JEVTANA is a microtubule inhibitor indicated in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing regimen.
IMPORTANT SAFETY INFORMATION
WARNING: NEUTROPENIA AND HYPERSENSITIVITY
- Neutropenic deaths have been reported. Obtain frequent blood counts to monitor for neutropenia. JEVTANA is contraindicated in patients with neutrophil counts of ≤1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features.
- 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 administration of appropriate therapy. Patients should receive premedication. JEVTANA is contraindicated in patients who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80.
JEVTANA is contraindicated in patients with neutrophil counts of ≤1,500/mm3, patients with a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80, patients with severe hepatic impairment (total bilirubin >3x upper limit of normal (ULN)), and in pregnant women (JEVTANA can cause fetal harm and potential loss of pregnancy).
WARNINGS AND PRECAUTIONS
Bone Marrow Suppression (BMS): BMS manifested as neutropenia, anemia, thrombocytopenia and/or pancytopenia may occur. Neutropenic deaths have been reported. Monitor blood counts frequently to determine if initiation of G-CSF and/or dosage modification is needed. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. 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. Caution is recommended in patients with hemoglobin <10 g/dl.
Increased Toxicities in Elderly Patients: Patients ≥65 years of age were more likely to experience fatal outcomes not related to disease progression and certain adverse reactions, including neutropenia and febrile neutropenia. Monitor closely.
Hypersensitivity Reactions: Severe hypersensitivity reactions can occur. Premedicate all patients with antihistamines, corticosteroids and H2 antagonists prior to JEVTANA. Observe patients closely, especially during the first and second infusions. Discontinue JEVTANA immediately if severe hypersensitivity occurs and treat as indicated.
Gastrointestinal (GI) Adverse Reactions: Nausea, vomiting and severe diarrhea may occur. Death related to diarrhea and electrolyte imbalance occurred in the clinical trial and mortality related to diarrhea has been reported. Intensive measures may be required for severe diarrhea and electrolyte imbalance. Rehydrate and treat with antiemetics and antidiarrheals as needed. If experiencing grade ≥3 diarrhea, dosage should be modified.
GI hemorrhage and perforation, ileus, enterocolitis, neutropenic enterocolitis, including fatal outcome, have been reported. Risk may be increased with neutropenia, age, steroid use, concomitant use of NSAIDs, antiplatelet therapy or anticoagulants, and 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 GI toxicity and should be evaluated and treated promptly. JEVTANA treatment delay or discontinuation may be necessary.
Renal Failure: Cases, including those with fatal outcomes, have been reported. Identify cause and manage aggressively.
Urinary Disorders including Cystitis: Cystitis, radiation cystitis, and hematuria, including that requiring hospitalization, has been reported with JEVTANA in patients who previously received pelvic radiation. Cystitis from radiation recall may occur late in treatment with JEVTANA. Monitor patients who previously received pelvic radiation for signs and symptoms of cystitis while on JEVTANA. Interrupt or discontinue JEVTANA in patients experiencing severe hemorrhagic cystitis. Medical and/or surgical supportive treatment may be required to treat severe hemorrhagic cystitis.
Respiratory Disorders: Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported and may be associated with fatal outcome. 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 Patients with Hepatic Impairment: JEVTANA dose should be reduced for patients with mild (total bilirubin >1 to ≤1.5 x ULN or AST >1.5 x ULN) and moderate (total bilirubin >1.5 to ≤3.0 x ULN and any AST) hepatic impairment, based on tolerability data in these patients. Administer JEVTANA 20 mg/m2 for mild hepatic impairment. Administer JEVTANA 15 mg/m2 for moderate hepatic impairment. Monitor closely.
ADVERSE REACTIONS (ARs)
Deaths due to causes other than disease progression within 30 days of last JEVTANA dose were reported in 22 (3.8%) patients in the 20 mg/m2 arm and 32 (5.4%) patients in the 25 mg/m2 arm. The most common fatal ARs were related to infections, and these occurred more commonly with 25 mg/m2(n=15) vs. 20 mg/m2 (n=8).
The most common 1-4 grade ARs and laboratory abnormalities (≥10%) with JEVTANA 20 mg/m2 or 25 mg/m2 were neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, and anorexia.
Grade 3-4 ARs occurring ≥5% more commonly with 25 mg/m2 versus 20 mg/m2 were leukopenia, neutropenia, and febrile neutropenia.
Please see full Prescribing Information, including Boxed WARNING.
ZALTRAP®, in combination with 5-fluorouracil, leucovorin, irinotecan-(FOLFIRI), is indicated for
patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed
following an oxaliplatin-containing regimen.
IMPORTANT SAFETY INFORMATION
WARNING: HEMORRHAGE, GASTROINTESTINAL PERFORATION, COMPROMISED WOUND HEALING
Severe and sometimes fatal hemorrhage, including gastrointestinal (GI) hemorrhage, has been reported in the patients who have received ZALTRAP in combination with FOLFIRI. Monitor patients for signs and symptoms of GI bleeding and other severe bleeding. Do not administer ZALTRAP to patients with severe hemorrhage.
GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP. Discontinue ZALTRAP therapy in patients who experience GI perforation.
Severe compromised wound healing can occur in patients receiving ZALTRAP/FOLFIRI. Discontinue ZALTRAP in patients with compromised wound healing. Suspend ZALTRAP for at least 4 weeks prior to elective surgery, and do not resume ZALTRAP for at least 4 weeks following major surgery and until the surgical wound is fully healed.
WARNINGS AND PRECAUTIONS
- Patients treated with ZALTRAP have an increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.
- Bleeding/hemorrhage (all grades) occurred in 38% of ZALTRAP/FOLFIRI patients vs. 19% of placebo/FOLFIRI patients. Grade 3–4 hemorrhagic events, including GI hemorrhage, hematuria, and post–procedural hemorrhage, occurred in 3% of ZALTRAP/FOLFIRI patients vs. 1% of placebo/FOLFIRI patients. Severe intracranial hemorrhage and pulmonary hemorrhage/hemoptysis including fatal events have occurred in patients receiving ZALTRAP.
- Monitor patients for signs and symptoms of bleeding. Do not initiate ZALTRAP in patients with severe hemorrhage. Discontinue ZALTRAP in patients who develop severe hemorrhage.
- GI perforation including fatal GI perforation can occur in patients receiving ZALTRAP.
- Across three clinical trials (colorectal, pancreatic, and lung cancer), GI perforation (all grades/Grade 3–4) occurred in 0.8% /0.8% of Zaltrap patients and 0.3% /0.2% for placebo patients.
- Monitor patients for signs and symptoms of GI perforation. Discontinue ZALTRAP in patients who experience GI perforation.
- ZALTRAP impairs wound healing in animal models. Grade 3 compromised wound healing occurred in 2 patients (0.3%) treated with ZALTRAP/FOLFIRI and none of the patients treated with placebo/FOLFIRI.
- Discontinue ZALTRAP in patients with compromised wound healing.
- Suspend ZALTRAP for at least 4 weeks prior to elective surgery and do not initiate/resume ZALTRAP until at least 4 weeks after major surgery and surgical wound is fully healed.
- For minor surgery such as central venous access port placement, biopsy, and tooth extraction, ZALTRAP may be initiated/resumed once the surgical wound is fully healed.
- Fistula formation involving GI and non–GI sites occurs at a higher incidence in patients treated with ZALTRAP. Fistulas (anal, enterovesical, enterocutaneous, colovaginal, intestinal sites) were reported in 1.5% (9/611) of ZALTRAP/FOLFIRI treated patients and 0.5% (3/605) of placebo/FOLFIRI patients. Grade 3 GI fistula formation occurred in 2 patients treated with Zaltrap (0.3%) and 1 placebo–treated patient (0.2%). Discontinue ZALTRAP therapy in patients who develop fistula.
- An increased risk of Grade 3–4 hypertension has been observed in patients receiving ZALTRAP.
- There is no clinical trial experience administering ZALTRAP to patients with NYHA class III or IV heart failure. In patients with mCRC, Grade 3 hypertension (defined as requiring adjustment in existing anti–hypertensive therapy or treatment with more than one drug) was reported in 1.5% of patients treated with placebo/FOLFIRI and 19% treated with ZALTRAP/FOLFIRI. Grade 4 hypertension (hypertensive crisis) was reported in 1 patient (0.2%) treated with ZALTRAP/FOLFIRI. Of patients treated with ZALTRAP/FOLFIRI who developed Grade 3–4 hypertension, 54% had onset during the first two cycles of treatment.
- Monitor blood pressure at least every two weeks, treat with appropriate anti–hypertensive therapy, and continue monitoring blood pressure regularly during ZALTRAP treatment. Temporarily suspend ZALTRAP until hypertension is controlled, and reduce ZALTRAP dose to 2 mg/kg for subsequent cycles. Discontinue ZALTRAP in patients with hypertensive crisis or hypertensive encephalopathy.
- Arterial thromboembolic events (ATE), including transient ischemic attack, cerebrovascular accident, and angina pectoris, occurred more frequently in patients who have received ZALTRAP. ATE occurred in 2.6% of ZALTRAP/FOLFIRI patients and 1.7% of placebo/FOLFIRI patients. Grade 3–4 events occurred in 11 patients (1.8%) treated with ZALTRAP/FOLFIRI and 4 patients (0.7%) treated with placebo/FOLFIRI. Discontinue ZALTRAP in patients who experience an ATE.
- Severe proteinuria, nephrotic syndrome, and thrombotic microangiopathy (TMA) occurred more frequently in patients treated with ZALTRAP.
- Proteinuria was reported in 62% of ZALTRAP/FOLFIRI patients compared to 41% of placebo/FOLFIRI patients. Grade 3–4 proteinuria occurred in 8% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients. Nephrotic syndrome occurred in 2 patients (0.5%) treated with ZALTRAP/FOLFIRI compared to none of the patients treated with placebo/FOLFIRI. TMA was reported in 3 of 2258 patients with cancer enrolled across completed studies.
- Monitor proteinuria by urine dipstick analysis and/or urinary protein creatinine ratio (UPCR) for the development or worsening of proteinuria. Obtain a 24-hour urine collection in patients with a dipstick of ≥2+ for protein or UPCR ˃1.
- Suspend ZALTRAP when proteinuria ≥2 grams/24 hours and resume ZALTRAP when proteinuria <2 grams/24 hours.
- If recurrent, suspend until proteinuria <2 grams/24hours and then reduce ZALTRAP dose to 2 mg/kg.
- Discontinue ZALTRAP if nephrotic syndrome or TMA develops.
- A higher incidence of neutropenic complications (febrile neutropenia and neutropenic infection) occurred in patients receiving ZALTRAP.
- Grade 3–4 neutropenia occurred in 37% of ZALTRAP/FOLFIRI patients compared to 30% of placebo/FOLFIRI patients. Grade 3–4 febrile neutropenia occurred in 4% of ZALTRAP/FOLFIRI patients compared to 2% of placebo/FOLFIRI patients. Grade 3–4 neutropenic infection/sepsis occurred in 1.5% of ZALTRAP/FOLFIRI patients compared to 1.2% of placebo/FOLFIRI patients.
- Monitor CBC with differential count at baseline and prior to initiation of each cycle of ZALTRAP. Delay administration of ZALTRAP/FOLFIRI until neutrophil count is ≥1.5 x 109/L.
- Incidence of severe diarrhea and dehydration is increased in patients treated with ZALTRAP/FOLFIRI.
- Grade 3–4 diarrhea was reported in 19% of ZALTRAP/FOLFIRI patients compared to 8% of placebo/FOLFIRI patients. Grade 3–4 dehydration was reported in 4% of ZALTRAP/FOLFIRI patients compared to 1% of placebo/FOLFIRI patients.
- The incidence of diarrhea is increased in patients ≥65 years of age compared to patients <65 years of age. Monitor closely.
- RPLS (also known as posterior reversible encephalopathy syndrome) was reported in 0.5% of 3795 patients treated with ZALTRAP monotherapy or in combination with chemotherapy. Confirm diagnosis of RPLS with MRI and discontinue ZALTRAP in patients who develop RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae or death.
- The most common adverse reactions (all grades, ≥20% incidence) reported at a higher incidence (2% or greater between–arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.
- The most common Grade 3–4 adverse reactions (≥5%) reported at a higher incidence (2% or greater between–arm difference) in the ZALTRAP/FOLFIRI arm, in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.
- Infections occurred at a higher frequency in patients receiving ZALTRAP/FOLFIRI (46%, all grades; 12%, Grade 3–4) than in patients receiving placebo/FOLFIRI (33%, all grades; 7%, Grade 3–4), including urinary tract infection, nasopharyngitis, upper respiratory tract infection, pneumonia, catheter site infection, and tooth infection.
- In patients with mCRC, venous thromboembolic events (VTE), consisting primarily of deep venous thrombosis and pulmonary embolism, occurred in 9% of patients treated with ZALTRAP/FOLFIRI and 7% of patients treated with placebo/FOLFIRI.
PREGNANCY AND NURSING MOTHERS
- ZALTRAP should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Females and males of reproductive potential should use highly effective contraception during and up to a minimum of 3 months after the last dose of treatment.
- It is not known whether ZALTRAP is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Please see full Prescribing Information, including Boxed WARNING.