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) capsules, for oral use
`Initial U.S. Approval: 2014
`
`-------------------------- 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)
`
`The indication is approved under accelerated approval based on objective
`response rate and duration of response. Continued approval for this indication
`may be contingent upon verification and description of clinical benefit in
`confirmatory trials. (1 1, 14)
`
`---------------------- DOSAGE AND ADMINISTRATION ---------------------
`Recommended dose is 400 mg taken twice daily. (2.2)
`•
`Continue treatment until disease progression or unacceptable toxicity.
`•
`(2.2)
`For adverse reactions, consider dose interruption of treatment or dose
`reduction. (2.3)
`
`•
`
`-------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Capsules: 50 mg (3)
`
`•
`
`•
`
`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)
`Embryo-Fetal toxicity: Lynparza can cause fetal harm. Advise females
`of reproductive potential of the potential risk to a fetus and to avoid
`pregnancy. (5.3, 8.1)
`
`----------------------------- ADVERSE REACTIONS -----------------------------
`• 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)
` 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 -----------------------------
`CYP3A Inhibitors: Avoid concomitant use of strong and moderate
`•
`CYP3A inhibitors. If the inhibitor cannot be avoided, reduce the dose.
`(2.3, 7.2)
`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)
`
`•
`
`----------------------------- CONTRAINDICATIONS -----------------------------
`None
`
`---------------------- USE IN SPECIFIC POPULATIONS ----------------------
`Nursing Mothers: Discontinue treatment or discontinue nursing. (8.3)
`•
`
`---------------------- WARNINGS AND PRECAUTIONS ----------------------
`• Myelodysplastic syndrome/Acute Myeloid Leukemia: (MDS/AML)
`occurred in patients exposed to Lynparza, and some cases were fatal.
`Monitor patients for hematological toxicity at baseline and monthly
`thereafter. Discontinue if MDS/AML is confirmed. (5.1)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`MEDICATION GUIDE
`
`Revised: 12/2014
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Treatment of gBRCA-mutated advanced ovarian cancer
`2 DOSAGE AND ADMINISTRATION
`2.1 Patient Selection
`2.2 Recommended Dosing
`2.3 Dose Adjustments for Adverse Reactions
`2.4 Dose Modifications for Use with CYP3A Inhibitors
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Myelodysplastic syndrome/Acute Myeloid Leukemia
`5.2 Pneumonitis
`5.3 Embryo-Fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Trial Experience
`7 DRUG INTERACTIONS
`7.1 Anticancer Agents
`7.2 Drugs that may Increase Olaparib Plasma Concentrations
`7.3 Drugs that may Decrease Olaparib Plasma Concentrations
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`Risk summary
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Females of Reproductive Potential
`8.7 Hepatic Impairment
`8.8 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`17 PATIENT COUNSELING INFORMATION
`MEDICATION GUIDE
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 1 of 16
`
`

`

`FULL PRESCRIBING INFORMATION
`
`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 BRCA mutated (as
`detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of
`chemotherapy.
`
`The indication is approved under accelerated approval based on objective response rate and duration of response [see
`Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification and description of
`clinical benefit in confirmatory trials.
`
`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 germline BRCA-mutations [see Indications and Usage (1) and Clinical Studies (14)]. Information
`on FDA-approved test for the detection of BRCA-mutations is available at http://www.fda.gov/companiondiagnostics.
`
`2.2 Recommended Dosing
`The recommended dose of Lynparza is 400 mg (eight 50 mg capsules) taken twice daily, 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)].
`
`2.3 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.
`
`2.4 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)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Lynparza (olaparib) is supplied as a white, opaque, hard capsule (50 mg), marked in black ink with “OLAPARIB 50 mg”
`on the cap and the AstraZeneca logo on the body.
`
`4 CONTRAINDICATIONS
`
`None
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 2 of 16
`
`

`

`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
`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 22 of 2,618
`(<1%) patients treated with Lynparza. The majority of MDS/AML cases (17 of 22 cases) 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 patients had previous chemotherapy with platinum agents and/or other DNA damaging agents.
`
`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 (≤CTCAE Grade 1). For prolonged
`hematological toxicities, interrupt Lynparza and monitor blood counts weekly until recovery. If the levels have not
`recovered to CTCAE 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. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving
`the recommended human dose of 400 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the
`patient of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
`
`Advise females of reproductive potential to avoid becoming pregnant while taking Lynparza. If contraceptive methods
`are being considered, use effective contraception during treatment and for at least one month after receiving the last dose
`of Lynparza [see Use in Specific Populations (8.6)].
`
`6 ADVERSE REACTIONS
`
`The following adverse reactions are discussed elsewhere in the labeling:
`
`• Myelodysplastic syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1)]
`
`• 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
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 3 of 16
`
`

`

`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. Table 1 presents the frequency of adverse
`reactions reported in ≥20% of 223 patients (in 6 studies) with gBRCA-mutated advanced ovarian cancer who had received
`3 or more prior lines of chemotherapy who were treated with Lynparza 400 mg twice daily. The median exposure to
`Lynparza in these patients was 158 days.
`
`Table 1 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Advanced Ovarian
`Cancer Receiving Lynparza
`
`
`
`
`Adverse Reaction
`
`Blood and Lymphatic disorders
`Anemia
`Gastrointestinal disorders
`Abdominal pain/discomfort
`Decrease appetite
`Nausea
`Vomiting
`Diarrhea
`Dyspepsia
`General disorders
`Fatigue/asthenia
`Infections and infestations
`Nasopharyngitis/URI
`Musculoskeletal and Connective Tissue disorders
`Arthralgia/musculoskeletal pain
`Myalgia
`
`
`
`3 or more lines of prior chemotherapy
`Grades 3-4
`Grades 1-4
`N=223
`N=223
`%
`%
`
`34
`
`43
`22
`64
`43
`31
`25
`
`66
`
`26
`
`21
`22
`
`18
`
`8
`1
`3
`4
`1
`0
`
`8
`
`0
`
`0
`0
`
`Table 2 presents the frequency of abnormal laboratory findings in the 223 patients with gBRCA-mutated advanced ovarian
`cancer who had received three or more prior lines of chemotherapy receiving Lynparza 400 mg twice daily.
`
`Table 2 Laboratory Abnormalities Reported in Patients with gBRCA-Mutated Advanced Ovarian Cancer
`Receiving Lynparza
`
`Laboratory Parameter*
`
`3 or more lines of prior chemotherapy
`Grades 3-4
`Grades 1-4
`N=223
`N=223
`%
`%
`90
`15
`Decrease in hemoglobin (anemia)
`25
`7
`Decrease in absolute neutrophil count (neutropenia)
`30
`3
`Decrease in platelets (thrombocytopenia)
`56
`17
`Decrease in lymphocytes (lymphopenia)
`57
`-
`Mean corpuscular volume elevation
`Increase in creatinine*
`30
`2
`* Patients were allowed to enter clinical studies with laboratory values of CTCAE grade 1.
`
`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, dysguesia, 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
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 4 of 16
`
`

`

`incontinence, vulvovaginal disorder, dry skin/ eczema, pruritis, 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.
`
`Table 3 Adverse Reactions Reported in ≥20% of Patients with gBRCA-Mutated Ovarian Cancer in the
`Randomized Trial
`
`Lynparza
`N=53
`
`
`Grades 1-4
`%
`
`25
`
`Grades 3-4
`%
`
`4
`
`Placebo
`N=43
`
`
`Grades 1-4
`%
`
`7
`
`Grades 3-4
`%
`
`2
`
`47
`25
`75
`32
`28
`25
`21
`
`68
`
`
`43
`
`
`32
`25
`25
`
`25
`
`
`0
`0
`2
`4
`4
`0
`0
`
`6
`
`
`0
`
`
`4
`2
`6
`
`0
`
`
`58
`14
`37
`9
`21
`14
`9
`
`53
`
`
`16
`
`
`21
`12
`21
`
`19
`
`
`2
`0
`0
`0
`2
`0
`0
`
`2
`
`
`0
`
`
`0
`0
`0
`
`2
`
`
`Adverse Reactions
`
`
`
`Blood and Lymphatic disorders
`Anemia
`Gastrointestinal disorders
`Abdominal pain/discomfort
`Decreased appetite
`Nausea
`Vomiting
`Diarrhea
`Dyspepsia
`Dysgeusia
`General disorders
`Fatigue (including asthenia,
`lethargy)
`Infections and infestations
`Nasopharyngitis/Pharyngitis/URI
`Musculoskeletal and Connective
`tissue disorders
`Arthralgia/Musculoskeletal pain
`Myalgia
`Back pain
`Nervous system disorder
`Headache
`Respiratory, Thoracic, Mediastinal
`disorders
` Cough
`Skin and Subcutaneous Tissue
`Dermatitis/Rash
`
`21
`
`25
`
`0
`
`0
`
`14
`
`14
`
`0
`
`0
`
`
`Table 4 Laboratory Abnormalities in Patients with gBRCA-Mutated Ovarian Cancer in the Randomized
`Trial
`
`Laboratory parameter*
`
`Lynparza
`
`Placebo
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 5 of 16
`
`

`

`
`
`N=53
`
`
`Grades 1-4
`Grades 3-4
`Grades 1-4
`%
`%
`%
`58
`8
`85
`Decrease in hemoglobin
`23
`8
`32
`Decrease in absolute neutrophil count
`19
`6
`26
`Decrease in platelets
`44
`-
`85
`Mean corpuscular volume elevation
`Increase in creatinine*
`5
`0
`26
`* Patients were allowed to enter clinical studies with laboratory values of CTCAE Grade 1.
`
`N=43
`
`
`Grades 3-4
`%
`2
`0
`0
`-
`0
`
`7 DRUG INTERACTIONS
`
`Olaparib is primarily metabolized by CYP3A.
`
`7.1 Anticancer Agents
`Clinical studies of Lynparza in combination with other myelosuppressive anticancer agents, including DNA damaging
`agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
`
`7.2 Drugs that may Increase Olaparib Plasma Concentrations
`In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 2.7-fold.
`A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 2-fold.
`
`Avoid concomitant use of strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, ketoconazole,
`voriconazole, nefazodone, posaconazole, ritinovir, lopinavir/ritinovir, indinavir, saquinavir, nelfinavir, boceprevir,
`telaprevir) and moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib,
`darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil). If the strong or moderate
`CYP3A inhibitors must be co-administered, reduce the dose of Lynparza [see Dosage and Administration (2.4)].
`
`Avoid grapefruit and Seville oranges during Lynparza treatment [see Dosage and Administration (2.4) and Clinical
`Pharmacology (12.3)].
`
`7.3 Drugs that may Decrease Olaparib Plasma Concentrations
`In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A
`moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by 50-60%.
`
`Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampicin, carbamazepine, St. John’s Wort) and
`moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin). If a moderate CYP3A inducer
`cannot be avoided, be aware of a potential for decreased efficacy of Lynparza [see Clinical Pharmacology (12.3)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`Pregnancy Category D [see Warnings and Precautions (5.3)]
`
`Risk summary
`Lynparza can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in
`animals. Olaparib was teratogenic and caused embryo-fetal toxicity in rats at exposures below those in patients receiving
`the recommended human dose of 400 mg twice daily. If this drug is used during pregnancy, or if a patient becomes
`pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for loss of the
`pregnancy.
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 6 of 16
`
`

`

`Animal Data
`
`In a fertility and early embryonic development study in female rats, olaparib was administered orally for 14 days before
`mating through to day 6 of pregnancy, which resulted in increased post-implantation loss at a dose level of 15 mg/kg/day
`(with maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended dose).
`
`In an embryo-fetal development study, pregnant rats received oral doses of 0.05 and 0.5 mg/kg/day olaparib during the
`period of organogenesis. A dose of 0.5 mg/kg/day (with maternal systemic exposures approximately 0.3% of human
`exposure (AUC0-24h) at the recommended dose) caused embryo-fetal toxicities including increased post-implantation loss
`and major malformations of the eyes (anophthalmia, microphthalmia), vertebrae/ribs (extra rib or ossification center;
`fused or absent neural arches, ribs, and sternebrae), skull (fused exoccipital) and diaphragm (hernia). Additional
`abnormalities or variants included incomplete or absent ossification (vertebrae/sternebrae, ribs, limbs) and other findings
`in the vertebrae/sternebrae, pelvic girdle, lung, thymus, liver, ureter and umbilical artery. Some findings noted above in
`the eyes, ribs and ureter were observed at a dose of 0.05 mg/kg/day olaparib at lower incidence.
`
`8.3 Nursing Mothers
`It is not known whether olaparib is excreted in human milk. Because many drugs are excreted in human milk and because
`of the potential for serious adverse reactions in nursing infants from olaparib, a decision should be made whether to
`discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
`
`8.4 Pediatric Use
`The safety and efficacy of Lynparza has not been established in pediatric patients.
`
`8.5 Geriatric Use
`In clinical studies of Lynparza enrolling 735 patients with advanced solid tumors [the majority (69%) of whom had
`ovarian cancer] who received Lynparza 400 mg twice daily as monotherapy, 148 (20%) of patients were aged ≥65 years.
`The safety profile was similar irrespective of age with the exception of AEs of CTCAE ≥3 which were reported more
`frequently in patients aged ≥65 years (53.4%) than those <65 years (43.4%). No individual adverse event or System
`Organ Class accounted for this observed difference.
`
`8.6 Females of Reproductive Potential
`Lynparza can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise
`female patients of reproductive potential to avoid pregnancy while taking Lynparza. If contraceptive methods are being
`considered, use highly effective contraception during treatment with Lynparza and for at least one month following the
`last dose of Lynparza. Instruct patients to contact their healthcare provider if they become pregnant, or if pregnancy is
`suspected, while taking Lynparza.
`
`8.7 Hepatic Impairment
`The effect of hepatic impairment on exposure to Lynparza has not been studied. Patients with bilirubin >1.5 X ULN and
`AST/ALT ≥2.5 X ULN (≥5 X ULN in the presence of liver metastases) were excluded from Lynparza clinical trials.
`There are no data in patients with baseline hepatic impairment (serum bilirubin >1.5 X ULN) [see Clinical Pharmacology
`(12.3)].
`
`8.8 Renal Impairment
`Based on preliminary data, a 1.5 fold increase in mean exposure (AUC) was observed in patients with mild renal
`impairment (CLcr = 50-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose
`adjustment to the starting dose is required in patients with CLcr of 50 to 80 mL/min, but patients should be monitored
`closely for toxicity. There are no data in patients with moderate or severe renal impairment (CLcr <50 mL/min) or
`patients on dialysis [see Clinical Pharmacology (12.3)].
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 7 of 16
`
`

`

`10 OVERDOSAGE
`
`There is no specific treatment in the event of Lynparza overdose, and symptoms of overdose are not established. In the
`event of an overdose, physicians should follow general supportive measures and should treat symptomatically.
`
`11 DESCRIPTION
`
`Olaparib is an inhibitor of the mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme.
`
`The chemical name is 4-[(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorophenyl)methyl]phthalazin-1(2H)-
`one and it has the following chemical structure:
`
`
`The empirical molecular formula for Lynparza is C24H23FN4O3 and the relative molecular mass is 434.46.
`
`Olaparib is a crystalline solid, is non-chiral and shows pH-independent low solubility of approximately 0.1 mg/mL across
`the physiological pH range.
`
`Lynparza is available in 50 mg capsules for oral administration. Each capsule contains olaparib as the active ingredient
`and the following inactive ingredients:
`
`• Capsule content: lauroyl polyoxylglycerides
`
`• Capsule shell: hypromellose, titanium dioxide, gellan gum, potassium acetate
`
`• Capsule printing ink: shellac, ferrosoferric oxide
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`Lynparza is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1, PARP2, and PARP3.
`PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle regulation, and DNA
`repair. Olaparib has been shown to inhibit growth of select tumor cell lines in vitro and decrease tumor growth in mouse
`xenograft models of human cancer both as monotherapy or following platinum-based chemotherapy. Increased
`cytotoxicity and anti-tumor activity following treatment with olaparib were noted in cell lines and mouse tumor models
`with deficiencies in BRCA. In vitro studies have shown that olaparib-induced cytotoxicity may involve inhibition of
`PARP enzymatic activity and increased formation of PARP-DNA complex, resulting in disruption of cellular homeostasis
`and cell death.
`
`12.3 Pharmacokinetics
`Absorption
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 8 of 16
`
`

`

`Following oral administration of olaparib via the capsule formulation, absorption is rapid with peak plasma concentrations
`typically achieved between 1 to 3 hours after dosing. On multiple dosing there is no marked accumulation (accumulation
`ratio of 1.4 – 1.5 for twice daily dosing), with steady state exposures achieved within 3 to 4 days.
`
`Limited data suggest that the systemic exposure (AUC) of olaparib increases less than proportionally with dose over the
`dose range of 100 to 400 mg, but the PK data were variable across trials.
`
`Co-administration with a high fat meal slowed the rate (Tmax delayed by 2 hours) of absorption, but did not significantly
`alter the extent of olaparib absorption (mean AUC increased by approximately 20%).
`
`Distribution
`
`Olaparib had a mean (± standard deviation) apparent volume of distribution at steady state of 167 ± 196 L after a single
`400 mg dose of olaparib. The in vitro protein binding of olaparib at plasma concentrations achieved following dosing at
`400 mg twice daily is approximately 82%.
`
`Metabolism
`
`In vitro, CYP3A4 was shown to be the enzyme primarily responsible for the metabolism of olaparib.
`
`Following oral dosing of 14C-olaparib to female patients, unchanged olaparib accounted for the majority of the circulating
`radioactivity in plasma (70%). It was extensively metabolized with unchanged drug accounting for 15% and 6% of
`radioactivity in urine and feces, respectively. The majority of the metabolism is attributable to oxidation reactions with a
`number of the components produced undergoing subsequent glucuronide or sulfate conjugation.
`
`Excretion
`
`A mean (± standard deviation) terminal plasma half-life of 11.9 ± 4.8 hours and apparent plasma clearance of 8.6 ± 7.1L/h
`were observed after a single 400 mg dose of olaparib.
`
`Following a single dose of 14C-olaparib, 86% of the dosed radioactivity was recovered within a 7-day collection period,
`44% via the urine and 42% via the feces. The majority of the material was excreted as metabolites.
`
`Based on preliminary data from a dedicated renal impairment trial, the mean AUC and Cmax of olaparib increased by 1.5-
`and 1.2-fold, respectively, when olaparib was dosed in patients with mild renal impairment (CLcr = 50-80 mL/min; N=14)
`compared to those with normal renal function (CLcr >80 mL/min; N=8). There are no data in patients with CLcr < 50
`mL/min or in patients on dialysis.
`
`Drug Interactions
`
`In vitro, olaparib was an inhibitor of CYP3A4 and an inducer of CYP2B6 at higher concentrations than are clinically
`achieved. Olaparib produced little/no inhibition of other CYP isozymes. In vitro studies have shown that olaparib is a
`substrate of CYP3A4.
`
`Based on the data from a drug-interaction trial (N=57), the AUC and Cmax of olaparib increased by 2.7- and 1.4-fold,
`respectively, when olaparib was administered in combination with itraconazole, a strong CYP3A inhibitor. Simulations
`using physiologically-based pharmacokinetic (PBPK) models suggested that a moderate CYP3A inhibitor (fluconazole)
`may increase the AUC and Cmax of olaparib by 2- and 1.1-fold, respectively.
`
`Based on the data from a drug-interaction trial (N=22), the AUC and Cmax of olaparib decreased by 87% and 71%,
`respectively, when olaparib was administered in combination with rifampicin, a strong CYP3A inducer. Simulations
`using PBPK models suggested that a moderate CYP3A inducer (efavirenz) may decrease the AUC and Cmax of olaparib by
`50 - 60% and 20 - 30%, respectively.
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 9 of 16
`
`

`

`In vitro studies have shown that olaparib is a substrate of P-gp and an inhibitor of BCRP, OATP1B1, OCT1, OCT2,
`OAT3, MATE1 and MATE2K. The clinical relevance of these findings is unknown.
`
`13 NONCLINICAL TOXICOLOGY
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenicity studies have not been conducted with olaparib.
`
`Olaparib was clastogenic in an in vitro chromosomal aberration assay in mammalian CHO cells and in an in vivo rat bone
`marrow micronucleus assay. This clastogenicity is consistent with genomic instability resulting from the primary
`pharmacology of olaparib and indicates potential for genotoxicity in humans. Olaparib was not mutagenic in a bacterial
`reverse mutation (Ames) test.
`
`In a fertility study, female rats received oral olaparib at doses of 0.05, 0.5, and 15 mg/kg/day for at least 14 days before
`mating through the first week of pregnancy. There were no adverse effects on mating and fertility rates at doses up to 15
`mg/kg/day (maternal systemic exposures approximately 11% of the human exposure (AUC0-24h) at the recommended
`dose).
`
`In a male fertility study, olaparib had no effect on mating and fertility in rats at oral doses up to 40 mg/kg/day following at
`least 70 days of olaparib treatment (with systemic exposures of approximately 7% of the human exposure (AUC0-24h) at
`the recommended dose).
`
`14 CLINICAL STUDIES
`
`The efficacy of Lynparza was investigated in a single-arm study in patients with deleterious or suspected deleterious
`germline BRCA-mutated (gBRCAm) advanced cancers (Study 1). A total of 137 patients with measurable, gBRCAm-
`associated ovarian cancer treated with three or more prior lines of chemotherapy were enrolled. All patients received
`Lynparza at a dose of 400 mg twice daily as monotherapy until disease progression or intolerable toxicity. Objective
`response rate (ORR) and duration of response (DOR) were assessed by the investigator according to RECIST v1.1.
`
`The median age of the patients was 58 years, the majority were Caucasian (94%) and 93% had an ECOG PS of 0 or 1.
`Deleterious or suspected deleterious, germline BRCA mutation status was verified retrospectively in 97% (59/61) of the
`patients for whom blood samples were available by the companion diagnostic BRACAnalysis CDxTM, which is FDA
`approved for selection of patients for Lynparza treatment.
`
`Efficacy results from Study 1 are summarized in Table 5.
`
`Table 5 Overall Response and Duration of Response in Patients with gBRCA-mutated Advanced
`Ovarian Cancer Who Received 3 or More Prior Lines of Chemotherapy in Study 1
`
`
`
`Objective Response Rate (95% CI)
`Complete Response
`Partial Response
`Median DOR in months (95% CI)
`
`
`
`N=137
`34% (26, 42)
`2%
`32%
`7.9 (5.6, 9.6)
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`16.1 How Supplied
`Lynparza 50 mg is a white, opaque, hard capsule, marked in black ink with: “OLAPARIB 50 mg” on the cap and
`AstraZeneca logo on the body; available in:
`
`Reference ID: 3675412
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1041, p. 10 of 16
`
`

`

`Bottles of 112 capsules
`
`NDC 0310-0657-58
`
`16.2 Storage
`Store at 25ºC (77°F), excursions permitted to 15-30ºC (59-86ºF) [see USP Controlled Room Temperature]
`
`Lynparza should not be exposed to temperatures greater than 40ºC or 104ºF. Do not take Lynparza if it is suspected of
`having been exposed to temperatures greater than 40ºC or 104ºF.
`
`17 PATIENT COUNSELING INFORMATION
`
`SEE FDA-APPROVED PATIENT LABELING (MEDICATION GUIDE)
`
`• Dosing Instructions: Inform patients on how to take Lynparza [see Dosage and Administration (2.1)]. Lynparza
`should be taken twice da