OLAPARIB
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 ACROSS THE PHYSIOLOGICAL PH RANGE.
LYNPARZA TABLETS FOR ORAL ADMINISTRATION CONTAIN 100 MG OR 150 MG OF OLAPARIB. INACTIVE INGREDIENTS IN THE TABLET CORE ARE COPOVIDONE, MANNITOL, COLLOIDAL SILICON DIOXIDE AND SODIUM STEARYL FUMARATE. THE TABLET COATING CONSISTS OF HYPROMELLOSE, POLYETHYLENE GLYCOL 400, TITANIUM DIOXIDE, FERRIC OXIDE YELLOW AND FERROSOFERRIC OXIDE (150 MG TABLET ONLY).
INDICATIONS
INDICATIONS
FIRST-LINE MAINTENANCE TREATMENT OF BRCA-MUTATED ADVANCED OVARIAN CANCER
LYNPARZA IS INDICATED FOR THE MAINTENANCE TREATMENT OF ADULT PATIENTS WITH DELETERIOUS OR SUSPECTED DELETERIOUS GERMLINE OR SOMATIC BRCA-MUTATED (GBRCAM OR SBRCAM) ADVANCED EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CANCER WHO ARE IN COMPLETE OR PARTIAL RESPONSE TO FIRST-LINE PLATINUMBASED CHEMOTHERAPY. SELECT PATIENTS WITH GBRCAM ADVANCED EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CANCER FOR THERAPY BASED ON AN FDA-APPROVED COMPANION DIAGNOSTIC FOR LYNPARZA [SEE DOSAGE AND ADMINISTRATION].
MAINTENANCE TREATMENT OF RECURRENT OVARIAN CANCER
LYNPARZA IS INDICATED FOR THE MAINTENANCE TREATMENT OF ADULT PATIENTS WITH RECURRENT EPITHELIAL OVARIAN, FALLOPIAN TUBE OR PRIMARY PERITONEAL CANCER, WHO ARE IN COMPLETE OR PARTIAL RESPONSE TO PLATINUM-BASED CHEMOTHERAPY.
ADVANCED GBRCA-MUTATED OVARIAN CANCER AFTER 3 OR MORE LINES OF CHEMOTHERAPY
LYNPARZA IS INDICATED FOR THE TREATMENT OF ADULT PATIENTS WITH DELETERIOUS OR SUSPECTED DELETERIOUS GBRCAM ADVANCED OVARIAN CANCER WHO HAVE BEEN TREATED WITH THREE OR MORE PRIOR LINES OF CHEMOTHERAPY. SELECT PATIENTS FOR THERAPY BASED ON AN FDA-APPROVED COMPANION DIAGNOSTIC FOR LYNPARZA. [SEE DOSAGE AND ADMINISTRATION].
GERMLINE BRCA-MUTATED HER2-NEGATIVE METASTATIC BREAST CANCER
LYNPARZA IS INDICATED IN PATIENTS WITH DELETERIOUS OR SUSPECTED DELETERIOUS GBRCAM, HER2-NEGATIVE METASTATIC BREAST CANCER, WHO HAVE BEEN TREATED WITH CHEMOTHERAPY IN THE NEOADJUVANT, ADJUVANT , OR METASTATIC SETTING. PATIENTS WITH HORMONE RECEPTOR (HR)-POSITIVE BREAST CANCER SHOULD HAVE BEEN TREATED WITH A PRIOR ENDOCRINE THERAPY OR BE CONSIDERED INAPPROPRIATE FOR ENDOCRINE THERAPY. SELECT PATIENTS FOR THERAPY BASED ON AN FDA-APPROVED COMPANION DIAGNOSTIC FOR LYNPARZA [SEE DOSAGE AND ADMINISTRATION].
DOSAGE
DOSAGE AND ADMINISTRATION
PATIENT SELECTION
INFORMATION ON FDA-APPROVED TESTS FOR THE DETECTION OF BRCA-MUTATIONS IS AVAILABLE AT HTTP://WWW.FDA.GOV/COMPANIONDIAGNOSTICS.
FIRST-LINE MAINTENANCE TREATMENT OF BRCA-MUTATED ADVANCED OVARIAN CANCER
SELECT PATIENTS WITH ADVANCED OVARIAN CANCER WHO ARE IN COMPLETE OR PARTIAL RESPONSE TO FIRST-LINE PLATINUM-BASED CHEMOTHERAPY FOR MAINTENANCE TREATMENT WITH LYNPARZA BASED ON THE PRESENCE OF DELETERIOUS OR SUSPECTED DELETERIOUS GBRCAM OR SBRCAM [SEE INDICATIONS AND CLINICAL STUDIES ]. AN FDA-APPROVED TEST FOR THE DETECTION OF TUMOR BRCA GENE MUTATION FOR THE FIRST-LINE MAINTENANCE TREATMENT OF ADVANCED OVARIAN CANCER IS NOT CURRENTLY AVAILABLE.
ADVANCED GBRCAM OVARIAN CANCER
SELECT PATIENTS WITH ADVANCED OVARIAN CANCER WITH LYNPARZA BASED ON THE PRESENCE OF DELETERIOUS OR SUSPECTED DELETERIOUS GBRCA-MUTATION [SEE INDICATIONS AND CLINICAL STUDIES ].
GBRCAM HER2-NEGATIVE METASTATIC BREAST CANCER
SELECT PATIENTS FOR THE TREATMENT OF HER2-NEGATIVE METASTATIC BREAST CANCER WITH LYNPARZA BASED ON THE PRESENCE OF DELETERIOUS OR SUSPECTED DELETERIOUS GBRCA-MUTATION [SEE INDICATIONS AND CLINICAL STUDIES ].
RECOMMENDED DOSING
THE RECOMMENDED DOSE OF LYNPARZA IS 300 MG (TWO 150 MG TABLETS) TAKEN ORALLY TWICE DAILY, WITH OR WITHOUT FOOD, FOR A TOTAL DAILY DOSE OF 600 MG. THE 100 MG TABLET IS AVAILABLE FOR DOSE REDUCTION.
IF A PATIENT MISSES A DOSE OF LYNPARZA, INSTRUCT PATIENT TO TAKE THEIR NEXT DOSE AT ITS SCHEDULED TIME.
INSTRUCT PATIENTS TO SWALLOW TABLETS WHOLE. DO NOT CHEW, CRUSH, DISSOLVE, OR DIVIDE TABLET [SEE HOW SUPPLIED].
FIRST-LINE MAINTENANCE TREATMENT OF BRCA-MUTATED ADVANCED OVARIAN CANCER
CONTINUE TREATMENT UNTIL DISEASE PROGRESSION, UNACCEPTABLE TOXICITY, OR COMPLETION OF 2 YEARS OF TREATMENT. PATIENTS WITH A COMPLETE RESPONSE (NO RADIOLOGICAL EVIDENCE OF DISEASE) AT 2 YEARS SHOULD STOP TREATMENT. PATIENTS WITH EVIDENCE OF DISEASE AT 2 YEARS, WHO IN THE OPINION OF THE TREATING HEALTHCARE PROVIDER CAN DERIVE FURTHER BENEFIT FROM CONTINUOUS TREATMENT, CAN BE TREATED BEYOND 2 YEARS.
MAINTENANCE TREATMENT OF RECURRENT OVARIAN CANCER
CONTINUE TREATMENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY.
ADVANCED GBRCA-MUTATED OVARIAN CANCER
CONTINUE TREATMENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY.
GERMLINE BRCA-MUTATED HER2-NEGATIVE METASTATIC BREAST CANCER
CONTINUE TREATMENT UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY.
DOSE ADJUSTMENTS FOR ADVERSE REACTIONS
TO MANAGE ADVERSE REACTIONS, CONSIDER INTERRUPTION OF TREATMENT OR DOSE REDUCTION. THE RECOMMENDED DOSE REDUCTION IS 250 MG (ONE 150 MG TABLET AND ONE 100 MG TABLET) TAKEN TWICE DAILY, FOR A TOTAL DAILY DOSE OF 500 MG.
IF A FURTHER DOSE REDUCTION IS REQUIRED, THEN REDUCE TO 200 MG (TWO 100 MG TABLETS) TAKEN TWICE DAILY, FOR A TOTAL DAILY DOSE OF 400 MG.
DOSE MODIFICATIONS FOR USE WITH CYP3A INHIBITORS
AVOID CONCOMITANT USE OF STRONG OR MODERATE CYP3A INHIBITORS AND CONSIDER ALTERNATIVE AGENTS WITH LESS CYP3A INHIBITION. IF A STRONG CYP3A INHIBITOR MUST BE CO-ADMINISTERED, REDUCE THE LYNPARZA DOSE TO 100 MG (ONE 100 MG TABLET) TAKEN TWICE DAILY (EQUIVALENT TO A TOTAL DAILY DOSE OF 200 MG). IF A MODERATE CYP3A INHIBITOR MUST BE CO-ADMINISTERED, REDUCE THE LYNPARZA DOSE TO 150 MG (ONE 150 MG TABLET) TAKEN TWICE DAILY (EQUIVALENT TO A TOTAL DAILY DOSE OF 300 MG) [SEE DRUG INTERACTIONS AND CLINICAL PHARMACOLOGY ].
DOSE MODIFICATIONS FOR PATIENTS WITH RENAL IMPAIRMENT
PATIENTS WITH MILD RENAL IMPAIRMENT (CLCR 51-80 ML/MIN AS ESTIMATED BY COCKCROFT-GAULT EQUATION) DO NOT REQUIRE AN ADJUSTMENT IN LYNPARZA DOSING. IN PATIENTS WITH MODERATE RENAL IMPAIRMENT (CLCR 31-50 ML/MIN) THE RECOMMENDED DOSE REDUCTION IS TO 200 MG (TWO 100 MG TABLETS) TWICE DAILY, FOR A TOTAL DAILY DOSE OF 400 MG. THE PHARMACOKINETICS OF LYNPARZA HAVE NOT BEEN EVALUATED IN PATIENTS WITH SEVERE RENAL IMPAIRMENT OR END-STAGE RENAL DISEASE (CLCR ?30 ML/MIN) [SEE USE IN SPECIFIC POPULATIONS AND CLINICAL PHARMACOLOGY ].
HOW SUPPLIED
DOSAGE FORMS AND STRENGTHS
TABLETS
· 150 MG: GREEN TO GREEN/GREY, OVAL, BI- CONVEX, FILM-COATED, WITH DEBOSSMENT 'OP150' ON ONE SIDE AND PLAIN ON THE REVERSE SIDE.
· 100 MG: YELLOW TO DARK YELLOW, OVAL, BI-CONVEX, FILM-COATED, WITH DEBOSSMENT 'OP100' ON ONE SIDE AND PLAIN ON THE REVERSE SIDE.
STORAGE AND HANDLING
LYNPARZA IS AVAILABLE AS 150 MG AND 100 MG TABLETS.
· 150 MG TABLETS: GREEN TO GREEN/GREY, OVAL, BI-CONVEX, FILM-COATED TABLET, WITH DEBOSSMENT 'OP150' ON ONE SIDE AND PLAIN ON THE REVERSE, ARE AVAILABLE IN:
o BOTTLES OF 60 TABLETS (NDC 0310-0679-60) AND
o BOTTLES OF 120 TABLETS (NDC 0310-0679-12).
· 100 MG TABLETS: YELLOW TO DARK YELLOW, OVAL, BI-CONVEX, FILM-COATED TABLET, WITH DEBOSSMENT 'OP100'ON ONE SIDE AND PLAIN ON THE REVERSE, ARE AVAILABLE IN:
o BOTTLES OF 60 TABLETS (NDC 0310-0668-60) AND
o BOTTLES OF 120 TABLETS (NDC 0310-0668-12).
STORAGE
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) [SEE USP CONTROLLED ROOM TEMPERATURE]. STORE IN ORIGINAL BOTTLE TO PROTECT FROM MOISTURE.
DISTRIBUTED BY: ASTRAZENECA PHARMACEUTICALS LP WILMINGTON, DE 19850. REVISED: DEC 2018
SIDE EFFECTS & DRUG INTERACTIONS
SIDE EFFECTS
THE FOLLOWING ADVERSE REACTIONS ARE DISCUSSED ELSEWHERE IN THE LABELING:
· MYELODYSPLASTIC SYNDROME /ACUTE MYELOID LEUKEMIA [SEE WARNINGS AND PRECAUTIONS]
· PNEUMONITIS [SEE WARNINGS AND PRECAUTIONS]
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.
FIRST-LINE MAINTENANCE TREATMENT OF BRCA-MUTATED ADVANCED OVARIAN CANCER
SOLO-1
THE SAFETY OF LYNPARZA FOR THE MAINTENANCE TREATMENT OF PATIENTS WITH BRCA-MUTATED ADVANCED OVARIAN CANCER FOLLOWING FIRST-LINE TREATMENT WITH PLATINUM-BASED CHEMOTHERAPY WAS INVESTIGATED IN SOLO-1 [SEE CLINICAL STUDIES]. PATIENTS RECEIVED LYNPARZA TABLETS 300 MG ORALLY TWICE DAILY (N=260) OR PLACEBO (N=130) UNTIL DISEASE PROGRESSION OR UNACCEPTABLE TOXICITY. THE MEDIAN DURATION OF STUDY TREATMENT WAS 25 MONTHS FOR PATIENTS WHO RECEIVED LYNPARZA AND 14 MONTHS FOR PATIENTS WHO RECEIVED PLACEBO.
AMONG PATIENTS WHO RECEIVED LYNPARZA, DOSE INTERRUPTIONS DUE TO AN ADVERSE REACTION OF ANY GRADE OCCURRED IN 52% AND DOSE REDUCTIONS DUE TO AN ADVERSE REACTION OCCURRED IN 28%. THE MOST FREQUENT ADVERSE REACTIONS LEADING TO DOSE INTERRUPTION OR REDUCTION OF LYNPARZA WERE ANEMIA (23%), NAUSEA (14%), AND VOMITING (10%). DISCONTINUATION DUE TO ADVERSE REACTIONS OCCURRED IN 12% OF PATIENTS RECEIVING LYNPARZA. THE MOST FREQUENT ADVERSE REACTIONS THAT LED TO DISCONTINUATION OF LYNPARZA WERE FATIGUE (3.1%), ANEMIA (2.3%), AND NAUSEA (2.3%).
TABLES 1 AND 2 SUMMARIZE ADVERSE REACTIONS AND LABORATORY ABNORMALITIES IN SOLO-1.
TABLE 1 : ADVERSE REACTIONS* IN SOLO-1 (?10% OF PATIENTS WHO RECEIVED LYNPARZA)
ADVERSE REACTION LYNPARZA TABLETS N=260 PLACEBO N=130
ALL GRADES (%) GRADES 3 - 4 (%) ALL GRADES (%) GRADES 3 - 4 (%)
GASTROINTESTINAL DISORDERS
NAUSEA 77 1 38 0
ABDOMINAL PAIN† 45 2 35 1
VOMITING 40 0 15 1
DIARRHEA‡ 37 3 26 0
CONSTIPATION 28 0 19 0
DYSPEPSIA 17 0 12 0
STOMATITIS§ 11 0 2 0
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
FATIGUE|| 67 4 42 2
BLOOD AND LYMPHATIC SYSTEM DISORDERS
ANEMIA 38 21 9 2
NEUTROPENIA¶ 17 6 7 3
LEUKOPENIA# 13 3 8 0
THROMBOCYTOPENIA** 11 1 4 2
INFECTIONS AND INFESTATIONS
UPPER RESPIRATORY TRACT INFECTION/ INFLUENZA/NASOPHARYNGITIS/BRONCHITIS 28 0 23 0
UTI†† 13 1 7 0
NERVOUS SYSTEM DISORDERS
DYSGEUSIA 26 0 4 0
DIZZINESS 20 0 15 1
METABOLISM AND NUTRITION DISORDERS
DECREASED APPETITE 20 0 10 0
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
DYSPNEA‡‡ 15 0 6 0
* GRADED ACCORDING TO THE NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (NCI CTCAE), VERSION 4.0. † INCLUDES ABDOMINAL PAIN, ABDOMINAL PAIN LOWER, ABDOMINAL PAIN UPPER, ABDOMINAL DISTENSION, ABDOMINAL DISCOMFORT, ABDOMINAL TENDERNESS ‡ INCLUDES COLITIS, DIARRHEA, GASTROENTERITIS § INCLUDES STOMATITIS, APHTHOUS ULCER; MOUTH ULCERATION || INCLUDES: ASTHENIA, FATIGUE, LETHARGY, MALAISE ¶ INCLUDES NEUTROPENIA, FEBRILE NEUTROPENIA # INCLUDES LEUKOPENIA, WHITE BLOOD CELL COUNT DECREASED ** INCLUDES PLATELET COUNT DECREASED, THROMBOCYTOPENIA †† INCLUDES: UROSEPSIS, URINARY TRACT INFECTION, URINARY TRACT PAIN, PYURIA ‡‡ INCLUDES DYSPNEA AND DYSPNEA EXERTIONAL
IN ADDITION, THE ADVERSE REACTIONS OBSERVED IN SOLO-1 THAT OCCURRED IN <10% OF PATIENTS RECEIVING LYNPARZA WERE INCREASED BLOOD CREATININE (8%), LYMPHOPENIA (6%), HYPERSENSITIVITY (2%), DERMATITIS (1%), AND INCREASED MEAN CELL VOLUME (0.4%).
TABLE 2 : LABORATORY ABNORMALITIES REPORTED IN ?25% OF PATIENTS IN SOLO-1
LABORATORY PARAMETER* LYNPARZA TABLETS N†=260 PLACEBO N†=130
GRADES 1-4 (%) GRADES 3-4 (%) GRADES 1-4 (%) GRADES 3-4 (%)
DECREASE IN HEMOGLOBIN 87 19 63 2
INCREASE IN MEAN CORPUSCULAR VOLUME 87 - 43 -
DECREASE IN LEUKOCYTES 70 7 52 1
DECREASE IN LYMPHOCYTES 67 14 29 5
DECREASE IN ABSOLUTE NEUTROPHIL COUNT 51 9 38 6
DECREASE IN PLATELETS 35 1 20 2
INCREASE IN SERUM CREATININE 34 0 18 0
* PATIENTS WERE ALLOWED TO ENTER CLINICAL STUDIES WITH LABORATORY VALUES OF CTCAE GRADE 1. † THIS NUMBER REPRESENTS THE SAFETY POPULATION. THE DERIVED VALUES IN THE TABLE ARE BASED ON THE TOTAL NUMBER OF EVALUABLE PATIENTS FOR EACH LABORATORY PARAMETER.
MAINTENANCE TREATMENT OF RECURRENT OVARIAN CANCER