Drug Safety-related Labeling Changes (SrLC)

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LYNPARZA (NDA-208558)

(OLAPARIB)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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07/10/2025 (SUPPL-31)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Pneumonitis

Additions and/or revisions underlined:

Pneumonitis, including severe and fatal cases, has occurred in patients treated with Lynparza.

In clinical studies, among patients who received Lynparza as a single agent or as part of a combination regimen [see Adverse Reactions (6.1)], the incidence of pneumonitis, including fatal cases, was 1.0% (29/2851).

. . .

5.4 Hepatotoxicity, Including Drug-Induced Liver Injury

Newly added subsection

Hepatotoxicity, including severe and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Lynparza [see Adverse Reactions (6.2)].

Evaluate bilirubin and transaminases at baseline and throughout treatment with Lynparza. For patients who develop abnormal liver tests after Lynparza, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity.

If DILI is suspected, withhold Lynparza. Upon confirmation of DILI, discontinue Lynparza.

6 Adverse Reactions

Addition of the following to the bulleted line listing:

. . .

• Hepatotoxicity, Including Drug-Induced Liver Injury [see Warnings and Precautions (5.4)]

. . .

 

6.1 Clinical Trials Experience

Extensive changes; please refer to label for complete information

 

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during post-approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary Disorders: Drug-induced liver injury.

. . .

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

. . .

Hepatotoxicity, Including Drug-Induced Liver Injury

Inform patients that liver problems, including drug-induced liver injury and abnormalities in liver tests, may develop during Lynparza treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.4)].

. . .

 

MEDICATION GUIDE

Additions and/or revisions underlined:

. . .

Lung problems (Pneumonitis). Lynparza can cause serious lung problems that can lead to death.

. . .

• Liver problems, including Drug-Induced Liver Injury (DILI). People taking Lynparza may develop liver problems which may be severe and can lead to death. Your healthcare provider should do blood tests before and during your treatment with Lynparza. Tell your healthcare provider right away if you notice discomfort on the right side of your stomach-area (abdominal), dark or “tea-colored” urine, or yellowing of your skin or the whites of your eyes (jaundice).

Your healthcare provide may change your dose, temporarily stop, or permanently stop treatment with Lynparza if you get certain side effects.

See “What are the possible side effects of LYNPARZA?” for more information about side effects.

. . .

What is Lynparza?

Lynparza is a prescription medicine used to treat adults who have:

• ovarian, fallopian tube, or primary peritoneal cancer:

• that is advanced and has a certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene. Lynparza is used. . .

• in combination with another anti-cancer medicine called bevacizumab when your cancer is advanced and homologous recombination deficiency (HRD) positive, which is identified by a certain type of abnormal BRCA gene or a positive laboratory tumor test for genomic instability. Lynparza is used as maintenance treatment after the cancer has responded to your first treatment with platinum-based chemotherapy.

• that has come back and has a certain type of inherited or acquired abnormal BRCA gene. Lynparza is used as maintenance treatment after the cancer has responded to treatment with platinum-based chemotherapy.

• human epidermal growth factor receptor 2 (HER2)-negative breast cancer with a certain type of inherited abnormal BRCA gene:

• with a high risk of recurrence. Lynparza is given after surgery (treatment after surgery is called adjuvant therapy). You should have received chemotherapy medicines before or after surgery to remove the tumor.

• that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive breast cancer, you should have either already received hormonal therapy or hormonal therapy is not the right treatment for you.

• pancreatic cancer (adenocarcinoma) that has spread to other parts of the body and has a certain type of abnormal inherited BRCA gene. Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of your first treatment with platinum-based chemotherapy.

• metastatic castration-resistant prostate cancer (mCRPC):

• with a certain type of inherited or acquired abnormal homologous recombination repair (HRR) genes. Lynparza is used when the cancer has spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone and has progressed after treatment with other anti-cancer medicines called enzalutamide or abiraterone.

• with a certain type of abnormal BRCA gene, and the cancer has spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone. Lynparza is used in combination with another anti-cancer medicine, abiraterone, together with the steroid medicine prednisone or prednisolone.

. . .

The most common side effects of Lynparza when used in combination with abiraterone and prednisone or prednisolone are:

. . .

Nausea or vomiting is common during treatment with Lynparza. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms. These are not all of the possible side effects of Lynparza.

. . .

11/06/2023 (SUPPL-28)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

(Additions and/or revisions underlined)

Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients treated with Lynparza and some cases were fatal.

In clinical studies, among 2219 patients with various BRCAm, gBRCAm, HRR gene-mutated or HRD- positive cancers who received Lynparza as a single agent or as part of combination regimen, consistent with approved indications, the cumulative incidence of MDS/AML was approximately 1.2% (26/2219) [see Adverse Reactions (6.1)]. Of these, 54% (14/26) had a fatal outcome. The median duration of therapy with Lynparza in patients who developed MDS/AML was approximately 2 years (range: < 6 months to > 4 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.

In SOLO1, patients with newly diagnosed advanced BRCAm ovarian cancer, the incidence of MDS/AML was 1.9% (5/260) in patients who received Lynparza and 0.8% (1/130) in patients who received placebo based on an updated analysis. In PAOLA-1, of patients with newly diagnosed advanced ovarian cancer with HRD-positive status, the incidence of MDS/AML was 1.6% (4/255) in patients who received Lynparza and 2.3% (3/131) in the control arm.

In SOLO2, patients with BRCAm platinum-sensitive relapsed ovarian cancer, the incidence of MDS/AML was 8% (15/195) in patients who received Lynparza and 4% (4/99) in patients who received placebo. The duration of Lynparza treatment prior to the diagnosis of MDS/AML ranged from 0.6 years to 4.5 years.

09/12/2023 (SUPPL-29)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

Extensive changes; please refer to label

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Newly added information:

Your healthcare provider will perform a test to make sure that Lynparza is right for you.

05/31/2023 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Venous Thromboembolism

Additions and/or revisions underlined

Venous thromboembolism (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza [see Adverse Reactions (6.1)].

In the combined data of two randomized, placebo-controlled clinical studies (PROfound and PROpel) in patients with metastatic castration-resistant prostate cancer (N=1180), VTE occurred in 8% of patients who received Lynparza, including pulmonary embolism in 6%. In the control arms, VTE occurred in 2.5% including pulmonary embolism in 1.5%.

Monitor patients for clinical signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined

…

Unless otherwise specified, the data described in the WARNINGS AND PRECAUTIONS reflect exposure to Lynparza as a single agent in 2901 patients; 2135 patients with exposure to 300 mg twice daily tablet dose including five controlled, randomized, trials (SOLO-1, SOLO-2, OlympiAD, POLO, and PROfound) and to 400 mg twice daily capsule dose in 766 patients in other trials that were pooled to conduct safety analyses. In addition to the 2901 patients, certain subsections in the WARNINGS AND PRECAUTIONS include adverse reactions observed with exposure to Lynparza with abiraterone (n=398) in PROpel. All patients with metastatic castration resistant prostate cancer received concomitant ADT or previous bilateral orchiectomy.

In the pooled safety population, 56% of patients were exposed for 6 months or longer and 28% were exposed for greater than one year in the Lynparza group.

…

Treatment of BRCA-mutated Metastatic Castration-Resistant Prostate Cancer in Combination with Abiraterone and Prednisone or Prednisolone

PROpel

The safety of Lynparza in combination with abiraterone and prednisone or prednisolone for the treatment of patients in the first-line mCRPC setting was investigated in PROpel [see Clinical Studies (14.8)].

Patients were randomized to receive either Lynparza tablets 300 mg orally twice daily plus abiraterone tablets 1000 mg once daily (Lynparza/abiraterone) (n=398), or placebo plus abiraterone 1000 mg once

daily (placebo/abiraterone) (n=396) until disease progression or unacceptable toxicity. Patients in both arms also received either prednisone or prednisolone 5 mg twice daily.

Fatal adverse reactions occurred in 6% of patients, including COVID-19 (3%) and pneumonias (0.5%).

Serious adverse reactions occurred in 39% of patients. Serious adverse reactions reported in > 2% of patients included anemia (6%), COVID-19 (6%), pneumonia (4.5%), pulmonary embolism (3.5%), and urinary tract infection (3%).

Permanent discontinuation of Lynparza due to adverse reactions occurred in 16% of patients treated in the Lynparza with abiraterone arm. The most common adverse reactions which resulted in permanent discontinuation of Lynparza were anemia (4.3%) and pneumonia (1.5%).

Dosage interruption of Lynparza due to adverse reactions occurred in 48% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage interruption of Lynparza were anemia (16%), COVID-19 (6%) fatigue (3.5%), nausea (2.8%), pulmonary embolism (2.3%), and diarrhea (2.3%).

Dose reduction of Lynparza due to adverse reactions occurred in 21% of patients treated in the Lynparza with abiraterone arm. The most common (>2%) adverse reactions requiring dosage reductions of Lynparza were anemia (11%) and fatigue (2.5%).

The most common adverse reactions (greater than or equal to 10%) in patients who received Lynparza/abiraterone were anemia (48%), fatigue (38%), nausea (30%), diarrhea (19%), decreased appetite (16%), lymphopenia (14%),

abdominal pain (13%), and dizziness (14%).

Tables 18 and 19 summarize adverse reactions and laboratory abnormalities in PROpel, respectively.

Please refer to label to view Table18 and 19.

…

Clinically relevant adverse reactions that occurred in <10% for patients receiving Lynparza plus abiraterone were headache (9%), VTE (8%), rash (7%), dysgeusia (6%), acute kidney injury (3%), and

stomatitis (2.5%).

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined

…

Of the 398 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with abiraterone and prednisone or prednisolone (PROpel), 268 (67%) patients were aged greater than or equal to 65 years, and this included 95 (24%) patients who were aged greater than or equal to 75 years.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

additions and/or revisions underlined:

…

What is Lynparza?

…

• prostate cancer with a certain type of abnormal inherited or acquired BRCA gene that has spread to other parts of the body (metastatic) and no longer responds to a medical or surgical treatment that lowers testosterone. Lynparza is used in combination with another anti-cancer medicine, abiraterone, together with the steroid medicine, prednisone or prednisolone.

  …

  What are the possible side effects of Lynparza? Lynparza may cause serious side effects.

  See “What is the most important information I should know about Lynparza?” The most common side effects of Lynparza when used alone are:

• nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.

  • tiredness or weakness

  • low white blood cell counts

  • low red blood cell counts

  • changes in the way food tastes

  • diarrhea

  • cough

  • loss of appetite

  • dizziness

  • headache          

  • shortness of breath

  • indigestion or heartburn

    The most common side effects of Lynparza when used in combination with abiraterone are:

  • low red blood cell counts

  • diarrhea

  • tiredness or weakness

  • loss of appetite

  • abdominal pain

  • nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.

  • low white blood cell counts provider if you get nausea or vomiting.  

  • dizziness

    …

10/27/2022 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Venous Thromboembolic Events

Additions and/or revisions underlined:

Venous thromboembolic events (VTE), including severe or fatal pulmonary embolism (PE), occurred in patients treated with Lynparza [see Adverse Reactions (6.1)]. VTE occurred in 7% of patients with metastatic castration resistant prostate cancer who received Lynparza plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study …

6 Adverse Reactions

Additions and/or revisions to bulleted line listing underlined:

• Venous Thromboembolic Events [see Warnings and Precautions (5.3)]

Following Table 2 Adverse Reactions in SOLO-1 (greater than or equal to 10% of Patients Who Received Lynparza), additions and/or revisions underlined:

In addition, the adverse reactions observed in SOLO-1 that occurred in <10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), VTE (3%), hypersensitivity (2%), MDS/AML (1%), dermatitis (1%), and increased mean cell volume (0.4%).

Following Table 6 Adverse Reactions in SOLO-2 (greater than or equal to 20% of Patients Who Received Lynparza), additions and/or revisions underlined:

In addition, the adverse reactions observed in SOLO-2 that occurred in <20% of patients receiving Lynparza were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%), thrombocytopenia (14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), MDS/AML (8%), edema (8%), rash (6%), VTE (5%), and lymphopenia (1%).

Following Table 8 Adverse Reactions* in Study 19 (greater than or equal to 20% of Patients Who Received Lynparza), additions and/or revisions underlined:

In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Lynparza were dysgeusia (16%), dizziness (15%), dyspnea (13%), pyrexia (10%), stomatitis (9%), edema (9%), increase in creatinine (7%), neutropenia (5%), thrombocytopenia (4%), leukopenia (2%), MDS/AML (1%), VTE (1%), and lymphopenia (1%).

Following Table 10 Adverse Reactions* in OlympiA (greater than or equal to 10% of Patients Who Received Lynparza), additions and/or revisions underlined:

In addition, adverse reactions in OlympiA that occurred in <10% of patients receiving Lynparza were cough (9.2%), lymphopenia (7%), dyspepsia (6%), upper abdominal pain (4.9%), rash (4.9%), dyspnea (4.2%), thrombocytopenia (4.2%), increase in creatinine (2%), VTE (0.5%), hypersensitivity (0.9%), dermatitis (0.5%), increase in mean corpuscular volume (0.2%), and MDS/AML (0.1%).

Following Table 12 Adverse Reactions* in OlympiAD (greater than or equal to 20% of Patients Who Received Lynparza), additions and/or revisions underlined:

In addition, adverse reactions in OlympiAD that occurred in <20% of patients receiving Lynparza were cough (18%), decreased appetite (16%), thrombocytopenia (11%), dysgeusia (9%), lymphopenia (8%), dyspepsia (8%), dizziness (7%), stomatitis (7%), upper abdominal pain (7%), rash (5%), increase in serum creatinine (3%), dermatitis (1%) and VTE (1%).

Following Table 14 Adverse Reactions* in POLO (Occurring in greater than or equal to 10% of Patients who Received Lynparza), additions and/or revisions underlined:

In addition, the adverse reactions observed in POLO that occurred in <10% of patients receiving Lynparza were cough (9%), abdominal pain upper (7%), blood creatinine increased (7%), dizziness (7%), headache (7%), dyspepsia (5%), leukopenia (5%), VTE (3%), hypersensitivity (2%), and lymphopenia (2%).

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

What is the most important information I should know about Lynparza? Lynparza may cause serious side effects, including:

Additions and/or revisions underlined:

Blood clots (venous thromboembolic events). Some people may develop a blood clot in a deep vein, usually in the leg (venous thrombosis), or a clot in the lungs (pulmonary embolism) which may be severe or lead to death. Tell your healthcare provider right away if you have any symptoms such as pain or swelling in an extremity, shortness of breath, chest pain, breathing that is more rapid than normal (tachypnea), or heart beats faster than normal (tachycardia). Your healthcare provider will monitor you for these symptoms and may prescribe blood thinner medicine.

What are the possible side effects of Lynparza? Lynparza may cause serious side effects.

See “What is the most important information I should know about Lynparza?”

The most common side effects of Lynparza are:

Newly added information:

• Low platelet counts

03/11/2022 (SUPPL-23)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

(Newly added information)

Adjuvant Treatment of BRCA-mutated HER2-negative High Risk Early Breast Cancer

OlympiA

The safety of Lynparza as monotherapy for the adjuvant treatment of patients with BRCA-mutated HER2- negative high risk early breast cancer was investigated in OlympiA [see Clinical Studies (14.5)]. This study was a randomized, double-blind, multi-center study in which patients received either Lynparza tablets 300 mg orally twice daily (n=911) or placebo (n=904) for a total of 1 year, or until disease recurrence, or unacceptable toxicity. The median duration of treatment was 1 year in both arms.

Dose interruptions due to an adverse reaction of any grade occurred in 31% of patients receiving Lynparza; dose reductions due to an adverse reaction occurred in 23% of patients receiving Lynparza. The most frequent adverse reactions leading to dose interruption of Lynparza were anemia (11%), neutropenia (6%), nausea (5%), leukopenia (3.5%), fatigue (3%), and vomiting (2.9%) and the most frequent adverse reactions leading to dose reduction of Lynparza were anemia (8%), nausea (4.7%), neutropenia (4.2%), fatigue (3.3%), leukopenia (1.8%), and vomiting (1.5%). Discontinuation due to adverse reactions occurred in 10% of patients receiving Lynparza. The adverse reactions that most frequently led to discontinuation of Lynparza were nausea (2%), anemia (1.8%), and fatigue (1.3%).

In addition, adverse reactions in OlympiA that occurred in <10% of patients receiving Lynparza were cough (9.2%), lymphopenia (7%), dyspepsia (6%), upper abdominal pain (4.9%), rash (4.9%), dyspnea

(4.2%), thrombocytopenia (4.2%), increase in creatinine (2%), hypersensitivity (0.9%), dermatitis (0.5%), increase in mean corpuscular volume (0.2%), and MDS/AML (0.1%).

Tables 12 and 13 summarize the adverse reactions and laboratory abnormalities, respectively, in patients in OlympiA.

Newly added: Table 12 Adverse Reactions* in OlympiA and Table 13 Laboratory Abnormalities Reported in Patients in OlympiA

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Medication Guide

Additions and revisions underlined:

Lynparza is a prescription medicine used to treat adults who have:

• human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with a certain type of inherited (germline) abnormal BRCA gene. Lynparza is given after surgery (treatment after surgery is called adjuvant therapy). You should have received chemotherapy medicines before or after surgery to remove the tumor. Your healthcare provider will perform a test to make sure that Lynparza is right for you.

01/31/2022 (SUPPL-21)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the 2901 patients with advanced solid tumors who received Lynparza as a single agent, 680 (23%) patients were aged greater than or equal to 65 years, and this included 206 (7%) patients who were aged greater than or equal to 75 years. Thirteen (0.4%) patients were aged greater than or equal to 85 years.

03/11/2021 (SUPPL-19)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

Additions and revisions underlined

Myelodysplastic syndrome (MDS)/Acute Myeloid Leukemia (AML) has occurred in patients treated with Lynparza and some cases were fatal.

In clinical studies enrolling 2901 patients with various cancers who received Lynparza as a single agent [see Adverse Reactions (6.1)], the cumulative incidence of MDS/AML was approximately 1.5% (43/2901). Of these, 51% (22/43) had a fatal outcome. The median duration of therapy with Lynparza in patients who developed MDS/AML was 2 years (range: < 6 months to > 10 years). All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy.

…

5.2 Pneumonitis

Additions and/or revisions underlined

In clinical studies enrolling 2901 patients with various cancers who received Lynparza as a single agent [see Adverse Reactions (6.1)], the incidence of pneumonitis, including fatal cases, was 0.8% (24/2901). If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions underlined

…

First-Line Maintenance Treatment of BRCA-mutated Advanced Ovarian Cancer

SOLO-1

…

In addition, the adverse reactions observed in SOLO-1 that occurred in <10% of patients receiving Lynparza were increased blood creatinine (8%), lymphopenia (6%), hypersensitivity (2%), MDS/AML (1%), dermatitis (1%), and increased mean cell volume (0.4%).

…

PAOLA-1

…

The adverse reactions that occurred in <10% of patients receiving Lynparza/bevacizumab were dysgeusia (8%), dyspnea (8%), stomatitis (5%), dyspepsia (4.3%), erythema (3%), dizziness (2.6%),

hypersensitivity (1.7%) and MDS/AML (0.7%).

…

Maintenance Treatment of Recurrent Ovarian Cancer

SOLO-2

…

In addition, the adverse reactions observed in SOLO-2 that occurred in <20% of patients receiving Lynparza were neutropenia (19%), cough (18%), leukopenia (16%), hypomagnesemia (14%),

thrombocytopenia (14%), dizziness (13%), dyspepsia (11%), increased creatinine (11%), MDS/AML (8%), edema (8%), rash (6%), and lymphopenia (1%).

…

Study 19

…

In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Lynparza were dysgeusia (16%), dizziness (15%), dyspnea (13%), pyrexia (10%), stomatitis (9%), edema (9%), increase in creatinine (7%), neutropenia (5%), thrombocytopenia (4%), leukopenia (2%), MDS/AML (1%) and lymphopenia (1%).

…

Advanced Germline BRCA-mutated Ovarian Cancer After 3 or More Lines of Chemotherapy

Pooled Data

…

The following adverse reactions and laboratory abnormalities have been identified in <10% of the 223 patients receiving Lynparza and not included in the table: leukopenia (9%), pyrexia (8%), peripheral neuropathy (5%), hypomagnesemia (5%), rash (5%), stomatitis (4%), MDS/AML (1.8%), and venous thrombosis (including pulmonary embolism) (1%).

…

03/11/2021 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions underlined

…

Skin and subcutaneous tissue disorders: Erythema nodosum, rash, dermatitis.

11/02/2020 (SUPPL-18)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Hypersensitivity (rash/dermatitis/angioedema).

05/19/2020 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

(Additions and/or revisions underlined)

In clinical studies enrolling 2351 patients with various cancers who received Lynparza as a single agent, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was <1.5% (28/2351) and the majority of events had a fatal outcome. Of these, 25/28 patients had a documented BRCA mutation, 2 patients had gBRCA wildtype and in 1 patient the BRCA mutation status was unknown. Additional cases of MDS/AML have been documented in patients treated with Lynparza in combination studies and in postmarketing reports. 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 received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (less than or equal to Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. 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

(Additions and/or revisions underlined)

In clinical studies enrolling 2351 patients with various cancers who received Lynparza as a single agent, the incidence of pneumonitis, including fatal cases, was <1% (20/2351). If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of the symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately.

5.4 Venous Thromboembolic Events

(Newly added subsection)

Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with metastatic castration resistant prostate cancer who received Lynparza plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving Lynparza and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following adverse reactions are discussed elsewhere in the labeling:

• Myelodysplastic Syndrome/Acute Myeloid Leukemia

• Pneumonitis

• Venous Thromboembolic Events

6.1 Clinical Trial Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 2351 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily as monotherapy, 596 (25%) patients were aged greater than or equal to 65 years, and this included 137 (6%) patients who were aged greater than or equal to 75 years. Seven (0.3%) patients were aged greater than or equal to 85 years.

Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab, 204 (38%) patients were aged greater than or equal to 65 years, and this included 31 (6%) patients who were aged greater than or equal to 75 years.

No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

What is the most important information I should know about Lynparza? Lynparza may cause serious side effects, including:

Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have ovarian cancer or breast cancer and who have received previous treatment with chemotherapy, radiotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with Lynparza. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with Lynparza.

Symptoms of low blood cell counts are common during treatment with Lynparza, but can be a sign of serious bone marrow problems, including MDS or AML. Symptoms may include:

• weakness                       blood in urine or stool

• weight loss                     shortness of breath

• fever                               feeling very tired

• frequent infections         bruising or bleeding more easily

Your healthcare provider will do blood tests to check your blood cell counts:

• before treatment with Lynparza

• every month during treatment with Lynparza

• weekly if you have low blood cell counts that last a long time. Your healthcare provider may stop treatment with Lynparza until your blood cell counts improve.

Lung problems (pneumonitis). Tell your healthcare provider if you have any new or worsening symptoms of lung problems, including shortness of breath, fever, cough, or wheezing. Your healthcare provider may do a chest x-ray if you have any of these symptoms. Your healthcare provider may temporarily or completely stop treatment if you develop pneumonitis. Pneumonitis may lead to death.

Blood clots (Venous Thromboembolic Events). Some people with prostate cancer who take Lynparza along with gonadotropin-releasing hormone (GnRH) analog therapy may develop a blood clot in a deep vein, usually in the leg (venous thrombosis) or a clot in the lung (pulmonary embolism). Tell your healthcare provider if you have any symptoms such as pain or swelling in an extremity, shortness of breath, chest pain, breathing that is more rapid than normal (tachypnea), or heart beats faster than normal (tachycardia). Your healthcare provider will monitor you for these symptoms and may prescribe blood thinner medicine.

What is Lynparza?

Lynparza is a prescription medicine used to treat adults who have:

…

• prostate cancer with certain inherited or acquired abnormal genes called homologous recombination repair (HRR genes). Lynparza is used when the cancer has spread to other parts of the body (metastatic), and no longer responds to a medical or surgical treatment that lowers testosterone, and has progressed after treatment with enzalutamide or abiraterone. Your healthcare provider will perform a test to make sure Lynparza is right for you.

…

What are the possible side effects of Lynparza? Lynparza may cause serious side effects.

See “What is the most important information I should know about Lynparza?” The most common side effects of Lynparza are:

• nausea or vomiting. Tell your healthcare provider if you get nausea or vomiting. Your healthcare provider may prescribe medicines to treat these symptoms.

• tiredness or weakness                         cough

• low red blood cell counts                      shortness of breath

• diarrhea                                                dizziness

• loss of appetite                                     indigestion or heartburn

• headache                                             low platelet counts

• low white blood cell counts                  upper stomach area (abdominal) pain

• changes in the way food tastes

These are not all of the possible side effects of Lynparza.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Venous Thromboembolic Events

Advise patients with metastatic castration-resistant prostate cancer to immediately report any signs or symptoms of thromboembolism such as pain or swelling in an extremity, shortness of breath, chest pain, tachypnea, and tachycardia.

…

05/08/2020 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1  Myelodysplastic Syndrome /Acute Myeloid Le ukemia

(Additions and/or revisions underlined)

Overall, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Lynparza monotherapy in clinical trials, including long-term follow up, was <1.5% (30/2783) and the majority of events had a fatal outcome. Of these, 26/30 patients had a documented BRCA mutation, 2 patients had gBRCA wildtype and in 2 patients the BRCA mutation status was unknown…

6 Adverse Reactions

6.1  Clinical Trial Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.5  Geriatric Use

(Additions and/or revisions underlined)

Of the 1585 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily as monotherapy, 443 (28%) patients were aged greater than or equal to 65 years, and this included 109 (7%) patients who were aged greater than or equal to  75 years. Six (0.4%) patients were aged greater than or equal to 85 years.

Of the 535 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily in combination with bevacizumab, 204 (38%) patients were aged greater than or equal to 65 years, and this included 31 (6%) patients who were aged greater than or equal to 75 years.

12/27/2019 (SUPPL-10)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.3 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

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 300 mg twice daily. Apprise pregnant women of the potential hazard to a fetus and the potential risk for loss of the pregnancy. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza. 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 3 months following the last dose of Lynparza.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Extensive changes; please refer to label)

7 Drug Interactions

7.1 Use with Anticancer Agents

(Subsection title revised)

7.2 Effect of Other Drugs on Lynparza

(Subsection title revised; Additions and/or revisions underlined)

Strong and Moderate CYP3A Inhibitors

Coadministration of CYP3A inhibitors can increase olaparib concentrations, which may increase the risk for adverse reactions. Avoid coadministration of strong or moderate CYP3A inhibitors. If the strong or moderate inhibitor must be coadministered, reduce the dose of Lynparza.

Strong and Moderate CYP3A Inducers

Concomitant use with a strong or moderate CYP3A inducer decreased olaparib exposure, which may reduce Lynparza efficacy. Avoid coadministration of strong or moderate CYP3A inducers.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Pregnancy Testing

Recommend pregnancy testing for females of reproductive potential prior to initiating treatment with Lynparza.

Contraception

Females

Lynparza can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for at least 6 months following the last dose.

Males

Based on findings in 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 3 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza.

8.4 Pediatric Use

(Additions and/or revisions underlined)

Safety and effectiveness of Lynparza have not been established in pediatric patients.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 687 patients with advanced solid tumors who received Lynparza tablets 300 mg orally twice daily as monotherapy, 146 (21%) patients were aged greater than or equal to 65 years, and this included 29 (4%) patients who were aged greater than or equal to 75 years. No patients were aged greater than or equal to 85 years. No overall differences in the safety or effectiveness of Lynparza were observed between these patients and younger patients.

8.6 Renal Impairment

(Additions and/or revisions underlined)

No dosage modification is recommended in patients with mild renal impairment (CLcr 51 to 80 mL/min estimated by Cockcroft-Gault). Reduce Lynparza dosage to 200 mg twice daily in patients with moderate renal impairment (CLcr 31 to 50 mL/min). There are no data in patients with severe renal impairment or end-stage disease (CLcr less than or equal to 30 mL/min)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

What is Lynparza?

Lynparza is a prescription medicine used to treat adults who have:

• advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with a certain type of inherited (germline) or acquired (somatic) abnormal BRCA gene. Lynparza is used as maintenance treatment after the cancer has responded to your first treatment with platinum-based  chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.

• ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, as maintenance treatment, when the cancer has come back. Lynparza is used after the cancer has responded to treatment with platinum-based chemotherapy.

• advanced ovarian cancer with a certain type of abnormal inherited BRCA gene, and have received treatment with 3 or more prior types of chemotherapy medicines. Your healthcare provider will perform a test to make sure that Lynparza is right for you.

• a certain type of abnormal inherited BRCA gene, human epidermal growth factor receptor 2 (HER2)-negative breast cancer that has spread to other parts of the body (metastatic). You should have received chemotherapy medicines, either before or after your cancer has spread. If you have hormone receptor (HR)-positive disease, you should have been treated with hormonal therapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.

• metastatic pancreatic cancer with a certain type of abnormal inherited BRCA gene. Lynparza is used as maintenance treatment after your cancer has not progressed on at least 16 weeks of treatment with platinum-based chemotherapy. Your healthcare provider will perform a test to make sure that Lynparza is right for you.

It is not known if Lynparza is safe and effective in children.

Before taking Lynparza, tell your healthcare provider about all of your medical conditions, including if you:

• have lung or breathing problems

• have kidney problems

• are pregnant, become pregnant, or plan to become pregnant. Lynparza can harm your unborn baby and may cause loss of pregnancy (miscarriage).

• If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with Lynparza.

• Females who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 6 months after the last dose of Lynparza. Talk to your healthcare provider about birth control methods that may be right for you. Tell your healthcare provider right away if you become pregnant or think you might be pregnant following treatment with Lynparza.

• Males with female partners who are pregnant or able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 3 months after the last dose of Lynparza.

• Do not donate sperm during treatment with Lynparza and for 3 months after your final dose.

• are breastfeeding or plan to breastfeed. It is not known if Lynparza passes into your breast milk. Do not breastfeed during treatment with Lynparza and for 1 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time.

Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. Taking Lynparza and certain other medicines may affect how Lynparza works and may cause side effects.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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 ‘myelodysplastic syndrome’ (MDS) or ‘acute myeloid leukemia’ (AML) which have been reported in patients treated with Lynparza.

Pneumonitis

Advise patients to contact their healthcare provider if they experience any new or worsening respiratory symptoms including shortness of breath, fever, cough, or wheezing.

Embryo-Fetal Toxicity

Inform pregnant women of the risk to a fetus and potential loss of the pregnancy. Advise females to inform their healthcare provider of known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 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 3 months after receiving the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza.

Lactation

Advise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose.

Drug Interactions

Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking Lynparza.

Nausea/Vomiting

Advise patients that mild or moderate nausea and/or vomiting is very common in patients receiving Lynparza and that they should contact their healthcare provider who will advise on available antiemetic treatment options.

12/19/2018 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trial Experience

(Extensive changes; please refer to labeling)

09/26/2018 (SUPPL-5)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.6 Hepatic Impairment

Additions and/or revisions underlined:

No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment. A 15% increase and an 8% increase in mean exposure (AUC), respectively, were observed in patients with mild and moderate hepatic impairment (Child-Pugh classification A and B) compared to patients with normal hepatic function. There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

01/12/2018 (SUPPL-1)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia

(additions underlined)

… All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of more than one primary malignancy or of bone marrow dysplasia.

…

5.3 Embryo-Fetal Toxicity

(additions underlined)

…

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 3 months following the last dose of Lynparza.

6 Adverse Reactions

6.1 Clinical Trial Experience

(additions underlined)

…

Treatment of gBRCAm HER2-negative Metastatic Breast Cancer

OlympiAD

The safety of Lynparza tablets as monotherapy was also evaluated in gBRCAm patients with HER2- negative metastatic breast cancer who had previously received up to two lines of chemotherapy for the treatment of metastatic disease in OlympiAD. This study was a randomized, open-label, multi-center study in which 296 patients received either Lynparza 300 mg twice daily (n=205) or a chemotherapy (capecitabine, eribulin, or vinorelbine) of the healthcare provider’s choice (n=91) until disease progression or unacceptable toxicity. The median duration of study treatment was 8.2 months in patients                 who received Lynparza and 3.4 months in patients who received chemotherapy. Dose interruptions due to an adverse reaction of any grade occurred in 35% of patients receiving Lynparza and 28% of those receiving chemotherapy; dose reductions due to an adverse reaction occurred in 25% of Lynparza patients and 31% of chemotherapy patients. Discontinuation occurred in 5% of Lynparza patients and 8% in chemotherapy patients.

Table 7 summarizes the adverse reactions that occurred in at least 20% of patients who received Lynparza in OlympiAD. Table 8 presents the laboratory abnormalities that occurred in at least 25% of patients who received Lynparza in OlympiAD.

Table 7 Adverse Reactionsa in OlympiAD (?20% of Patients who received Lynparza)

(please refer to label to view Table 7)

In addition, adverse reactions in OlympiAD that occurred in <20% of patients receiving Lynparza were cough, decreased appetite, thrombocytopenia, dysgeusia, lymphopenia, dizziness, dyspepsia, stomatitis, upper abdominal pain, rash, increase in serum creatinine and dermatitis.

 

Table 8 Laboratory Abnormalities Reported ?25% of Patients in OlympiAD

(please refer to label to view Table 8)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(additions underlined)

…

Males

Based on findings in 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 3 months following the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza.

8.5 Geriatric Use

(additions underlined)

In clinical studies of Lynparza enrolling 687 patients with advanced solid tumors who received Lynparza tablets 300 mg twice daily as monotherapy, 146 (21%) patients were aged ?65 years, and this included 29 (4%) patients who were aged greater than or equal to 75 years. No patients were aged ?85 years. No overall differences in the safety or effectiveness of Lynparza were observed between younger and older patients.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(additions underlined)

…

• 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 Lynparza and for 6 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 3 months after receiving the last dose of Lynparza. Advise male patients not to donate sperm during therapy and for 3 months following the last dose of Lynparza.

  …