life: 95 hours.1

Special Populations

Hepatic impairment is expected to result in increased serum cabazitaxel concentrations.1 (See Hepatic Impairment under Cautions.)

Mild to moderate renal impairment (Clcr 30 to <80 mL/minute) does not substantially alter cabazitaxel pharmacokinetics.1 Not studied in severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease.1

Medicines used to treat cancer are very strong and can have many unwanted effects. Before receiving this medicine, make sure you understand all the risks and benefits. It is important for you to work closely with your doctor during your treatment.

You will receive this medicine in a hospital or cancer treatment center. A nurse or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins.

This medicine is usually given together with oral prednisone. Your doctor will tell you how much prednisone to take and how often.

You may also receive other medicines to help prevent allergic reactions and nausea from the injection.

Read and follow the patient instructions that come with this medicine. Talk to your doctor or pharmacist if you have any questions.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
• Signs of fluid and electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or very bad upset stomach or throwing up.
• Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight.
• Dizziness or passing out.
• Shortness of breath, a big weight gain, or swelling in the arms or legs.
• A heartbeat that does not feel normal.
• Feeling very tired or weak.
• Very bad and sometimes deadly kidney problems have happened with this medicine. Call your doctor right away if you are unable to pass urine or if you have blood in the urine or a change in the amount of urine passed.

• If you need to store Jevtana at home, talk with your doctor, nurse, or pharmacist about how to store it.

Bone Marrow Suppression

Bone marrow suppression manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported. In the randomized trial, five patients (1.3%) 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. Grade 3–4 neutropenia has been observed in 82% of patients treated with Jevtana in the randomized trial.

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 is contraindicated in patients with neutrophils ≤1,500/mm3 [see Contraindications (4)].

Caution is recommended in patients with hemoglobin <10 g/dl.

Hypersensitivity Reactions

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.

Premedicate all patients prior to the initiation of the infusion of Jevtana [see Dosage and Administration (2.1)]. Observe patients closely for hypersensitivity reactions, especially during the first and second infusions. Severe hypersensitivity reactions require immediate discontinuation of the Jevtana infusion and appropriate therapy. Jevtana is contraindicated in patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80 [see Contraindications (4)].

Gastrointestinal Adverse Reactions

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. Antiemetic prophylaxis is recommended. Treat patients 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)].

Gastrointestinal (GI) hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported in patients treated with Jevtana [see Adverse Reactions (6.2)]. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, adhesions, ulceration and GI bleeding.

Abdominal pain and tenderness, fever, persistent constipation, diarrhea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Jevtana treatment delay or discontinuation may be necessary.

Renal Failure

In the randomized clinical trial, renal failure of any grade occurred in 4% of the patients being treated with Jevtana, including four cases with fatal outcome. 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.

Respiratory Disorders

Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported and may be associated with fatal outcome [see Adverse Reactions (6.2)]. Patients with underlying lung disease may be at higher risk for these events. Acute respiratory distress syndrome may occur in the setting of infection.

Interrupt Jevtana if new or worsening pulmonary symptoms develop. Closely monitor, promptly investigate, and appropriately treat patients receiving Jevtana. Consider discontinuation. The benefit of resuming Jevtana treatment must be carefully evaluated.

Use in 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)].

Use in Patients with Hepatic Impairment

Cabazitaxel is extensively metabolized in the liver.

Jevtana is contraindicated in patients with severe hepatic impairment (total bilirubin >3 × ULN) [see Contraindications (4)]. Dose should be reduced for patients with mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) and moderate (total bilirubin >1.5 to ≤3.0 × ULN and any AST) hepatic impairment, based on tolerability data in these patients [see Dosage and Administration (2.3) and Use in Specific Populations (8.7)]. Administration of cabazitaxel to patients with mild and moderate hepatic impairment should be undertaken with caution and close monitoring of safety.

Embryo-Fetal Toxicity

Jevtana is not indicated for use in female patients.

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. Females of childbearing potential should be advised to avoid becoming pregnant during treatment with Jevtana [see Use in Specific Populations (8.1)].

The efficacy and safety of Jevtana in combination with prednisone were evaluated in a randomized, open-label, international, multicenter study in patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

A total of 755 patients were randomized to receive either Jevtana 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles.

This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3, platelets >100,000 cells/mm3, hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.

Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the Jevtana group.

Efficacy results for the Jevtana arm versus the control arm are summarized in Table 3 and Figure 1.

Investigator-assessed tumor response of 14.4% (95% CI: 9.6–19.3) was higher for patients in the Jevtana arm compared to 4.4% (95% CI: 1.6–7.2) for patients in the mitoxantrone arm, p=0.0005.

Call your doctor for instructions if you miss an appointment for your Jevtana injection.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.