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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

Tablet, Oral:

Lynparza: 100 mg, 150 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

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

Capsule: 1 to 3 hours; Tablet: 1.5 hours

Half-Life Elimination

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

Protein Binding

~82%

Special Populations: Renal Function Impairment

Capsules; 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 with patients with normal renal function.

Tablets: The mean AUC and Cmax 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.

Special Populations: Hepatic Function Impairment

The mean AUC and the mean Cmax increased by 15% and 13%, respectively, in patients with mild impairment (Child-Pugh class A), compared with patients with normal hepatic function.

Use: Labeled Indications

Ovarian cancer, advanced (BRCA-mutated): Capsules, tablets: Treatment 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

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

Off Label Uses

Breast cancer, metastatic, HER2-negative, BRCA-mutated

Data from a phase III randomized, controlled, international, multicenter study supports the use of olaparib (tablets) in the treatment of HER2-negative (hormone-receptor positive or triple negative) metastatic breast cancer in patients with a confirmed or suspected deleterious germline BRCA mutation; patients had received no more than 2 prior lines of chemotherapy for the treatment of metastatic disease [Robson 2017].

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: Olaparib is available as 100 mg and 150 mg tablets and as 50 mg capsules. Do not substitute the 50 mg capsules for the 100 mg or 150 mg tablets on a mg-per-mg basis due to differences in dosing and bioavailability.

Ovarian cancer, advanced (BRCA-mutated): Oral:

Capsules: 400 mg twice daily (12 hours apart) until disease progression or unacceptable toxicity (Domchek 2016)

Tablets: 300 mg twice daily (12 hours apart) until disease progression or unacceptable toxicity

Ovarian cancer, recurrent (maintenance): Oral: Tablets: 300 mg twice daily (12 hours apart) until disease progression or unacceptable toxicity

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

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 (consider alternative agents with less CYP3A inhibition). If coadministration with a moderate CYP3A inhibitor cannot be avoided, reduce dose to 200 mg twice daily (capsules) or 150 mg twice daily (tablets). If coadministration with a strong CYP3A inhibitor cannot be avoided, reduce dose to 150 mg twice daily (capsules) or 100 mg twice daily (tablets).

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:

Capsules: Reduce dose to 300 mg twice daily.

Tablets: Reduce dose to 200 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

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate-to-severe impairment (Child-Pugh classes B and C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Adjustment for Toxicity

Consider therapy interruption or dose reduction if adverse reactions occur.

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

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

Pneumonitis: Discontinue

Secondary AML/MDS: Discontinue

Administration

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

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).

Olaparib is available as 100 mg and 150 mg tablets and as 50 mg capsules. Due to differences in dosing and bioavailability, do not substitute the 50 mg capsules for the 100 mg or 150 mg tablets on a mg-per-mg basis.

Dietary Considerations

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

Storage

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).

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.

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

Ciprofloxacin (Systemic): May increase the serum concentration of Olaparib. 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 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 (High risk with Inhibitors). Monitor therapy

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. 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 (High risk with Inhibitors). Monitor therapy

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

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

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

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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 (10% to <20%), edema (<20%)

Central nervous system: Fatigue (≤66%), headache (10% to 26%), dizziness (<20%)

Dermatologic: Skin rash (<20%)

Endocrine & metabolic: Hypomagnesemia (<20%)

Gastrointestinal: Nausea (64% to 76%), abdominal pain (43%), vomiting (35% to 43%), diarrhea (28% to 33%), dysgeusia (10% to 27%), dyspepsia (25%), constipation (22%), decreased appetite (21% to 22%), stomatitis (20%)

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

Hematologic & oncologic: Increased MCV (57% to 85%), decreased absolute lymphocyte count (52% to 67%; grades 3/4: 10% to 17%), decreased white blood cell count (58%; grades 3/4: 4%), decreased neutrophils (25% to 51%; grades 3/4: 7% to 8%), anemia (23% to 44%; grades 3/4: 4% to 20%), decreased platelet count (30% to 42%; grades 3/4: 2% to 4%)

Infection: Influenza (≤36%)

Neuromuscular & skeletal: Weakness (≤66%), musculoskeletal pain (21% to 32%), arthralgia (≤30%), myalgia (≤30%), back pain (10% to 20%)

Renal: Increased serum creatinine (30% to 45%)

Respiratory: Nasopharyngitis (≤36%), rhinitis (≤36%), sinusitis (≤36%), respiratory tract infection (22%), cough (10% to 20%), dyspnea (<20%)

Miscellaneous: Fever (<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

Genitourinary: Dysuria, urinary incontinence, vulvovaginal disease

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

<1%, postmarketing, and/or case reports: Dermatitis, hypersensitivity reaction, 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. The duration of olaparib 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; some of these patients had a prior history of cancer 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: 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.

Dosage form specific issues:

• Dosage form selection: Olaparib is available as 100 mg and 150 mg tablets and as 50 mg capsules. Do not substitute the 50 mg capsules for the 100 mg or 150 mg tablets on a mg-per-mg basis due to differences in dosing and bioavailability.

Monitoring Parameters

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 women of reproductive potential); monitor for signs/symptoms of AML/MDS and pneumonitis. Monitor adherence.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies at doses less than human exposure. Based on animal reproduction studies and the 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 6 months after the last olaparib dose. In women of reproductive potential, pregnancy testing is recommended prior to treatment initiation.

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, mouth irritation, mouth sores, common cold symptoms, flu-like signs, heartburn, muscle pain, joint pain, nausea, vomiting, rhinitis, pharyngitis, or change in taste. Have patient report immediately to prescriber signs of a urinary tract infection (hematuria, burning or painful urination, polyuria, fever, lower abdominal pain, or pelvic pain), signs of infection, signs of a severe pulmonary disorder (lung or breathing problems like difficulty breathing, shortness of breath, or a cough that is new or worse), 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 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.

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