TALZENNA- talazoparib tosylate capsule
Pfizer Laboratories Div Pfizer Inc
TALZENNA is indicated for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA [see Dosage and Administration (2.1)].
Select patients for the treatment of advanced breast cancer with TALZENNA based on the presence of germline BRCA mutations [see Indications and Usage (1), Clinical Studies (14)]. Information on the FDA-approved test for the detection of BRCA mutations is available at http://www.fda.gov/companiondiagnostics.
The recommended dose of TALZENNA is 1 mg taken orally once daily, with or without food.
The 0.25 mg capsule is available for dose reduction.
Patients should be treated until disease progression or unacceptable toxicity occurs.
The hard capsules should be swallowed whole and must not be opened or dissolved. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.
To manage adverse reactions, consider interruption of treatment with or without dose reduction based on severity and clinical presentation. Recommended dose reductions are indicated in Table 1 and Table 2. Treatment with TALZENNA should be discontinued if more than three dose reductions are required.
|Recommended starting dose||1 mg (one 1 mg capsule) once daily|
|First dose reduction||0.75 mg (three 0.25 mg capsules) once daily|
|Second dose reduction||0.5 mg (two 0.25 mg capsules) once daily|
|Third dose reduction||0.25 mg (one 0.25 mg capsule) once daily|
Table 2. Dose Modification and Management
Monitor complete blood counts monthly and as clinically indicated [see Warnings and Precautions (5.2)].
|Adverse Reactions||Withhold TALZENNA until levels resolve to||Resume TALZENNA|
|Hemoglobin <8 g/dL||≥9 g/dL||Resume TALZENNA at a reduced dose|
|Platelet count <50,000/μL||≥75,000/μL|
|Neutrophil count <1,000/μL||≥1500/µL|
|Non-hematologic Grade 3 or Grade 4||≤Grade 1||Consider resuming TALZENNA at a reduced dose or discontinue|
For patients with moderate renal impairment (CLcr 30 – 59 mL/min), the recommended dose of TALZENNA is 0.75 mg once daily. For patients with severe renal impairment (CLcr 15 – 29 mL/min), the recommended dose of TALZENNA is 0.5 mg once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Reduce the TALZENNA dose to 0.75 mg once daily when coadministered with certain P-gp inhibitors. For additional information on interacting P-gp inhibitors, see Drug Interactions (7.1) and Clinical Pharmacology (12.3).
When the P-gp inhibitor is discontinued, increase the TALZENNA dose (after 3–5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the P-gp inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].
- 0.25 mg capsule with an ivory cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 0.25″ in black)
- 1 mg capsule with a light red cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 1″ in black)
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been reported in patients who received TALZENNA. Overall, MDS/AML has been reported in 2 out of 584 (0.3%) solid tumor patients treated with TALZENNA in clinical studies. The duration of TALZENNA treatment in these two patients prior to developing MDS/AML was 4 months and 24 months, respectively. Both patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.
Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Monitor complete blood counts for cytopenia at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If the levels have not recovered after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.
Myelosuppression consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia, have been reported in patients treated with TALZENNA [see Adverse Reactions (6)]. Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 39%, 21%, and 15% of patients receiving TALZENNA. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients.
Monitor complete blood count for cytopenia at baseline and monthly thereafter. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. If this occurs, dose modifications (dosing interruption with or without dose reduction) are recommended [see Dosing Modifications (2.3)].
Based on its mechanism of action and findings from animal data, TALZENNA can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, administration of talazoparib to pregnant rats during the period of organogenesis caused fetal malformations and structural skeletal variations, and embryo-fetal death at exposures that were 0.24 times the area under the concentration-time curve (AUC) in patients receiving the recommended human dose of 1 mg daily. Apprise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of TALZENNA [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1)].
Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for at least 4 months following the last dose of TALZENNA [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]
- Myelosuppression [see Warnings and Precautions (5.2)]
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.
Treatment of gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer
The safety of TALZENNA as monotherapy was evaluated in gBRCAm patients with HER2-negative locally advanced or metastatic breast cancer who had previously received no more than 3 lines of chemotherapy for the treatment of locally advanced/metastatic disease. EMBRACA was a randomized, open-label, multi-center study in which 412 patients received either TALZENNA 1 mg once daily (n=286) or a chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare provider’s choice (n=126) until disease progression or unacceptable toxicity. The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA and 50% of those receiving chemotherapy; dose reductions due to any cause occurred in 53% of TALZENNA patients and 40% of chemotherapy patients. Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients and 6% chemotherapy patients.
Table 3 and Table 4 summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study.
|TALZENNAN=286 (%)||ChemotherapyN=126 (%)|
|Adverse Reactions||Grades 1–4||Grade 3||Grade 4||Grades 1–4||Grade 3||Grade 4|
|Abbreviations: AR=adverse reaction; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; N=number of patients.|
|Blood and lymphatic system disorders|
|Metabolism and nutrition disorders|
|Nervous system disorders|
|Skin and subcutaneous tissue disorders|
|General disorders and administration site conditions|
The following adverse reactions have been identified in <20% of the 286 patients receiving TALZENNA, and thus were not included in Table 3: abdominal pain (19%), dizziness (17%), leukopenia (17%), dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and lymphopenia (7%).
|TALZENNAN *=286 (%)||ChemotherapyN *=126 (%)|
|Parameter||Grades 1–4||Grade 3||Grade 4||Grades 1–4||Grade 3||Grade 4|
|Abbreviation: N=number of patients.|
|Decrease in hemoglobin||90||39||0||77||6||0|
|Decrease in leukocytes||84||14||0.3||73||22||2|
|Decrease in neutrophils||68||17||3||70||21||17|
|Decrease in lymphocytes||76||17||0.7||53||8||0.8|
|Decrease in platelets||55||11||4||29||2||0|
|Increase in glucose †||54||2||0||51||2||0|
|Increase in aspartate aminotransferase||37||2||0||48||3||0|
|Increase in alkaline phosphatase||36||2||0||34||2||0|
|Increase in alanine aminotransferase||33||1||0||37||2||0|
|Decrease in calcium||28||1||0||16||0||0|
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