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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
LYNPARZA (NDA-206162)
(OLAPARIB)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
09/27/2018 (SUPPL-11)
8 Use in Specific Populations
8.6 Hepatic ImpairmentNo adjustment to the starting dose is required in patients with mild or moderate hepatic impairment. A 15% increase and an 8% increase in mean exposure (AUC), respectively, were observed in patients with mild and moderate hepatic impairment (Child-Pugh classification A and B), compared to patients with normal hepatic function. There are no data in patients with severe hepatic impairment (Child-Pugh classification C).
10/23/2017 (SUPPL-8)
5 Warnings and Precautions
5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia(Additions and/or revisions are underlined)
Overall, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Lynparza monotherapy in clinical trials, including long-term follow up, was less than 1.5% (21/1680) and the majority of events had a fatal outcome. Of these, 19/21 patients had a documented BRCA mutation, 1 patient had gBRCA wildtype and in 1 patient the BRCA mutation status was unknown.
Additional cases of MDS/AML have been documented in patients treated with Lynparza in combination studies. The duration of therapy with Lynparza in patients who developed secondary MDS/cancer-therapy related AML varied from < 6 months to > 2 years. All of these patients had received previous chemotherapy...
Do not start Lynparza until patients have recovered from hematological toxicity caused by previous chemotherapy (Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment…
(Additions and/or revisions are underlined)
Pneumonitis, including fatal cases, occurred in less than 1% of patients treated with Lynparza. If patients present with new or worsening respiratory symptoms such as dyspnea, cough and fever, or a radiological abnormality occurs, interrupt Lynparza treatment and promptly assess the source of symptoms. If pneumonitis is confirmed, discontinue Lynparza treatment and treat the patient appropriately.
6 Adverse Reactions
6.1 Clinical Trial Experience(Additions and/or revisions are underlined)
Treatment of Advanced gBRCAm Ovarian Cancer after 3 or More Lines of Chemotherapy Pooled data
Treatment with Lynparza capsules 400 mg twice daily 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 Lynparza in these patients was 5.2 months.
Table 2 Laboratory Abnormalities Reported in greater than or equal to 25% Patients in Pooled Data
Study 19
The safety of Lynparza 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 Lynparza 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 Lynparza and 4.6 months in patients who received placebo.
Adverse reactions led to dose interruptions in 35% of those receiving Lynparza and 10% of those receiving placebo; dose reductions in 26% of Lynparza patients and 4% of placebo patients; and discontinuation in 6% of Lynparza patients and 2% in placebo patients.
Table 3 summarizes the adverse reactions that occurred in at least 20% of patients who received Lynparza in Study 19. Table 4 presents the laboratory abnormalities that occurred in at least 25% of patients from Study 19.
Table 3 Adverse Reactions in Study 19 (greater than or equal to 20% of Patients who Received Lynparza)
In addition, the adverse reactions in Study 19 that occurred in <20% of patients receiving Lynparza were dyspepsia, stomatitis, dysgeusia, dizziness, increase in creatinine, neutropenia, thrombocytopenia, leukopenia, lymphopenia, dyspnea, pyrexia and edema.
Table 4 Laboratory Abnormalities Reported in greater than or equal to 25% Patients in Study 19
7 Drug Interactions
7.2 Drugs That May Increase Olaparib Plasma Concentrations(Additions and/or revisions are underlined)
Olaparib is primarily metabolized by CYP3A. In patients (N=57), co-administration of itraconazole, a strong CYP3A inhibitor, increased AUC of olaparib by 170%. A moderate CYP3A inhibitor, fluconazole, is predicted to increase the AUC of olaparib by 121%.
Avoid concomitant use of strong CYP3A inhibitors such as itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, and telaprevir. Avoid use of moderate CYP3A inhibitors such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, and verapamil. If the strong or moderate CYP3A inhibitors must be co-administered, reduce the dose of Lynparza.
Avoid grapefruit, grapefruit juice, Seville oranges and Seville orange juice during Lynparza treatment since they are CYP3A inhibitors.
(Additions and/or revisions are underlined)
Avoid concomitant use of strong CYP3A inducers such as phenytoin, rifampicin, carbamazepine, and St. John’s Wort. Avoid concomitant use of moderate CYP3A4 inducers such as bosentan, efavirenz, etravirine, modafinil, and nafcillin.
8 Use in Specific Populations
8.4 Geriatric Use(Additions and/or revisions are underlined)
In clinical studies of Lynparza enrolling 482 patients with advanced solid tumors who received Lynparza tablets 300 mg twice daily as monotherapy, 135 (28%) patients were aged greater than or equal to 65 years. There appeared to be no major difference in the safety profile of patients treated with olaparib aged less than 65 years versus greater than or equal to 65 years, nor within the age categories of 65 to 74 years, 75 to 84 years. No patients were aged greater than or equal to 85 years.
(Additions and/or revisions are underlined)
No adjustment to the starting dose is required in patients with mild hepatic impairment. A 15% increase in mean exposure (AUC)….
(Additions and/or revisions are underlined)
No adjustment to the starting dose is required in patients with mild renal impairment, but patients should be monitored closely for toxicity. A 24% increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 51-80 mL/min) compared to patients with normal renal function (CLcr greater than 80 mL/min). A 44% increase in AUC was observed in patients with moderate renal impairment (CLcr = 31-50 mL/min) compared to patients with normal renal function (CLcr greater than 80 mL/min). For patients with moderate renal impairment, reduce the dose of Lynparza capsules to 300 mg twice daily. There are no data in patients with severe renal impairment or end-stage disease (CLcr less than or equal to 30 mL/min).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Administration Instructions: Inform patients on how to take Lynparza. Lynparza should be taken twice daily with or without food. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Inform patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice while taking Lynparza08/17/2017 (SUPPL-7)
6 Adverse Reactions
6.2 Postmarketing Experience(new subsection added)
The following adverse reactions have been identified during post-approval use of Lynparza. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune System Disorders: Hypersensitivity (rash/dermatitis)
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
(additions underlined)
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Dosing Instructions: Inform patients on how to take Lynparza . Lynparza should be taken twice daily with or without food. Instruct patients that if they miss a dose of Lynparza, not to take an extra dose to make up for the one that they missed. They should take their next normal dose at the usual time. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsule. Patient should not take Lynparza with grapefruit or Seville oranges.
Inform patients not to substitute Lynparza capsules (50 mg) with Lynparza tablets (100 mg and 150 mg) on a milligram-to-milligram basis due to differences in the dosing and bioavailability of each formulation Advise the patient to read the FDA-approved patient labeling (Medication Guide).
…
01/26/2017 (SUPPL-3)
5 Warnings and Precautions
5.3 Embryo-Fetal Toxicity(Additions and/or revisions are underlined)
In an animal reproduction study, administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. Apprise pregnant women of the potential hazard to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Lynparza.
6 Adverse Reactions
6.1 Clinical Trial Experience(Additions and/or revisions are underlined)
The median exposure to Lynparza in these patients was 158 days.
Table 1 and Table 2 summarize the common adverse reactions and abnormal laboratory findings, respectively, observed in patients treated with Lynparza.
Table 2 Laboratory Abnormalities Reported in Greater Than or Equal to 25% Patients with gBRCA Mutated Advanced Ovarian Cancer Receiving Lynparza (Table revised; please refer to label)
Table 4 Laboratory Abnormalities in Greater Than or Equal to 25% Patients with gBRCA-Mutated Ovarian Cancer in the Randomized Trial
7 Drug Interactions
7.3 Drugs that may Decrease Olaparib Plasma Concentrations(Additions and/or revisions are underlined)
In patients (N=22), co-administration of rifampicin, a strong CYP3A inducer, decreased AUC of olaparib by 87%. A moderate CYP3A inducer, efavirenz, is predicted to decrease the AUC of olaparib by approximately 50%.
8 Use in Specific Populations
8.1 Pregnancy(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
Based on findings in animals and its mechanism of action, Lynparza can cause fetal harm when administered to a pregnant woman. There are no available data on Lynparza use in pregnant women to inform the drug associated risk. In an animal reproduction study, the administration of olaparib to pregnant rats during the period of organogenesis caused teratogenicity and embryo-fetal toxicity at exposures below those in patients receiving the recommended human dose of 400 mg twice daily. Apprise pregnant women of the potential hazard to the fetus and the potential risk for loss of the pregnancy.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. The estimated background risk in the U.S. general population of major birth defects is 2-4%; and the risk for spontaneous abortion is approximately 15-20% in clinically recognized pregnancies.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Risk Summary
No data are available regarding the presence of olaparib in human milk, or on its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infants from Lynparza, advise a lactating woman not to breastfeed during treatment with Lynparza and for one month after receiving the last dose.
(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential prior to initiating treatment with Lynparza.
Contraception
Females
Advise females of reproductive potential to use highly effective contraception during treatment with Lynparza and for at least 6 months following the last dose.
(Additions and/or revisions are underlined)
No adjustment to the starting dose is required in patients with mild hepatic impairment. A 1.2-fold increase in mean exposure (AUC) 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
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Dosing Instructions: Inform patients on how to take Lynparza. Lynparza should be taken twice daily with or without food.
Embryo-Fetal Toxicity: …Advise females of reproductive potential to use effective contraception during treatment with Lynparza and for 6 months after receiving the last dose.
Lactation: Advise patients not to breastfeed while taking Lynparza and for one month after receiving the last dose.
(Additions and/or revisions are underlined)
What should I tell my healthcare provider before taking Lynparza?
Before you take Lynparza, tell your healthcare provider about all of your medical conditions including if you:
If you are able to become pregnant, your healthcare provider may do a pregnancy test before you start treatment with Lynparza.
Females who are able to become pregnant should use effective birth control (contraception) during treatment with Lynparza and for 6 months after receiving the last dose of Lynparza.
…Do not breastfeed during treatment with Lynparza and for 1 month after receiving the last dose of Lynparza. Talk to your healthcare provider about the best way to feed your baby during this time.
How should I take Lynparza?
Take Lynparza by mouth 2 times a day. Each dose should be taken 12 hours apart.
Take Lynparza with or without food.
10/19/2016 (SUPPL-2)
5 Warnings and Precautions
5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia (subsection updated, additions underlined)…. Overall, MDS/AML were reported in <1% patients treated with Lynparza in clinical studies. The majority of MDS/AML reports were fatal, and the duration of therapy with Lynparza 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.
8 Use in Specific Populations
8.8 Renal Impairment ( Additions underlined)A 1.2 fold increase in mean exposure (AUC) was observed in patients with mild renal impairment (CLcr = 51-80 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). No dose adjustment to the starting dose is required in patients with mild renal impairment, but patients should be monitored closely for toxicity. A 1.4 fold increase in AUC was observed in patients with moderate renal impairment (CLcr = 31-50 mL/min) compared to patients with normal renal function (CLcr >80 mL/min). For patients with moderate renal impairment, reduce the dose of Lynparza to 300 mg twice daily. There are no data in patients with severe renal impairment or end-stagedisease (CLcr ?30 mL/min).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Medication Guide (addition underlined)Lynparza may cause serious side effects that can lead to death, including:
Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have ovarian cancer or who have received previous treatment with chemotherapy, radiotherapy or certain other medicines for their cancer have developed MDS or AML during treatment with Lynparza.