HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use - LYNPARZA safely and effectively. See full prescribing information for - LYNPARZA. LYNPARZA - ® (olaparib ...
These highlights do not include all the information needed to use LYNPARZA safely and effectively. See full prescribing information for LYNPARZA.
LYNPARZA ® (olaparib) capsules, for oral use
Initial U.S. Approval: 2014
RECENT MAJOR CHANGES
Indications and Usage (1.1) 08/2017
Dosage and Administration (2.2) 01/2017
Dosage and Administration (2.5) 10/2016
Warnings and Precautions (5.1) 10/2016
Warnings and Precautions (5.3) 01/2017
INDICATIONS AND USAGE
Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. (1.1)
DOSAGE AND ADMINISTRATION
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To avoid substitution errors and overdose, do not substitute Lynparza capsules with Lynparza tablets on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. ( 2.2)
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Recommended dose is 400 mg taken orally twice daily with or without food. ( 2.3)
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Continue treatment until disease progression or unacceptable toxicity. ( 2.3)
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For adverse reactions, consider dose interruption of treatment or dose reduction. ( 2.4)
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For moderate renal impairment (CLcr 31-50 mL/min), reduce dose to 300 mg twice daily. ( 2.6)
DOSAGE FORMS AND STRENGTHS
Capsules: 50 mg. (3)
CONTRAINDICATIONS
None. (4)
WARNINGS AND PRECAUTIONS
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Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): occurred in patients exposed to Lynparza, and the majority of reports were fatal. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. (5.1)
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Pneumonitis: occurred in patients exposed to Lynparza, and some cases were fatal. Interrupt treatment if pneumonitis is suspected. Discontinue if pneumonitis is confirmed. (5.2)
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Embryo-Fetal Toxicity: Lynparza can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.3, 8.1, 8.3)
ADVERSE REACTIONS
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Most common adverse reactions (≥20%) in clinical trials were anemia, nausea, fatigue (including asthenia), vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash and abdominal pain/discomfort. (6.1)
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Most common laboratory abnormalities (≥25%) were increase in creatinine, mean corpuscular volume elevation, decrease in hemoglobin, decrease in lymphocytes, decrease in absolute neutrophil count, and decrease in platelets. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
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CYP3A Inhibitors: Avoid concomitant use of strong and moderate CYP3A inhibitors. If the inhibitor cannot be avoided, reduce the dose. ( 2.3, 7.2)
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CYP3A Inducers: Avoid concomitant use of strong and moderate CYP3A inducers. If a moderate CYP3A inducer cannot be avoided, be aware of a potential for decreased efficacy. ( 7.3)
USE IN SPECIFIC POPULATIONS
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Lactation: Advise women not to breastfeed. ( 8.2)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 8/2017
FULL PRESCRIBING INFORMATION: CONTENTS*
Table of Contents
1 INDICATIONS AND USAGE
1.1 Treatment of gBRCA-mutated Advanced Ovarian Cancer Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline ...
1.1 Treatment of gBRCA-mutated Advanced Ovarian Cancer
Lynparza is indicated as monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection - Select patients for the treatment of advanced ovarian cancer with Lynparza based on the presence of deleterious or suspected deleterious ...
2.2 Important Administration Instructions
Lynparza is also available as 100 mg and 150 mg tablets. DO NOT substitute Lynparza capsules (50 mg) with Lynparza tablets (100 mg and 150 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Refer to the full prescribing information for Lynparza tablets for specific tablet dosing.
2.3 Recommended Dosing
The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken orally twice daily with or without food, for a total daily dose of 800 mg. Continue treatment until disease progression or unacceptable toxicity.
If a patient misses a dose of Lynparza, instruct patients to take their next dose at its scheduled time.
Swallow capsule whole. Do not chew, dissolve, or open capsule. Do not take capsules which appear deformed or show evidence of leakage [see How Supplied/Storage and Handling (16.2)].
2.4 Dose Adjustments for Adverse Reactions
To manage adverse reactions, consider dose interruption of treatment or dose reduction.
The recommended dose reduction is to 200 mg (four 50 mg capsules) taken twice daily, for a total daily dose of 400 mg.
If a further final dose reduction is required, then reduce to 100 mg (two 50 mg capsules) taken twice daily, for a total daily dose of 200 mg.
2.5 Dose Modifications for Use with CYP3A Inhibitors
Avoid concomitant use of strong and moderate CYP3A inhibitors and consider alternative agents with less CYP3A inhibition. If the inhibitor cannot be avoided, reduce the Lynparza dose to 150 mg (three 50 mg capsules) taken twice daily for a strong CYP3A inhibitor or 200 mg (four 50 mg capsules) taken twice daily for a moderate CYP3A inhibitor [see Drug Interactions (7.2)].
2.6 Dose Modifications for Patients with Renal Impairment
Patients with mild renal impairment (CLcr 51-80 mL/min as estimated by Cockcroft-Gault) do not require an adjustment in Lynparza dosing. In patients with moderate renal impairment (CLcr 31-50 mL/min) the recommended dose reduction is to 300 mg (six 50 mg capsules) taken twice daily, for a total daily dose of 600 mg. The pharmacokinetics of olaparib have not been eva luated in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
3 DOSAGE FORMS AND STRENGTHS
Capsules (50 mg): white, opaque, marked in black ink with “OLAPARIB 50 mg” on the cap and the AstraZeneca logo on the body.
Capsules (50 mg): white, opaque, marked in black ink with “OLAPARIB 50 mg” on the cap and the AstraZeneca logo on the body.
4 CONTRAINDICATIONS
None.
None.
5 WARNINGS AND PRECAUTIONS
5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia - Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients ...
5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been confirmed in 6 out of 298 (2%) patients enrolled in a single arm trial of Lynparza monotherapy, in patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced cancers. In a randomized placebo controlled trial, MDS/AML occurred in 3 out of 136 (2%) patients with advanced ovarian cancer treated with Lynparza. Overall, MDS/AML were reported in <1% patients treated with Lynparza in clinical studies. The majority of MDS/AML reports were fatal, and the duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of previous cancer or of bone marrow dysplasia.
Monitor complete blood count testing at baseline and monthly thereafter. Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). For prolonged hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less 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 Lynparza.
5.2 Pneumonitis
Pneumonitis, including fatal cases, occurred in <1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Lynparza and initiate prompt investigation. If pneumonitis is confirmed, discontinue Lynparza.
5.3 Embryo-Fetal Toxicity
Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. Apprise pregnant women of the potential hazard to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].
6 ADVERSE REACTIONS
The following adverse reactions are discussed elsewhere in the labeling: • Myelodysplastic Syndrome/Acute Myeloid Leukemia - [see - Warnings and ...
The following adverse reactions are discussed elsewhere in the labeling:
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Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) ]
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Pneumonitis [see Warnings and Precautions (5.2) ]
6.1 Clinical Trial Experience
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.
Lynparza 400 mg twice daily as monotherapy, has been studied in 300 patients with gBRCA-mutated advanced ovarian cancer, and 223 of these patients had received 3 or more prior lines of chemotherapy.
In the 223 patients with gBRCA-mutated ovarian cancer who received 3 or more prior lines of chemotherapy (including 137 patients in Study 1 with measureable disease) [see Clinical Studies (14)] adverse reactions led to dose interruption in 40% of patients, dose reduction in 4%, and discontinuation in 7%. There were 8 (4%) patients with adverse reactions leading to death, two were attributed to acute leukemia, and one each was attributed to COPD, cerebrovascular accident, intestinal perforation, pulmonary embolism, sepsis, and suture rupture. The median exposure to Lynparza in these patients was 158 days.
Table 1 and Table 2 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with Lynparza.
The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Lynparza and not included in the table: cough, constipation, dysgeusia, peripheral edema, back pain, dizziness, headache, urinary tract infection, dyspnea, and rash.
The following adverse reactions and laboratory abnormalities have been identified in ≥1 to <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, hyperglycemia, anxiety, depression, insomnia, dysuria, urinary incontinence, vulvovaginal disorder, dry skin/ eczema, pruritus, hypertension, venous thrombosis (including pulmonary embolism), and hot flush.
Table 3 presents adverse reactions reported in ≥20% of patients from a randomized trial of Lynparza 400 mg twice daily as maintenance monotherapy compared to placebo in patients with platinum sensitive, relapsed, high-grade serous ovarian cancer following treatment with 2 or more platinum-containing regimens. Table 4 presents the laboratory abnormalities in patients from this randomized trial. Of the 96 patients with gBRCA-mutation, 53 received Lynparza, and 43 received placebo. The median duration on treatment with Lynparza was 11.1 months for patients with a gBRCA-mutation compared to 4.4 months for patients with gBRCA-mutation on placebo.
Adverse reactions led to dose interruptions in 26% of those receiving Lynparza and 7% of those receiving placebo; dose reductions in 15% of Lynparza and 5% of placebo patients; and discontinuation in 9% of Lynparza and 0% in placebo patients. One (2%) patient on Lynparza died as a result of an adverse reaction.
