Olaparib

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Lynparza: 50 mg [DSC]

Tablet, Oral:

Lynparza: 100 mg, 150 mg

Pharmacology

Mechanism of Action

Olaparib is a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, including PARP1, PARP2, and PARP3. PARP enzymes are involved in DNA transcription, cell cycle regulation, and DNA repair. Olaparib is a potent oral PARP inhibitor which induces synthetic lethality in BRCA1/2 deficient tumor cells through the formation of double-stranded DNA breaks which cannot be accurately repaired, which leads to disruption of cellular homeostasis and cell death (Ledermann 2012).

Pharmacokinetics/Pharmacodynamics

Absorption

Rapid; delayed with a high-fat/high-calorie meal (extent of absorption not significantly altered).

Distribution

Tablet: 158 ± 136 L; Capsule: 167 ± 196 L.

Metabolism

Primarily hepatic via CYP3A; the majority of metabolism is through oxidation with some metabolites undergoing subsequent glucuronide or sulfate conjugation.

Excretion

Urine (44%, mostly as metabolites); feces (42%, mostly as metabolites).

Clearance: Tablet: 7.4 ± 3.9 hours.

Time to Peak

Tablet: 1.5 hours; Capsule: 1 to 3 hours.

Half-Life Elimination

Tablet: 14.9 ± 8.2 hours; Capsule: Terminal: 11.9 ± 4.8 hours

Protein Binding

~82%.

Use in Specific Populations

Special Populations: Renal Function Impairment

Tablets: The mean AUC and C_max increased by 24% and 15%, respectively, in patients with mild renal impairment (CrCl 51 to 80 mL/minute), and by 44% and 26%, respectively, in patients with moderate renal impairment (CrCl 31 to 50 mL/minute) compared with patients with normal renal function.

Capsules; The mean AUC and C_max each increased by 1.2-fold when administered to patients with mild renal impairment (CrCl 51 to 80 mL/minute), and by 1.4- and 1.3-fold, respectively, in patients with moderate renal impairment (CrCl 31 to 50 mL/minute) compared with patients with normal renal function.

Special Populations: Hepatic Function Impairment

Tablets: The mean AUC and the mean C_max increased by 15% and 13%, respectively, in patients with mild impairment (Child-Pugh class A), compared with patients with normal hepatic function. The mean AUC increased by 8% and the mean C_max decreased by 13% in patients with moderate impairment (Child-Pugh class B), compared with patients with normal hepatic function.

Use: Labeled Indications

Breast cancer, metastatic (BRCA-mutated, HER2-negative): Tablets: Treatment of deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer in adults who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting; patients with hormone receptor-positive disease should have received a prior endocrine therapy or be considered inappropriate for endocrine therapy (select patients for therapy based on an approved olaparib companion diagnostic test).

Ovarian cancer, advanced (BRCA-mutated): Tablets, capsules: Treatment of deleterious or suspected deleterious gBRCAm advanced ovarian cancer in adults who have been treated with 3 or more prior lines of chemotherapy (select patients for therapy based on an approved olaparib companion diagnostic test).

Ovarian cancer, advanced (BRCA-mutated), first-line maintenance therapy: Tablets: First-line maintenance treatment of deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer in adults who are in complete or partial response to first-line platinum-based chemotherapy (select patients for therapy based on an approved olaparib companion diagnostic test).

Ovarian cancer, recurrent (maintenance therapy): Tablets: Maintenance treatment of recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in adults who are in complete or partial response to platinum-based chemotherapy.

Pancreatic cancer, metastatic (BRCA-mutated), first-line maintenance therapy: Tablets: First-line maintenance treatment of deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma in adults whose disease has not progressed on at least 16 weeks of first-line, platinum-based chemotherapy (select patients for therapy based on an approved olaparib companion diagnostic test).

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to olaparib or any component of the formulation.

Dosage and Administration

Dosing: Adult

Note: Olaparib is available in tablets and (in some regions) capsules. Due to differences in dosing and bioavailability, do not substitute capsules for tablets (or vice versa) on a mg-per-mg basis.

Breast cancer, metastatic, HER2-negative, germline BRCA-mutated (gBRCAm): Oral: Tablets: 300 mg twice daily until disease progression or unacceptable toxicity (Robson 2017).

Ovarian cancer, advanced, gBRCAm: Oral:

Tablets: 300 mg twice daily until disease progression or unacceptable toxicity.

Capsules: 400 mg twice daily until disease progression or unacceptable toxicity (Domchek 2016).

Ovarian cancer, advanced, germline or somatic BRCA-mutated, first-line maintenance therapy: Oral: Tablets: 300 mg twice daily until disease progression or unacceptable toxicity or completion of 2 years of therapy. Patients with a complete response (no radiologic evidence of disease) at 2 years should discontinue olaparib; patients with evidence of disease at 2 years may continue treatment (beyond 2 years) if further olaparib treatment may provide benefit (Moore 2018).

Ovarian cancer, recurrent, maintenance therapy: Oral: Tablets: 300 mg twice daily until disease progression or unacceptable toxicity (Pujade-Lauraine 2017).

Pancreatic cancer, metastatic, gBRCAm, first-line maintenance therapy: Oral: Tablets: 300 mg twice daily until disease progression or unacceptable toxicity (Golan 2019).

Missed doses: If a dose is missed, administer the next dose at its scheduled time.

Dosage adjustment for concomitant therapy:

CYP3A inhibitors: Avoid concomitant use with moderate or strong CYP3A inhibitors (consider alternative agents with less CYP3A inhibition). If coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce olaparib dose to 150 mg twice daily (tablets) or 200 mg twice daily (capsules). If coadministration with a strong CYP3A inhibitor cannot be avoided, reduce olaparib dose to 100 mg twice daily (tablets) or 150 mg twice daily (capsules). After the CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the olaparib dose that was administered prior to initiating a CYP3A inhibitor.

CYP3A inducers: Avoid concomitant use with moderate or strong CYP3A4 inducers; a potential for reduced olaparib efficacy exists if moderate CYP3A inducers cannot be avoided.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Consider therapy interruption or dose reduction if adverse reactions occur.

Tablets: The recommended first dose reduction is to 250 mg twice daily; if further reduction is required, reduce dose to 200 mg twice daily.

Capsules: The recommended first dose reduction is to 200 mg twice daily; if further reduction is required, reduce dose to 100 mg twice daily.

Pneumonitis: Discontinue

Secondary acute myeloid leukemia/myelodysplastic syndrome (AML/MDS): Discontinue

Administration

Oral: Administer approximately every 12 hours with or without food. Swallow tablets whole; do not chew, crush, dissolve, or divide tablet. Swallow capsules whole; do not chew, dissolve, or open capsule; do not administer if capsules appear deformed or show evidence of leakage.

Based on a pharmacokinetic study (in tablets), the rate of absorption was slower and the peak exposure was decreased when administered with a high-fat meal; however, the extent of absorption was not affected; nausea and vomiting were reported more frequently when olaparib was administered in a fasted state (Plummer 2015).

Olaparib is available in tablets and (in some regions) capsules. Due to differences in dosing and bioavailability, do not substitute capsules for tablets (or vice versa) on a mg-per-mg basis.

Dietary Considerations

Avoid grapefruit, grapefruit juice, Seville oranges, or Seville orange juice.

Storage

Tablets: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture.

Capsules: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Do not expose capsules to temperatures >40°C (104°F).

Drug Interactions

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bitter Orange: May increase the serum concentration of Olaparib. Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Ciprofloxacin (Systemic): May increase the serum concentration of Olaparib. Monitor therapy

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Olaparib. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Olaparib. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Olaparib. Management: Avoid use of moderate CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 100 mg twice daily. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Grapefruit Juice: May increase the serum concentration of Olaparib. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (14%)

Central nervous system: Fatigue (≤67%), headache (15% to 26%), dizziness (7% to 20%)

Endocrine & metabolic: Hypomagnesemia (5% to 14%)

Gastrointestinal: Nausea (58% to 77%), abdominal pain (45%), vomiting (30% to 43%), diarrhea (21% to 37%), constipation (16% to 28%), dysgeusia (9% to 27%), dyspepsia (8% to 25%), decreased appetite (16% to 22%), stomatitis (4% to 20%; grades 3/4: 1%)

Genitourinary: Urinary tract infection (13% to 14%)

Hematologic & oncologic: Increased MCV (57% to 89%), decrease in absolute neutrophil count (25% to 51%; grades 3/4: 7% to 11%), anemia (23% to 44%; grades 3/4: 7% to 21%), neutropenia (5% to 27%; grades 3/4: 6% to 9%), leukopenia (2% to 25%; grades 3/4: 3% to 5%), thrombocytopenia (4% to 14%; grades 3/4: 1%)

Infection: Influenza (≤36%)

Neuromuscular & skeletal: Asthenia (≤66%), arthralgia (≤30%), myalgia (≤30%), musculoskeletal pain (≤21%), back pain (14%)

Renal: Increased serum creatinine (3% to 45%)

Respiratory: Nasopharyngitis (≤36%), respiratory tract infection (≤36%), rhinitis (≤36%), sinusitis (≤36%), bronchitis (≤28%), cough (16% to 18%), dyspnea (13% to 15%)

1% to 10%:

Cardiovascular: Edema (8% to 9%), pulmonary embolism (≤1%), venous thrombosis (≤1%)

Central nervous system: Peripheral neuropathy (5%), depression, insomnia

Dermatologic: Skin rash (5% to 6%), dermatitis (1%)

Gastrointestinal: Upper abdominal pain (7%)

Hematologic & oncologic: Lymphocytopenia (1% to 8%), myelodysplastic syndrome (acute myeloid leukemia; 1%)

Hypersensitivity: Hypersensitivity reaction (2%)

Miscellaneous: Fever (8% to 10%)

<1%, postmarketing, and/or case reports: Pneumonitis

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: Anemia, neutropenia, thrombocytopenia, and lymphopenia have been reported. Monitor complete blood counts at baseline and monthly thereafter; do not initiate olaparib until any hematologic toxicity caused by previous chemotherapy has resolved to ≤ grade 1. If prolonged hematologic toxicity occurs during therapy, interrupt treatment and monitor blood counts weekly until recovered; if counts do not recover to ≤ grade 1 after 4 weeks, further evaluation (including bone marrow and cytogenetic analyses) is necessary.
• GI toxicity: Nausea and vomiting (usually mild to moderate) may commonly occur.
• Hypersensitivity: Hypersensitivity reactions, including rash and dermatitis, have been reported.
• Pulmonary toxicity: Pneumonitis (including some fatalities) has occurred rarely. Interrupt treatment for new or worsening respiratory symptoms such as cough, dyspnea, fever, wheezing, or radiologic abnormalities; evaluate promptly. Discontinue treatment if pneumonitis is confirmed.
• Secondary malignancy: Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) have been reported (rarely) in clinical trials and long-term follow up, mostly in patients with documented BRCA mutation. Most MDS/AML cases were fatal. Additional cases of MDS/AML have been reported in patients treated with olaparib in combination studies and postmarketing reports. The duration of olaparib therapy prior to development of the secondary cancers ranged from <6 months to >2 years; all patients had received prior chemotherapy with platinum agents and/or other DNA-damaging medications, including radiation; some of these patients had a prior history of more than one primary malignancy or bone marrow dysplasia. If prolonged hematologic toxicity occurs and blood counts do not recover to ≤ grade 1 after 4 weeks, further evaluation (including bone marrow and cytogenetic analyses) is necessary. If MDS/AML is confirmed, discontinue therapy.

Disease-related concerns:

• Renal impairment: Dosage adjustment is recommended for moderate impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Dosage form selection: Olaparib is available in tablets and (in some regions) capsules. Due to differences in dosing and bioavailability, do not substitute capsules for tablets (or vice versa) on a mg-per-mg basis.

Other warnings/precautions:

• BRCA-mutation status: Select patients for the treatment of advanced ovarian cancer, metastatic pancreatic cancer, or HER2-negative metastatic breast cancer based on the presence of deleterious or suspected deleterious germline BRCA-mutations (gBRCAm). Select patients for first-line maintenance treatment of advanced ovarian cancer based on the presence of gBRCAm or somatic BRCA-mutations [sBRCAm]). Information on approved tests for the detection of BRCA-mutations may be found at http://www.fda.gov/companiondiagnostics.

Monitoring Parameters

BRCA-mutation status (metastatic breast cancer, advanced ovarian cancer, first-line maintenance treatment of advanced ovarian cancer, and metastatic pancreatic cancer); complete blood count at baseline and monthly thereafter, or as clinically indicated (weekly until recovery for prolonged hematologic toxicity), renal function, pregnancy test (prior to treatment initiation in females of reproductive potential); monitor for signs/symptoms of acute myeloid leukemia/myelodysplastic syndrome and pneumonitis. Monitor adherence.

Pregnancy

Pregnancy Considerations

Based on the mechanism of action, and data from animal reproduction studies, in utero exposure to olaparib may cause fetal harm.

Pregnancy testing is recommended prior to treatment initiation in females of reproductive potential. Females of reproductive potential should use highly effective contraception during therapy and for at least 6 months after the last olaparib dose. Males with female partners of reproductive potential or with female partners who are pregnant should use effective contraception during treatment and for 3 months after the last olaparib dose; male patients also should not donate sperm during therapy and for 3 months following the last olaparib dose.

Patient Education

What is this drug used for?

• It is used to treat ovarian cancer.
• It is used to treat breast cancer.

Frequently reported side effects of this drug

• Back pain
• Constipation
• Lack of appetite
• Diarrhea
• Dizziness
• Fatigue
• Headache
• Abdominal pain
• Mouth irritation
• Mouth sores
• Common cold symptoms
• Flu-like signs
• Heartburn
• Muscle pain
• Joint pain
• Nausea
• Vomiting
• Nose irritation
• Throat irritation
• Change in taste

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Infection
• Severe pulmonary disorder or lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse
• Swelling of arms or legs
• Blood in the urine
• Black, tarry, or bloody stools
• Shortness of breath
• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in your urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding
• Severe loss of strength and energy
• Weight loss
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Patient Education

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.