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JollyRX
Empire Heights A , Shuraa Gold, 9th Floor, Office 412, Business Bay Dubai, AE
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Brand Name: Olanib 150 

Originator/Innovator Brand: LYNPARZA.

Initial U.S. Approval: 2014

Dosage Form: Tablets

Composition: Each film coated tablet contains Olaparib INN 150 mg.

INDICATIONS AND USAGE

Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germ line BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

MECHANISM OF ACTION

Olaparib 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.

DOSAGE AND ADMINISTRATION

The recommended dose of Olaparib is 300 mg (two 150 mg tablets) taken twice daily, equivalent to a total daily dose of 600 mg. It is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity. Patients with platinum-sensitive relapsed (PSR) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy should start treatment with Olaparib no later than 8 weeks after completion of their final dose of the platinum-containing regimen.

Important differences in posology between Olaparib tablets and capsules

Olaparib tablets (100 mg and 150 mg) should not be substituted for Olaparib capsules (50 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Therefore, the specific dose recommendations for each formulation should be followed.

Missing dose

If a patient misses a dose of Olaparib, they should take their next normal dose at its scheduled time.

Dose adjustments for adverse reactions

Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia and dose reduction can be considered. The recommended dose reduction is to 250 mg twice daily (equivalent to a total daily dose of 500 mg). If a further dose reduction is required, then reduction to 200 mg twice daily (equivalent to a total daily dose of 400 mg) is recommended.

Dose adjustments for co-administration with CYP3A inhibitors

Concomitant use of strong or moderate CYP3A inhibitors is not recommended and alternative agents should be considered. If a strong CYP3A inhibitor must be co-administered, the recommended Olaparib dose reduction is to 100 mg taken twice daily (equivalent to a total daily dose of 200 mg). If a moderate CYP3A inhibitor must be co-administered, the recommended Olaparib dose reduction is to 150 mg (one 150 mg tablet) taken twice daily (equivalent to a total daily dose of 300 mg). 

Special populations

Elderly

No adjustment in starting dose is required for elderly patients.There are limited clinical data in patients aged 75 years and over.

Renal impairment

For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommended dose of Olaparib is 200 mg twice daily (equivalent to a total daily dose of 400 mg). Olaparib can be administered in patients with mild renal impairment (creatinine clearance 51 to 80 ml/min) with no dose adjustment. Olaparib is not recommended for use in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 ml/min), as safety and pharmacokinetics have not been studied in these patients. Olaparib may only be used in patients with severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events.

Hepatic impairment

Olaparib can be administered to patients with mild or moderate hepatic impairment (Child-Pugh classification A or B) with no dose adjustment. Olaparib is not recommended for use in patients with severe hepatic impairment (Child-Pugh classification C), as safety and pharmacokinetics have not been studied in these patients.

Non-Caucasian patients

There are limited clinical data available in non-Caucasian patients. However, no dose adjustment is required on the basis of ethnicity.

Paediatric population

The safety and efficacy of Olaparib in children and adolescents have not been established. No data are available.

Method of administration

Olaparib is for oral use. Olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets may be taken without regard to meals.

CONTRAINDICATIONS

Hypersensitivity to Olaparib or to any of the excipients.

WARNINGS AND PRECAUTIONS

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 Olaparib 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 Olaparib. Overall, MDS/AML were reported in <1% patients treated with Olaparib in clinical studies. The majority of MDS/AML reports were fatal, and the duration of therapy with Olaparib in patients who developed secondary MDS/ cancer- therapy related AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of previous cancer or of bone marrow dysplasia.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start Olaparib until patients have recovered from hematological toxicity caused by previous chemotherapy (CTCAE Grade 1). For prolonged hematological toxicities, interrupt Olaparib 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 Olaparib.

Pneumonitis

Pneumonitis, including fatal cases, occurred in <1% of patients treated with Olaparib. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Olaparib and initiate prompt investigation. If pneumonitis is confirmed, discontinue Olaparib.

Embryo-Fetal Toxicity

Olaparib 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 300 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while taking Olaparib. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Olaparib.

SIDE EFFECTS

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. Most common laboratory abnormalities (≥25%) were increase in creatinine, mean corpuscular volume elevation, decrease in hemoglobin, decrease in lymphocytes, decrease in leucocytes, decrease in absolute neutrophil count, and decrease in platelets.

DRUG INTERACTIONS

Anticancer Agents

Clinical studies of Olaparib in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Drugs that may Increase Olaparib Plasma Concentrations

Olaparib is primarily metabolized by CYP3A. 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 Olaparib. Avoid grapefruit and Seville oranges during Olaparib treatment.

Drugs that may Decrease Olaparib Plasma Concentrations

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 Olaparib.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy category is D. Olaparib 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 300 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.

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.

Populations With Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with Olaparib. Olaparib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use highly effective contraception during treatment with Olaparib and for at least 6 months following the last dose.

Pediatric Use

The safety and efficacy of Olaparib has not been established in pediatric patients.

Geriatric Use

In clinical studies it was found that 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.

Hepatic Impairment

No adjustment to the starting dose is required in patients with mild hepatic impairment. A 1.2-fold increase in mean exposure (AUC) of Olaparib was observed in patients with mild hepatic impairment (based on Child-Pugh classification A) compared to patients with normal hepatic function. There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment

No dose adjustment to the starting dose is required in patients with mild renal impairment, but patients should be monitored closely for toxicity. For patients with moderate renal impairment, reduce the dose of Olaparib to 200 mg twice daily (please see Dosage and Administration). There are no data in patients with severe renal impairment or end-stage disease (CLcr ≤30 mL/min).

OVERDOSAGE

There is no specific treatment in the event of Olaparib overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

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.

Adverse reactions presented below were reported from clinical trials in 782 patients with ovarian cancer (555 received Olaparib, 227 received placebo).

Maintenance Treatment of Recurrent Ovarian Cancer

SOLO-2

The safety of Olaparib for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian cancer was investigated in SOLO-2. This study was a placebo-controlled, double-blind study in which 294 patients received either Olaparib 300 mg (2 x 150 mg tablets) twice daily (n=195) or placebo tablets twice daily (n=99) until disease progression or unacceptable toxicity. The median duration of study treatment was 19.4 months for patients who received Olaparib and 5.6 months for patients who received placebo. Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Olaparib and 18% of those receiving placebo; dose reductions due to an adverse reaction occurred in 27% of Olaparib patients and 3% of placebo patients. The most frequent adverse reactions leading to dose interruption or reduction of Olaparib were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation occurred in 11% of Olaparib patients and 2% in placebo patients.

In addition, the adverse reactions observed in SOLO-2 that occurred in <20% of patients receiving Olaparib were neutropenia, rash, cough, dyspepsia, leukopenia, hypomagnesemia, dizziness, thrombocytopenia, increase in creatinine, lymphopenia and edema.

Study 19

The safety of Olaparib capsules as maintenance monotherapy was also evaluated in patients with platinum sensitive ovarian cancer who had received 2 or more previous platinum containing regimens in Study 19, a randomized, placebo-controlled, double-blind, multi-center study in which 264 patients received Olaparib 400 mg twice daily (n=136) or placebo (n=128). At the time of final analysis, the median duration of exposure was 8.7 months in patients who received Olaparib and 4.6 months in patients who received placebo. Adverse reactions led to dose interruptions in 35% of those receiving Olaparib and 10% of those receiving placebo; dose reductions in 26% of Olaparib and 4% of placebo; and discontinuation in 6% of Olaparib and 2% in placebo. In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Olaparib were dyspepsia, stomatitis, dysgeusia, dizziness, increase in creatinine, neutropenia, thrombocytopenia, leukopenia, lymphopenia, dyspnea, pyrexia and edema.

Treatment of Advanced gBRCAm Ovarian Cancer After 3 or More Lines of Chemotherapy

Pooled data

Treatment with Olaparib (capsule formulation) as monotherapy was studied in 223 patients (pooled from 6 studies) with gBRCAm advanced ovarian cancer who had received 3 or more prior lines of chemotherapy. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4% of patients, and discontinuation in 7% of patients. There were 8 (4%) patients with adverse reactions 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. The median exposure to Olaparib capsules in these patients was 5.2 months.

The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Olaparib and not included in the table: cough, constipation, dysgeusia, 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 Olaparib and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, and venous thrombosis (including pulmonary embolism).

Treatment of gBRCAm HER2-negative Metastatic Breast Cancer

OlympiAD

The safety of Olaparib 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 Olaparib 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 Olaparib 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 Olaparib and 28% of those receiving chemotherapy; dose reductions due to an adverse reaction occurred in 25% of Olaparib patients and 31% of chemotherapy patients. Discontinuation occurred in 5% of Olaparib patients and 8% in chemotherapy patients.

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

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Olanib 150


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Description of product

Brand Name: Olanib 150 

Originator/Innovator Brand: LYNPARZA.

Initial U.S. Approval: 2014

Dosage Form: Tablets

Composition: Each film coated tablet contains Olaparib INN 150 mg.

INDICATIONS AND USAGE

Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germ line BRCA mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

MECHANISM OF ACTION

Olaparib 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.

DOSAGE AND ADMINISTRATION

The recommended dose of Olaparib is 300 mg (two 150 mg tablets) taken twice daily, equivalent to a total daily dose of 600 mg. It is recommended that treatment be continued until progression of the underlying disease or unacceptable toxicity. Patients with platinum-sensitive relapsed (PSR) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy should start treatment with Olaparib no later than 8 weeks after completion of their final dose of the platinum-containing regimen.

Important differences in posology between Olaparib tablets and capsules

Olaparib tablets (100 mg and 150 mg) should not be substituted for Olaparib capsules (50 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation. Therefore, the specific dose recommendations for each formulation should be followed.

Missing dose

If a patient misses a dose of Olaparib, they should take their next normal dose at its scheduled time.

Dose adjustments for adverse reactions

Treatment may be interrupted to manage adverse reactions such as nausea, vomiting, diarrhoea, and anaemia and dose reduction can be considered. The recommended dose reduction is to 250 mg twice daily (equivalent to a total daily dose of 500 mg). If a further dose reduction is required, then reduction to 200 mg twice daily (equivalent to a total daily dose of 400 mg) is recommended.

Dose adjustments for co-administration with CYP3A inhibitors

Concomitant use of strong or moderate CYP3A inhibitors is not recommended and alternative agents should be considered. If a strong CYP3A inhibitor must be co-administered, the recommended Olaparib dose reduction is to 100 mg taken twice daily (equivalent to a total daily dose of 200 mg). If a moderate CYP3A inhibitor must be co-administered, the recommended Olaparib dose reduction is to 150 mg (one 150 mg tablet) taken twice daily (equivalent to a total daily dose of 300 mg). 

Special populations

Elderly

No adjustment in starting dose is required for elderly patients.There are limited clinical data in patients aged 75 years and over.

Renal impairment

For patients with moderate renal impairment (creatinine clearance 31 to 50 ml/min) the recommended dose of Olaparib is 200 mg twice daily (equivalent to a total daily dose of 400 mg). Olaparib can be administered in patients with mild renal impairment (creatinine clearance 51 to 80 ml/min) with no dose adjustment. Olaparib is not recommended for use in patients with severe renal impairment or end-stage renal disease (creatinine clearance ≤ 30 ml/min), as safety and pharmacokinetics have not been studied in these patients. Olaparib may only be used in patients with severe renal impairment if the benefit outweighs the potential risk, and the patient should be carefully monitored for renal function and adverse events.

Hepatic impairment

Olaparib can be administered to patients with mild or moderate hepatic impairment (Child-Pugh classification A or B) with no dose adjustment. Olaparib is not recommended for use in patients with severe hepatic impairment (Child-Pugh classification C), as safety and pharmacokinetics have not been studied in these patients.

Non-Caucasian patients

There are limited clinical data available in non-Caucasian patients. However, no dose adjustment is required on the basis of ethnicity.

Paediatric population

The safety and efficacy of Olaparib in children and adolescents have not been established. No data are available.

Method of administration

Olaparib is for oral use. Olaparib tablets should be swallowed whole and not chewed, crushed, dissolved or divided. Olaparib tablets may be taken without regard to meals.

CONTRAINDICATIONS

Hypersensitivity to Olaparib or to any of the excipients.

WARNINGS AND PRECAUTIONS

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 Olaparib 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 Olaparib. Overall, MDS/AML were reported in <1% patients treated with Olaparib in clinical studies. The majority of MDS/AML reports were fatal, and the duration of therapy with Olaparib in patients who developed secondary MDS/ cancer- therapy related AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Some of these patients also had a history of previous cancer or of bone marrow dysplasia.

Monitor complete blood count testing at baseline and monthly thereafter. Do not start Olaparib until patients have recovered from hematological toxicity caused by previous chemotherapy (CTCAE Grade 1). For prolonged hematological toxicities, interrupt Olaparib 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 Olaparib.

Pneumonitis

Pneumonitis, including fatal cases, occurred in <1% of patients treated with Olaparib. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with Olaparib and initiate prompt investigation. If pneumonitis is confirmed, discontinue Olaparib.

Embryo-Fetal Toxicity

Olaparib 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 300 mg twice daily. If the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Advise females of reproductive potential to avoid becoming pregnant while taking Olaparib. If contraceptive methods are being considered, use effective contraception during treatment and for at least one month after receiving the last dose of Olaparib.

SIDE EFFECTS

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. Most common laboratory abnormalities (≥25%) were increase in creatinine, mean corpuscular volume elevation, decrease in hemoglobin, decrease in lymphocytes, decrease in leucocytes, decrease in absolute neutrophil count, and decrease in platelets.

DRUG INTERACTIONS

Anticancer Agents

Clinical studies of Olaparib in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Drugs that may Increase Olaparib Plasma Concentrations

Olaparib is primarily metabolized by CYP3A. 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 Olaparib. Avoid grapefruit and Seville oranges during Olaparib treatment.

Drugs that may Decrease Olaparib Plasma Concentrations

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 Olaparib.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy category is D. Olaparib 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 300 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.

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.

Populations With Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with Olaparib. Olaparib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use highly effective contraception during treatment with Olaparib and for at least 6 months following the last dose.

Pediatric Use

The safety and efficacy of Olaparib has not been established in pediatric patients.

Geriatric Use

In clinical studies it was found that 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.

Hepatic Impairment

No adjustment to the starting dose is required in patients with mild hepatic impairment. A 1.2-fold increase in mean exposure (AUC) of Olaparib was observed in patients with mild hepatic impairment (based on Child-Pugh classification A) compared to patients with normal hepatic function. There are no data in patients with moderate or severe hepatic impairment.

Renal Impairment

No dose adjustment to the starting dose is required in patients with mild renal impairment, but patients should be monitored closely for toxicity. For patients with moderate renal impairment, reduce the dose of Olaparib to 200 mg twice daily (please see Dosage and Administration). There are no data in patients with severe renal impairment or end-stage disease (CLcr ≤30 mL/min).

OVERDOSAGE

There is no specific treatment in the event of Olaparib overdose, and symptoms of overdose are not established. In the event of an overdose, physicians should follow general supportive measures and should treat symptomatically.

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.

Adverse reactions presented below were reported from clinical trials in 782 patients with ovarian cancer (555 received Olaparib, 227 received placebo).

Maintenance Treatment of Recurrent Ovarian Cancer

SOLO-2

The safety of Olaparib for the maintenance treatment of patients with platinum sensitive gBRCAm ovarian cancer was investigated in SOLO-2. This study was a placebo-controlled, double-blind study in which 294 patients received either Olaparib 300 mg (2 x 150 mg tablets) twice daily (n=195) or placebo tablets twice daily (n=99) until disease progression or unacceptable toxicity. The median duration of study treatment was 19.4 months for patients who received Olaparib and 5.6 months for patients who received placebo. Dose interruptions due to an adverse reaction of any grade occurred in 45% of patients receiving Olaparib and 18% of those receiving placebo; dose reductions due to an adverse reaction occurred in 27% of Olaparib patients and 3% of placebo patients. The most frequent adverse reactions leading to dose interruption or reduction of Olaparib were anemia (22%), neutropenia (9%), and fatigue/asthenia (8%). Discontinuation occurred in 11% of Olaparib patients and 2% in placebo patients.

In addition, the adverse reactions observed in SOLO-2 that occurred in <20% of patients receiving Olaparib were neutropenia, rash, cough, dyspepsia, leukopenia, hypomagnesemia, dizziness, thrombocytopenia, increase in creatinine, lymphopenia and edema.

Study 19

The safety of Olaparib capsules as maintenance monotherapy was also evaluated in patients with platinum sensitive ovarian cancer who had received 2 or more previous platinum containing regimens in Study 19, a randomized, placebo-controlled, double-blind, multi-center study in which 264 patients received Olaparib 400 mg twice daily (n=136) or placebo (n=128). At the time of final analysis, the median duration of exposure was 8.7 months in patients who received Olaparib and 4.6 months in patients who received placebo. Adverse reactions led to dose interruptions in 35% of those receiving Olaparib and 10% of those receiving placebo; dose reductions in 26% of Olaparib and 4% of placebo; and discontinuation in 6% of Olaparib and 2% in placebo. In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Olaparib were dyspepsia, stomatitis, dysgeusia, dizziness, increase in creatinine, neutropenia, thrombocytopenia, leukopenia, lymphopenia, dyspnea, pyrexia and edema.

Treatment of Advanced gBRCAm Ovarian Cancer After 3 or More Lines of Chemotherapy

Pooled data

Treatment with Olaparib (capsule formulation) as monotherapy was studied in 223 patients (pooled from 6 studies) with gBRCAm advanced ovarian cancer who had received 3 or more prior lines of chemotherapy. Adverse reactions led to dose interruption in 40% of patients, dose reduction in 4% of patients, and discontinuation in 7% of patients. There were 8 (4%) patients with adverse reactions 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. The median exposure to Olaparib capsules in these patients was 5.2 months.

The following adverse reactions and laboratory abnormalities have been identified in ≥10 to <20% of the 223 patients receiving Olaparib and not included in the table: cough, constipation, dysgeusia, 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 Olaparib and not included in the table: leukopenia, stomatitis, peripheral neuropathy, pyrexia, hypomagnesemia, and venous thrombosis (including pulmonary embolism).

Treatment of gBRCAm HER2-negative Metastatic Breast Cancer

OlympiAD

The safety of Olaparib 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 Olaparib 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 Olaparib 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 Olaparib and 28% of those receiving chemotherapy; dose reductions due to an adverse reaction occurred in 25% of Olaparib patients and 31% of chemotherapy patients. Discontinuation occurred in 5% of Olaparib patients and 8% in chemotherapy patients.

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

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