46/18. Talazoparib-(TALZENNA)- @-(Oct-2018)- for the treatment of locally advanced or metastatic breast cancer
Drug Name:46/18. Talazoparib-(TALZENNA)- @-(Oct-2018)- for the treatment of locally advanced or metastatic breast cancer
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
• P-gp Inhibitors: Reduce TALZENNA dose for certain P-gp inhibitors, and monitor for potential increased adverse reactions as appropriate.
• BCRP Inhibitors: Monitor for potential increased adverse reactions.
Indication:
BRIEF SUMMARY
TALAZOPARIB- (Oct 2018)
Indn- For the treatment of Locallised Advanced or Metastatic Breast Cancer patients with Germine BRCA Mutations
Comp- Capsules: 0.25 mg, 1 mg • The recommended dose is 1 mg taken as a single oral daily dose, with or without food. • Patients should be treated until disease progression or unacceptable toxicity occurs.
ADR- • Most common (=20%) adverse reactions of any grade were: Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite. • Most common laboratory abnormalities (=25%) were: Decreases in hemoglobin, platelets, neutrophils,
CI- None.
WARNINGS -
• Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML has been reported in 2 out of 584 (0.3%) solid tumor patients treated with in clinical studies. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed
Pat Infrm-
• MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions.
This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called MDS or AML, which have been reported in patients who received PARP inhibitors
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U.S. FDA APPROVED DRUGS DURING 2018
Sr.No- 46
HIGHLIGHTS OF PRESCRIBING INFORMATION-
These highlights do not include all the information needed to use TALZENNA safely and effectively.
See full prescribing information for TALZENNA. TALZENNA™ (talazoparib) capsules, for oral use
Initial U.S. Approval: 2018
INDICATIONS AND USAGE-
TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA.
Adverse Reaction:
ADVERSE REACTIONS-
• Most common (=20%) adverse reactions of any grade were: Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite. • Most common laboratory abnormalities (=25%) were: Decreases in hemoglobin, platelets, neutrophils,
Contra-Indications:
CONTRAINDICATIONS- None.
WARNINGS AND PRECAUTIONS-
• Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML has been reported in 2 out of 584 (0.3%) solid tumor patients treated with TALZENNA in clinical studies. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed.
• Myelosuppression: TALZENNA may affect hematopoiesis and can cause anemia, neutropenia, and/or thrombocytopenia.
• Embryo-Fetal Toxicity: TALZENNA can cause fetal harm. Advise of the potential risk to the fetus and to use effective contraception.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE-
TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA.
DOSAGE AND ADMINISTRATION
• The recommended dose of TALZENNA is 1 mg taken as a single oral daily dose, with or without food.
• Patients should be treated until disease progression or unacceptable toxicity occurs.
• For adverse reactions, consider dosing interruption or dose reduction.
• For patients with moderate renal impairment (CLcr 30 - 59 mL/min), the recommended dose of TALZENNA is 0.75 mg once daily.
DOSAGE FORMS AND STRENGTHS- Capsules: 0.25 mg, 1 mg
Patient Information:
PATIENT COUNSELING INFORMATION-
Advise the patient to read the FDA-approved patient labeling (Patient Information)
• MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or a need for blood transfusions.
This may be a sign of hematological toxicity or a more serious uncommon bone marrow problem called MDS or AML, which have been reported in patients who received PARP inhibitors .
• Myelosuppression: Advise patients that TALZENNA may affect hematopoiesis and can cause anemia, leukopenia/neutropenia, and/or thrombocytopenia.
• Administration Instructions: Advise patients that TALZENNA can be taken once daily with or without food. Instruct patients that if they miss a dose of TALZENNA, they should take their next normal dose at the usual time. Also advise patients to swallow each capsule whole, and that capsules must not be opened or dissolved.
• Embryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with TALZENNA and for at least 7 months after the last dose.
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 after receiving the last dose of TALZENNA.
• Lactation: Advise patients not to breastfeed while taking TALZENNA and for at least 1 month after receiving the last dose.
This product’s label may have been updated. For current full prescribing information, please visit www.talzenna.com. LAB-1271-0.6.
Contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY-
1.Mechanism of Action- Talazoparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2, which play a role in DNA repair. In vitro studies with cancer cell lines that harbored defects in DNA repair genes, including BRCA 1 and 2, have shown that talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis.
Talazoparib anti-tumor activity was observed in human patient-derived xenograft breast cancer tumor models that expressed mutated or wild-type BRCA 1 and 2.
2. Pharmacodynamics- Cardiac Electrophysiology The effect of talazoparib on cardiac repolarization was evaluated in 37 patients with advanced solid tumors. Talazoparib had no large QTc prolongation (i.e., >20 ms) at the recommended dose.
3. Pharmacokinetics- After oral administration of 1 mg TALZENNA once daily in patients, the recommended dose, the geometric mean [% coefficient of variation (CV%)] of AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 208 (37%) ng.hr/mL and 16.4 (32%) ng/mL, respectively.
The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to 2 mg (2 times the recommended dose). The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within 2 to 3 weeks.
Absorption- Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between 1 to 2 hours after dosing.
Food Effect- Following a single oral dose of 0.5 mg TALZENNA with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean Cmax of talazoparib was decreased by 46%, the median Tmax was delayed from 1 to 4 hours, and AUCinf was not affected.
Distribution- The mean apparent volume of distribution of talazoparib is 420 L. In vitro, protein binding of talazoparib is 74% and is independent of talazoparib concentration.
Elimination- The mean terminal plasma half-life (±standard deviation) of talazoparib is 90 (±58) hours, and the mean apparent oral clearance (inter-subject variability) is 6.45 L/h (31.1%) in cancer patients.
Metabolism- Talazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways of talazoparib in humans include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation.
Excretion- Excretion of talazoparib in urine was the major route of elimination. Approximately 68.7% (54.6% unchanged) of the total administered radioactive dose [14C]talazoparib was recovered in urine, and 19.7% (13.6% unchanged) was recovered in feces.
Specific Populations- Age (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, 9 Others, and 63 Not Reported), and body weight (36 to 162 kg) had no clinically relevant effect on the PK of talazoparib.
Pediatric Patients- The pharmacokinetics of talazoparib have not been evaluated in patients < 30 mL/min) or in patients requiring hemodialysis.
Patients with Hepatic Impairment- Mild hepatic impairment (total bilirubin =1.0 × ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST) had no effect on the PK of talazoparib.
The PK of talazoparib have not been studied in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST).
Drug Interaction Studies-
Effect of Other Drugs on Talazoparib Effect of P-gp inhibitors: Coadministration with P-gp inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil in clinical studies increased talazoparib exposure by 45%
Coadministration with P-gp inhibitors including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin in clinical studies increased talazoparib exposure by 8%.
Effect of P-gp inducers: The effect of P-gp inducers on PK of talazoparib has not been studied.
Effect of BCRP inhibitors: The effect of BCRP inhibitors on PK of talazoparib has not been studied.Coadministration with BCRP inhibitors may increase talazoparib exposure.
Effect of acid-reducing agents on talazoparib: Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor 2 antagonists (H2RA), or other acid reducing agents has no effect on the absorption of talazoparib.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary- Based on findings from animal studies and its mechanism of action .
TALZENNA can cause embryo-fetal harm when administered to a pregnant woman.
There are no available data on TALZENNA use in pregnant women to inform a drug-associated risk.
Apprise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown.
In the general U.S. population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.
2. Lactation Risk Summary- There are no data on the presence of talazoparib in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child.
Because of the potential for serious adverse reactions in a breastfed child from talazoparib, advise lactating women not to breastfeed during treatment with TALZENNA and for at least 1 month after the final dose.
3. Females and Males of Reproductive Potential Pregnancy Testing- A pregnancy test is recommended for females of reproductive potential prior to initiating TALZENNA treatment.
Contraception Females- TALZENNA can cause fetal harm when administered to pregnant women.
Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of TALZENNA.
Males- Based on genotoxicity and animal reproduction studies, advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment with TALZENNA and for at least 4 months following the last dose.
Infertility Males- Based on animal studies, TALZENNA may impair fertility in males of reproductive potential.
4. Pediatric Use The safety and effectiveness of TALZENNA have not been established in pediatric patients.
5. Geriatric Use- In clinical trials of TALZENNA enrolling 494 patients with advanced solid tumors who received TALZENNA 1 mg daily as monotherapy, 85 (17%) patients were =65 years of age, and this included 19 (4%) patients who were =75 years old. There were 5 patients =85 years old.
No overall differences in safety or effectiveness of TALZENNA were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
6. Renal Impairment- Reduce the recommended dose of TALZENNA in patients with moderate renal impairment (CLcr 30 - 59 mL/min).
No dose adjustment is required for patients with mild renal impairment (CLcr 60 - 89 mL/min). TALZENNA has not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or patients requiring hemodialysis
7. Hepatic Impairment- TALZENNA has not been studied in patients with moderate hepatic impairment (total bilirubin >1.5 to 3.0 × upper limit of normal [ULN] and any aspartate aminotransferase [AST]) or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST).
No dose adjustment is required for patients with mild hepatic impairment (total bilirubin =1 × ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST).
OVERDOSAGE- There is no specific treatment in the event of TALZENNA overdose, and symptoms of overdose have not been established. In the event of overdose, discontinue treatment with TALZENNA, consider gastric decontamination, follow general supportive measures, and treat symptomatically.