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Olaparib

Pronunciation

(oh LAP a rib)

Index Terms

  • AZD2281
  • KU-0059436
  • PARP inhibitor AZD2281

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Lynparza: 50 mg

Brand Names: U.S.

  • Lynparza

Pharmacologic Category

  • Antineoplastic Agent, PARP Inhibitor

Pharmacology

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).

Absorption

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

Distribution

167 ± 196 L

Metabolism

Primarily hepatic via CYP3A4; the majority of metabolism is through oxidation with some metabolites undergoing subsequent glucuronide or sulfate conjugation

Excretion

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

Time to Peak

1 to 3 hours

Half-Life Elimination

Terminal: 11.9 ± 4.8 hours

Protein Binding

~82%

Special Populations: Renal Function Impairment

The mean AUC and Cmax 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 to patients with normal renal function.

Use: Labeled Indications

Ovarian cancer, advanced: Treatment (monotherapy) of deleterious or suspected deleterious germline BRCA mutated (as detected by an approved test) advanced ovarian cancer in patients who have been treated with 3 or more prior lines of chemotherapy

Contraindications

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

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

Dosing: Adult

Note: Administer only to patients with deleterious or suspected deleterious germline BRCA mutations, as detected by an approved test.

Ovarian cancer, advanced: Oral: 400 mg twice daily until disease progression or unacceptable toxicity

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

Dosage adjustment for concomitant therapy with CYP3A inhibitors: Avoid concomitant use with moderate or strong CYP3A inhibitors. If coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce dose to 200 mg twice daily. If coadministration with a strong CYP3A inhibitor cannot be avoided, reduce dose to 150 mg twice daily.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl 51 to 80 mL/minute: No dosage adjustment necessary; monitor closely for toxicity, as an increase in mean AUC has been observed in patients with mild impairment.

CrCl 31 to 50 mL/minute: Reduce dose to 300 mg twice daily.

CrCl ≤30 mL/minute: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

ESRD: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Patients with bilirubin >1.5 times ULN and AST/ALT ≥2.5 times ULN (≥5 times ULN in the presence of liver metastases) were excluded from clinical trials.

Dosing: Adjustment for Toxicity

Consider therapy interruption or dose reduction if adverse reactions occur. The recommended dose reduction is to 200 mg twice daily; if further reduction is required, reduce dose to 100 mg twice daily.

Pneumonitis: Discontinue

Secondary AML/MDS: Discontinue

Administration

Oral: Swallow capsule 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, 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).

Hazardous agent; use appropriate precautions for handling and disposal (meets NIOSH 2016 criteria). NIOSH recommends single-gloving for administration of an intact capsule (NIOSH 2016).

Dietary Considerations

Avoid grapefruit or Seville oranges.

Storage

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

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. 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 such concurrent use cannot be avoided, the dose of olaparib should be reduced to 200 mg twice daily. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. 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. Monitor therapy

Adverse Reactions

≥10%:

Cardiovascular: Peripheral edema (10% to <20%)

Central nervous system: Fatigue (including weakness; 66% to 68%), headache (10% to 25%), dizziness (10% to <20%)

Dermatologic: Skin rash (10% to 25%)

Gastrointestinal: Nausea (64% to 75%), abdominal pain (43%), vomiting (32% to 43%), diarrhea (28% to 31%), dyspepsia (25%), decreased appetite (22% to 25%), dysgeusia (10% to 21%), constipation (10% to <20%)

Genitourinary: Urinary tract infection (10% to <20%)

Hematologic & oncologic: Decreased hemoglobin (85% to 90%; grades 3/4: 8% to 15%), increased MCV (57% to 85%), decreased absolute lymphocyte count (56%; grades 3/4: 17%), anemia (25% to 34%; grades 3/4: 4% to 18%), decreased neutrophils (25% to 32%; grades 3/4: 7% to 8%), decreased platelet count (26% to 30%; grades 3/4: 3% to 6%)

Neuromuscular & skeletal: Musculoskeletal pain (21% to 32%), myalgia (22% to 25%), back pain (10% to 25%)

Renal: Increased serum creatinine (26% to 30%)

Respiratory: Upper respiratory tract infection (26% to 43%), cough (10% to 21%), dyspnea (10% to <20%)

1% to ≤10%:

Cardiovascular: Hypertension, venous thrombosis (including pulmonary embolism)

Central nervous system: Anxiety, depression, insomnia, peripheral neuropathy

Dermatologic: Pruritus, xeroderma (including eczema)

Endocrine & metabolic: Hot flash, hyperglycemia, hypomagnesemia

Gastrointestinal: Stomatitis

Genitourinary: Dysuria, urinary incontinence, vulvovaginal disease

Hematologic & oncologic: Myelodysplastic syndrome (acute myeloid leukemia; 2%), leukopenia

Miscellaneous: Fever

<1% (Limited to important or life-threatening): 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.

• Gastrointestinal toxicity: Nausea and vomiting (usually mild to moderate) may commonly occur.

• 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 a clinical trial of patients with deleterious or suspected deleterious germline BRCA-mutated advanced cancers receiving olaparib monotherapy. Most MDS/AML cases were fatal. The duration of therapy prior to development of the secondary cancers ranged from less than 6 months to greater than 2 years; all patients had received prior chemotherapy with platinum agents and/or other DNA-damaging medications, including radiation. 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: Monitor closely for toxicity in patients with mild or moderate 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.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (meets NIOSH 2016 criteria).

Monitoring Parameters

Complete blood count at baseline and monthly thereafter, or as clinically indicated (weekly until recovery for prolonged hematologic toxicity), renal function; monitor for signs/symptoms of AML/MDS and pneumonitis

Pregnancy Risk Factor

D

Pregnancy Considerations

Adverse events were observed in animal reproduction studies at doses less than human exposure. Based on its mechanism of action, olaparib may be expected to cause adverse events to the fetus. Women of reproductive potential should use highly effective contraception during therapy and for at least one month after treatment is discontinued.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, constipation, lack of appetite, diarrhea, dizziness, headache, abdominal pain, heartburn, muscle pain, joint pain, nausea, vomiting, rhinitis, pharyngitis, or change in taste. Have patient report immediately to prescriber signs of infection, signs of a severe pulmonary disorder (lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse), painful urination; swelling of arms or legs; hematuria; black, tarry, or bloody stools; shortness of breath; bruising; bleeding; severe loss of strength and energy; or weight loss (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare 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.

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