Post-Marketing Safety Concerns With Palbociclib A Disproportionality Analysis of the FDA Adverse Event

doi:10.21203/rs.3.rs-3239639/v1

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Post-Marketing Safety Concerns With Palbociclib A Disproportionality Analysis of the FDA Adverse Event

https://doi.org/10.21203/rs.3.rs-3239639/v1

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Purpose: By using U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, the adverse reactions (ADRs) of palbociclib were mined through disproportionality analysis, so as to provide reference for rational use of palbociclib.

Methods: Data mining of palbociclib-associated adverse events (AEs) was done by reporting odds ratio (ROR), proportional reporting odds ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinkage (MGPS) algorithms.

Findings: At the SOC level, the four algorithms simultaneously detected 18 positive signals, and at the PT level, the four algorithms simultaneously detected 65 positive signals. The PTs that lead to severe outcome are mainly associated with pulmonary toxicity, hematological toxicity and myelosuppression. Palbociclib-associated AEs had a median onset time of 79 days (interquartile range [IQR] 20-264 days), with the majority occurring within the first 1, 2, 3 months, and one year of treatment.

Implications: The study identified potential palbociclib side effects and offered warnings for high-risk AEs, providing further data for palbociclib safety studies in breast cancer patients. Nonetheless, prospective clinical trials are needed to validate these results and explain their relationship.

Health sciences/Diseases/Cancer

Biological sciences/Drug discovery/Drug safety

breast cancer

data mining

FAERS

palbociclib

pharmacovigilance

Large sample study based on real world
The FAERS database was used to comprehensively evaluate the adverse reactions of palbociclib

Breast cancer has become a significant health problem for women due to its extremely high morbidity and mortality rates¹. In 2021, breast cancer surpassed lung cancer as the world's number one cancer among common cancer diagnoses, especially among women. It poses a severe burden globally². Breast cancer is the most prevalent malignancy, with more than 7.7 million women living five years from diagnosis³. The pathogenesis of breast cancer is unknown, but it is associated with many factors, such as gender, age, hormonal status, genetics, fertility, ionizing radiation, alcohol consumption, diet, obesity, and nicotinism⁴.

Breast cancer is classified histologically into benign and invasive types. Drug therapy plays a vital role in the treatment of invasive breast cancer. Drug therapy includes endocrine therapy, chemotherapy, and targeted therapy⁵. Palbociclib is authorized for first-line endocrine therapy in treating locally advanced or metastatic hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer in combination with an aromatase inhibitor^6–8.

Palbociclib was licensed by the United States Food and Drug Administration (FDA) in February 2015 as the first reversible inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6)⁹. The approved clinical indication in the U.S. and China is for an aromatase inhibitor (AI) combination in patients with locally advanced or metastatic breast cancer that is HR+, HER2-. CDK4/6 can form a complex with cyclin D1 and phosphorylate retinoblastoma protein (Rb), accelerating cell growth from the G1 to the S phase¹⁰. More importantly, palbociclib can improve radiotherapy's efficacy by increasing the cells' sensitivity to radiation by arresting the cell cycle in the G phase¹¹, since palbociclib prevents CDK4/6 from binding to cytochrome D, thus limiting the growth of tumor cells^{12, 13}.

Although palbociclib has good efficacy, it also has a variety of AEs. Most adverse effects are now documented in clinical research; further post-marketing, real-world data are needed. Moreover, the relationship between the different doses of palbociclib and adverse effects and the distribution of time to adverse effects were not reported. The severity of the adverse effects of palbociclib has not been described based on a large sample size¹⁴. These will be systematically represented in this study.

The FAERS database is a publicly available spontaneous reporting system (SRS). It not only includes a large number of adverse drug reaction reports but is also the largest pharmacovigilance database available. In this study, we will perform data mining on FAERS to assess the risk of adverse drug reactions after the marketing of pebociclib¹⁵.

Data Source

All AE reports related to palbociclib from the first quarter of 2015 (when palbociclib was approved by the FDA) through the third quarter of 2022 were extracted from the FAERS database and analyzed to identify potential AEs that may be associated with palbociclib. The FAERS data file consisted of seven data sets of patient demographic and administrative information (DEMO), drug information (DRUG), adverse event codes (REAC), patient outcome codes (OUTC), reporting source (RPSR), treatment start date and end date for the reported drug (THER), indication for dosing (INDI), and deleted cases. In addition, all FAERS raw data were imported into MySQL 8.0.26 for further analysis. A total of 12367994 reports were extracted from the FAERS database. Since the database is dynamically changing, some data may have duplicates, missing, or errors, so data cleaning is required. Firstly, the original data need to be deduplicated. According to the FDA deduplication rule, the latest FDA_DT is selected when the CASEID is the same, and the higher PRIMARYID is set when the CASEID and FDA_DT are the same. Finally, 10763,737 reports are obtained (Fig. 1).

Adverse Event and Drug Identification

AEs in the FAERS database were coded by Medical Dictionary for Regulatory Activities 25.1 (MedDRA). The structural hierarchy of the MedDRA terminology was divided into five levels: system organ class (SOC), high-level group term (HLGT), high-level term (HLT), the preferred term (PT), and lowest-level term (LLT). The AEs extracted from the FAERS database were used to analyze SOCs and PTs. The disproportionality analysis method calculated the signal strength corresponding to each SOC and PT. The raw data can be searched by the generic and trade names of the drugs, and our study was conducted using palbociclib and IBRANCE. The role_code of AEs mainly includes primary suspicious (PS), secondary suspicious (SS), concomitant (C), and interaction (I). This study targeted reports with a role_cod of "PS."

Data Mining

Disproportionation analysis is an analytical method used in pharmacovigilance studies to calculate the signal strength of associated AEs by comparing the proportion of AEs between a particular drug and all other drugs¹⁶. Based on the principle that a positive signal is considered to be generated when a specific AE for a particular drug is significantly higher than the background frequency in the database and reaches a certain threshold or criterion, it is determined that a positive signal has been generated. Frequentist disproportionality analysis and Bayesian disproportionality analysis were used to analyze the relationship between drugs and AEs using ROR, PRR, information component (IC) and empirical Bayesian geometric mean (EBGM)^{17, 18}. In this study, when the results of all four algorithms were positive, the AE was judged to be valid, and the formulas for the four algorithms are shown in Supplementary Table S1.

The time to occurrence of AEs and the proportion of serious outcomes were calculated. The onset time was the period between EVENT DT (the date the AEs began) and START DT (the date of palbociclib initiation). In addition, reports containing input mistakes (EVENT DT before START DT), incorrect date entries, and missing particular data were removed. The most common severe outcomes were death, life-threatening events, hospitalization, and disability. The proportion was calculated by dividing the number of severe consequences by the total number of reported events. MYSQL 8.0.26, Navicat Premium 16.0.0, and Excel 2019 were used for data processing and statistical analysis.

Descriptive Analysis

After deleting duplicates, FAERS received 10,763,737 reports from January 2015 to September 2022. Among them, 61821 cases were reported with palbociclib as PS, and 195616 AEs were suspected to be associated with palbociclib. The clinical characteristics of palbociclib-related AEs are shown in Table 1. From 2015 to 2022, the number of AEs for palbociclib steadily rose. The proportion of females (93.41%) was higher than that of males (2.30%). The majority of patients in the reports were ≥ 40 years old. The majority of submissions were made by customers (42.17%), with reports coming mainly from the United States (82.18%), Argentina (4.14%), India (3.17%), Canada (1.78%), and Japan (1.46%). Female breast cancer (22.52%), metastatic breast cancer (20%), and breast cancer (15.53%) were the most frequently reported indications, which were consistent with FDA-approved indications. The most often reported severe consequence was hospitalization (13.23%), whereas death or life-threatening events were documented in 7686 (12.43%) and 307 (0.50%) instances, respectively.

Table 1

Clinical characteristics of reports with palbociclib from the FAERS database (January 2015 to September 2022)
Characteristics	Case number, n	Case proportion, %
Number of events	61821
Gender
Female	57748	93.41
Male	1421	2.30
Unknown	2652	4.29
Age (years)
༜18	51	0.08
18 ≤ and ༜40	1455	2.35
≥ 40	51821	83.82
Unknown	8494	13.74
Indications (Top five)
Breast cancer female	13921	22.52
Breast cancer metastatic	12366	20.00
Breast cancer	9600	15.53
Neoplasm malignant	1755	2.84
Breast cancer stage IV	787	1.27
Serious Outcome
Death	7686	12.43
Life-threatening	307	0.50
Hospitalization	8179	13.23
Disability	162	0.26
Congenital anomaly	6	0.01
Required intervention to prevent permanent impairment/damage	73	0.12
Other serious medical events	17306	27.99
Reported Countries (Top five)
America	50802	82.18
Argentina	2559	4.14
India	1897	3.07
Canada	1098	1.78
Japan	901	1.46
Reported person
Health profession
Pharmacist	17555	28.40
Physician	8513	13.77
Other health-professional	7942	12.85
Non-healthcare professional
Consumer	26071	42.17
Unknown	1737	2.81
Reporting year
2022(Q1-Q3)	12056	19.50
2021	9206	14.89
2020	9956	16.10
2019	9193	14.87
2018	7224	11.69
2017	7184	11.62
2016	4490	7.26
2015	1963	3.18

The results showed that the number of reports (patients) and AEs increased with drug dose increase. For example, there were 3964 reports, including 12090 AEs when the single dose was 75 mg, 8313 reports, including 27688 AEs when the single dose was 100mg, and 29674 reports, including 116709 AEs when the single dose was 125mg (Fig. 2).

Disproportionality Analysis

Signal at the SOC level

Table 2 shows the signal strengths and reports of palbociclib at the level of the SOC. Statistics showed that 13 SOCs had positive signals, and these SOCs met at least one of the four algorithms. These SOCs are listed in Table 3.

Table 2

Signal strength of reports of Palbociclib at the System Organ Class (SOC) level in the FAERS database.
System organ class (SOC)	Palbociclib cases reporting SOC	ROR (95%two-sided CI)	PRR (χ2)	IC (IC025)	EBGM (EBGM05)
General disorders and administration site conditions	35415	1.98(1.96-2.00)*	1.80(223914.57)	0.84(0.83)*	1.79(1.78)
Gastrointestinal disorders	25566	3.19(3.14–3.23)*	2.90(237544.14)*	1.52(1.50)*	2.87(2.83)*
Investigations	25517	1.36(1.34–1.38)*	1.31(33128.29)	0.39(0.37)*	1.31(1.30)
Skin and subcutaneous tissue disorders	12847	1.46(1.44–1.49)*	1.43(12710.16)	0.51(0.49)*	1.43(1.41)
Nervous system disorders	12685	1.12(1.10–1.14)*	1.11(1338.98)	0.15(0.12)*	1.11(1.09)
Injury, poisoning and procedural complications	11311	0.59(0.58–0.60)	0.61(46020.52)	-0.71(-0.73)	0.61(0.60)
Respiratory, thoracic and mediastinal disorders	10356	1.37(1.34–1.40)*	1.35(6074.30)	0.43(0.40)*	1.35(1.33)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	9982	1.27(1.25–1.30)*	1.26(3524.86)	0.33(0.30)*	1.26(1.23)
Musculoskeletal and connective tissue disorders	9622	2.18(2.13–2.22)*	2.12(21334.42)*	1.07(1.04)*	2.10(2.07)*
Blood and lymphatic system disorders	8539	3.55(3.47–3.62)*	3.43(29995.53)*	1.76(1.73)*	3.38(3.32)*
Infections and infestations	8324	0.53(0.52–0.54)	0.55(40544.80)	-0.86(-0.89)	0.55(0.54)
Psychiatric disorders	5274	0.39(0.38–0.41)	0.41(49482.89)	-1.28(-1.32)	0.41(0.40)
Metabolism and nutrition disorders	4529	0.69(0.67–0.71)	0.70(3285.67)	-0.52(-0.56)	0.70(0.68)
Vascular disorders	3336	1.29(1.25–1.34)*	1.29(458.05)	0.36(0.31)*	1.29(1.25)
Eye disorders	2443	0.58(0.55–0.60)	0.58(2556.66)	-0.78(-0.84)	0.58(0.56)
Surgical and medical procedures	1802	0.10(0.09–0.10)	0.11(202520.21)	-3.22(-3.29)	0.11(0.10)
Renal and urinary disorders	1685	0.75(0.71–0.79)	0.75(253.76)	-0.41(-0.48)	0.75(0.72)
Cardiac disorders	1322	0.25(0.24–0.26)	0.25(12395.98)	-1.97(-2.04)	0.26(0.24)
Immune system disorders	1217	1.11(1.05–1.18)*	1.11(11.77)	0.15(0.07)*	1.11(1.06)
Hepatobiliary disorders	1141	1.23(1.16–1.30)*	1.23(36.02)	0.29(0.21)*	1.22(1.17)
Ear and labyrinth disorders	1110	1.4(1.32–1.48)*	1.39(79.62)	0.47(0.39)*	1.39(1.32)
Reproductive system and breast disorders	669	0.50(0.46–0.53)	0.50(372.16)	-1.00(-1.11)	0.50(0.47)
Social circumstances	373	0.17(0.15–0.19)	0.17(2753.05)	-2.56(-2.70)	0.17(0.16)
Product issues	343	0.08(0.07–0.08)	0.08(14039.90)	-3.69(-3.85)	0.08(0.07)
Endocrine disorders	144	0.35(0.3–0.41)	0.35(57.59)	-1.51(-1.74)	0.35(0.31)
Congenital, familial and genetic disorders	55	0(0–0)	0(5813403.56)	-10.27(-10.63)	0(0)
Pregnancy, puerperium and perinatal conditions	9	0(0-0.01)	0(4866.07)	-8.08(-8.84)	0(0)
*Indicates statistically significant signals in algorithm. ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ2, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean.

Table 3

Signal strength of reports of Palbociclib at the System Organ Class (SOC) level in the FAERS database (Meet at least one algorithm).
System organ class (SOC)	Palbociclib cases reporting SOC	ROR (95%two-sided CI)	PRR (χ2)	IC (IC025)	EBGM (EBGM05)
General disorders and administration site conditions	35415	1.98(1.96-2.00)*	1.80(223914.57)	0.84(0.83)*	1.79(1.78)
Gastrointestinal disorders	25566	3.19(3.14–3.23)*	2.90(237544.14)*	1.52(1.50)*	2.87(2.83)*
Investigations	25517	1.36(1.34–1.38)*	1.31(33128.29)	0.39(0.37)*	1.31(1.30)
Skin and subcutaneous tissue disorders	12847	1.46(1.44–1.49)*	1.43(12710.16)	0.51(0.49)*	1.43(1.41)
Nervous system disorders	12685	1.12(1.10–1.14)*	1.11(1338.98)	0.15(0.12)*	1.11(1.09)
Respiratory, thoracic and mediastinal disorders	10356	1.37(1.34–1.40)*	1.35(6074.30)	0.43(0.40)*	1.35(1.33)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	9982	1.27(1.25–1.30)*	1.26(3524.86)	0.33(0.30)*	1.26(1.23)
Musculoskeletal and connective tissue disorders	9622	2.18(2.13–2.22)*	2.12(21334.42)*	1.07(1.04)*	2.10(2.07)*
Blood and lymphatic system disorders	8539	3.55(3.47–3.62)*	3.43(29995.53)*	1.76(1.73)*	3.38(3.32)*
Vascular disorders	3336	1.29(1.25–1.34)*	1.29(458.05)	0.36(0.31)*	1.29(1.25)
Immune system disorders	1217	1.11(1.05–1.18)*	1.11(11.77)	0.15(0.07)*	1.11(1.06)
Hepatobiliary disorders	1141	1.23(1.16–1.30)*	1.23(36.02)	0.29(0.21)*	1.22(1.17)
Ear and labyrinth disorders	1110	1.4(1.32–1.48)*	1.39(79.62)	0.47(0.39)*	1.39(1.32)
*Indicates statistically significant signals in algorithm. ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ2, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean.

Signal at the PT level

A total of 302 positive signals were detected in 22 SOCs that met at least one of the four algorithms. Table 4 displays the number of PTs and signal strengths that match four methods, including 61 PTs and 16 SOCs, while Supplemental Table S2 lists the remaining PTs and SOCs.

Table 4

丨Signal strength of palbociclib at the Preferred Term (PT) level in FAERS database
SOC	Preferred Terms (PTs)	Palbociclib Cases Reporting PT	ROR (95%two-sided CI)	PRR (χ2)	IC (IC025)	EBGM (EBGM05)
Blood and lymphatic system disorders	Neutropenia	3285	8.04(7.76–8.33)	7.92(6673.17)	2.92(2.87)	7.59(7.37)
	Bone marrow failure*	898	12.66(11.83–13.56)	12.61(552.62)	3.55(3.46)	11.75(11.10)
	Leukopenia	754	5.28(4.91–5.67)	5.26(301.53)	2.36(2.25)	5.12(4.82)
	Pancytopenia*	353	2.31(2.08–2.57)	2.31(32.35)	1.19(1.04)	2.29(2.10)
	Cytopenia	213	5.38(4.69–6.17)	5.37(24.29)	2.39(2.19)	5.23(4.66)
	White blood cell disorder*	90	9.97(8.05–12.33)	9.96(5.30)	3.24(2.93)	9.43(7.89)
	Myelosuppression*	256	4.98(4.4–5.64)	4.97(33.82)	2.28(2.10)	4.85(4.37)
Ear and labyrinth disorders	Hypoacusis*	540	3.40(3.12–3.71)	3.40(117.39)	1.74(1.62)	3.35(3.11)
Eye disorders	Lacrimation increased	304	3.30(2.94–3.7)	3.30(36.25)	1.70(1.54)	3.25(2.95)
Gastrointestinal disorders	Nausea	5716	2.39(2.32–2.45)	2.35(8798.71)	1.22(1.18)	2.33(2.27)
	Constipation*	1853	2.79(2.67–2.93)	2.78(1139.85)	1.46(1.39)	2.75(2.64)
	Oral pain	590	8.36(7.70–9.09)	8.34(217.98)	3.00(2.88)	7.97(7.44)
	Stomatitis	1996	10.73(10.25–11.23)	10.63(2645.13)	3.33(3.26)	10.03(9.65)
	Glossodynia	161	2.50(2.14–2.92)	2.50(7.54)	1.31(1.09)	2.48(2.17)
	Mouth ulceration	183	3.02(2.61–3.49)	3.02(12.10)	1.58(1.37)	2.98(2.64)
	Gingival pain	104	4.69(3.86–5.70)	4.69(5.41)	2.20(1.92)	4.58(3.89)
	Oral mucosal blistering	129	5.74(4.81–6.84)	5.73(9.17)	2.48(2.23)	5.57(4.81)
General disorders and administration site conditions	Fatigue	10722	4.38(4.30–4.47)	4.20(54631.34)	2.04(2.01)	4.11(4.05)
	Death*	6039	2.19(2.13–2.25)	2.15(8577.46)	1.10(1.06)	2.14(2.09)
	Disease progression*	1648	4.99(4.75–5.24)	4.96(1401.22)	2.27(2.20)	4.84(4.64)
	Illness*	649	3.03(2.81–3.28)	3.03(152.76)	1.58(1.47)	2.99(2.80)
Immune system disorders	Immune system disorder*	224	5.19(4.54–5.93)	5.18(26.42)	2.34(2.15)	5.05(4.52)
Immune system disorders	Decreased immune responsiveness*	375	12.02(10.82–13.35)	12.00(95.51)	3.49(3.34)	11.22(10.28)
Injury, poisoning and procedural complications	Product dose omission issue*	1770	2.59(2.47–2.72)	2.58(952.81)	1.35(1.28)	2.55(2.46)
Injury, poisoning and procedural complications	Product dose omission in error*	196	5.15(4.47–5.94)	5.15(20.16)	2.33(2.13)	5.02(4.45)
Investigations	Tumour marker increased*	478	34.62(31.35–38.22)	34.53(174.12)	4.83(4.70)	28.52(26.25)
	White blood cell count decreased*	8257	28.46(27.79–29.15)	27.30(51225.58)	4.55(4.52)	23.43(22.97)
	Full blood count decreased*	1149	17.47(16.44–18.58)	17.38(947.97)	3.98(3.89)	15.76(14.97)
	Haemoglobin decreased*	1035	3.49(3.28–3.71)	3.48(439.94)	1.78(1.69)	3.42(3.25)
	Neutrophil count decreased*	1447	12.86(12.19–13.57)	12.77(1438.39)	3.57(3.50)	11.89(11.37)
	Red blood cell count decreased*	1195	14.55(13.71–15.44)	14.47(1000.42)	3.74(3.65)	13.34(12.69)
	Platelet count decreased	1543	4.78(4.55–5.03)	4.75(1201.69)	2.22(2.14)	4.64(4.45)
	Blood count abnormal*	1177	16.28(15.33–17.29)	16.19(985.89)	3.89(3.80)	14.78(14.05)
	Body height decreased*	129	3.03(2.55–3.61)	3.03(6.04)	1.58(1.34)	2.99(2.59)
	Blood test abnormal*	322	6.98(6.24–7.80)	6.97(61.48)	2.75(2.59)	6.72(6.12)
	Haematocrit decreased*	164	3.31(2.83–3.86)	3.30(10.57)	1.70(1.48)	3.26(2.86)
	Laboratory test abnormal*	336	2.95(2.65–3.29)	2.95(39.89)	1.54(1.39)	2.91(2.66)
	Blood calcium decreased*	107	3.06(2.53–3.70)	3.06(4.19)	1.59(1.32)	3.02(2.57)
	White blood cell count abnormal*	302	14.28(12.7-16.07)	14.26(63.74)	3.72(3.55)	13.17(11.93)
	Full blood count abnormal*	762	29.89(27.66–32.3)	29.78(438.31)	4.66(4.55)	25.22(23.63)
Metabolism and nutrition disorders	Decreased appetite	2399	3.25(3.12–3.38)	3.22(2219.27)	1.67(1.61)	3.18(3.07)
Musculoskeletal and connective tissue disorders	Musculoskeletal chest pain*	173	3.66(3.15–4.25)	3.66(12.77)	1.85(1.63)	3.60(3.17)
Musculoskeletal and connective tissue disorders	Bone pain*	782	4.10(3.81–4.40)	4.08(282.04)	2.00(1.90)	4.01(3.77)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Neoplasm progression*	7697	89.49(87.01–92.05)	86.01(46801.68)	5.81(5.77)	56.06(54.75)
	Neoplasm recurrence*	133	14.57(12.20–17.40)	14.56(12.40)	3.75(3.49)	13.42(11.56)
	Second primary malignancy*	405	12.88(11.64–14.26)	12.86(112.75)	3.58(3.44)	11.97(10.99)
	Breast cancer metastatic*	225	8.74(7.64–9.99)	8.73(32.08)	3.06(2.87)	8.32(7.44)
	Cancer pain*	89	10.59(8.54–13.13)	10.59(5.25)	3.32(3.01)	9.98(8.34)
Nervous system disorders	Neuropathy peripheral*	886	2.87(2.69–3.07)	2.86(269.04)	1.50(1.40)	2.83(2.68)
	Ageusia*	199	2.70(2.35–3.11)	2.70(12.70)	1.42(1.22)	2.67(2.38)
	Taste disorder	273	4.72(4.18–5.32)	4.71(37.39)	2.20(2.03)	4.60(4.16)
Psychiatric disorders	Eating disorder*	202	2.82(2.45–3.24)	2.82(13.72)	1.48(1.28)	2.78(2.48)
Reproductive system and breast disorders	Breast pain*	126	3.76(3.15–4.49)	3.76(6.91)	1.89(1.64)	3.70(3.19)
Respiratory, thoracic and mediastinal disorders	Epistaxis	944	3.78(3.54–4.03)	3.77(389.10)	1.89(1.8)	3.70(3.51)
	Pulmonary oedema*	316	2.44(2.18–2.72)	2.43(28.02)	1.27(1.11)	2.41(2.20)
	Pleural effusion*	462	2.62(2.39–2.87)	2.62(65.91)	1.37(1.24)	2.59(2.40)
	Pulmonary thrombosis*	133	3.69(3.11–4.38)	3.69(7.59)	1.86(1.62)	3.63(3.14)
Skin and subcutaneous tissue disorders	Onychoclasis*	191	8.13(7.03–9.41)	8.13(22.67)	2.96(2.75)	7.78(6.89)
	Alopecia	4562	6.16(5.98–6.35)	6.04(11760.18)	2.55(2.51)	5.86(5.71)
	Nail disorder*	177	7.43(6.39–8.64)	7.43(18.96)	2.84(2.62)	7.14(6.29)
	Night sweats*	234	2.42(2.12–2.75)	2.41(15.19)	1.26(1.08)	2.39(2.15)
Surgical and medical procedures	Therapy cessation*	542	2.53(2.33–2.76)	2.53(86.86)	1.32(1.20)	2.50(2.33)
Surgical and medical procedures	Therapy change*	192	5.87(5.08–6.78)	5.86(20.50)	2.51(2.30)	5.69(5.04)
Vascular disorders	Hot flush*	1243	5.68(5.37–6.01)	5.65(846.74)	2.46(2.38)	5.49(5.24)
Vascular disorders	Lymphoedema*	193	9.32(8.06–10.77)	9.31(23.98)	3.14(2.94)	8.85(7.83)
*Emerging findings of palbociclib associated AEs from FAERS database.
ROR, reporting odds ratio; CI,confidence interval; PRR, proportional reporting ratio; χ, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean.

In this study, a total of 17 PTs signals were significant and consistent with the package insert, including neutropenia (PT:10029354), leukopenia (PT:10024384), cytopenia (PT:10066274), etc. These PTs are listed in Table 5.

Table 5

Signal strength of palbociclib reported in the package insert at the Preferred Term (PT) level in FAERS database
SOC	Preferred Terms (PTs)	Palbociclib Cases Reporting PT	ROR (95%two-sided CI)	PRR (χ2)	IC (IC025)	EBGM (EBGM05)
Blood and lymphatic system disorders	Neutropenia	3285	8.04(7.76–8.33)	7.92(6673.17)	2.92(2.87)	7.59(7.37)
	Leukopenia	754	5.28(4.91–5.67)	5.26(301.53)	2.36(2.25)	5.12(4.82)
	Cytopenia	213	5.38(4.69–6.17)	5.37(24.29)	2.39(2.19)	5.23(4.66)
Eye disorders	Lacrimation increased	304	3.30(2.94–3.7)	3.30(36.25)	1.70(1.54)	3.25(2.95)
Gastrointestinal disorders	Nausea	5716	2.39(2.32–2.45)	2.35(8798.71)	1.22(1.18)	2.33(2.27)
	Oral pain	590	8.36(7.70–9.09)	8.34(217.98)	3.00(2.88)	7.97(7.44)
	Stomatitis	1996	10.73(10.25–11.23)	10.63(2645.13)	3.33(3.26)	10.03(9.65)
	Glossodynia	161	2.50(2.14–2.92)	2.50(7.54)	1.31(1.09)	2.48(2.17)
	Mouth ulceration	183	3.02(2.61–3.49)	3.02(12.10)	1.58(1.37)	2.98(2.64)
	Gingival pain	104	4.69(3.86–5.70)	4.69(5.41)	2.20(1.92)	4.58(3.89)
	Oral mucosal blistering	129	5.74(4.81–6.84)	5.73(9.17)	2.48(2.23)	5.57(4.81)
General disorders and administration site conditions	Fatigue	10722	4.38(4.30–4.47)	4.20(54631.34)	2.04(2.01)	4.11(4.05)
Investigations	Platelet count decreased	1543	4.78(4.55–5.03)	4.75(1201.69)	2.22(2.14)	4.64(4.45)
Metabolism and nutrition disorders	Decreased appetite	2399	3.25(3.12–3.38)	3.22(2219.27)	1.67(1.61)	3.18(3.07)
Nervous system disorders	Taste disorder	273	4.72(4.18–5.32)	4.71(37.39)	2.20(2.03)	4.60(4.16)
Respiratory, thoracic and mediastinal disorders	Epistaxis	944	3.78(3.54–4.03)	3.77(389.10)	1.89(1.8)	3.70(3.51)
Skin and subcutaneous tissue disorders	Alopecia	4562	6.16(5.98–6.35)	6.04(11760.18)	2.55(2.51)	5.86(5.71)
ROR, reporting odds ratio; CI,confidence interval; PRR, proportional reporting ratio; χ, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean.

Notably, we found 48 PTs with significant signals but not reported in the package insert, such as bone marrow failure (PT:10065553), pancytopenia (PT:10033661), white blood cell disorder (PT:10061414), etc. These PTs are listed in Table 6.

Table 6

丨Signal strength of palbociclib not reported in the package insert at the Preferred Term (PT) level in FAERS database
SOC	Preferred Terms (PTs)	Palbociclib Cases Reporting PT	ROR (95%two-sided CI)	PRR (χ2)	IC (IC025)	EBGM (EBGM05)
Blood and lymphatic system disorders	Bone marrow failure*	898	12.66(11.83–13.56)	12.61(552.62)	3.55(3.46)	11.75(11.10)
	Pancytopenia*	353	2.31(2.08–2.57)	2.31(32.35)	1.19(1.04)	2.29(2.10)
	White blood cell disorder*	90	9.97(8.05–12.33)	9.96(5.30)	3.24(2.93)	9.43(7.89)
	Myelosuppression*	256	4.98(4.4–5.64)	4.97(33.82)	2.28(2.10)	4.85(4.37)
Ear and labyrinth disorders	Hypoacusis*	540	3.40(3.12–3.71)	3.40(117.39)	1.74(1.62)	3.35(3.11)
Gastrointestinal disorders	Constipation*	1853	2.79(2.67–2.93)	2.78(1139.85)	1.46(1.39)	2.75(2.64)
General disorders and administration site conditions	Death*	6039	2.19(2.13–2.25)	2.15(8577.46)	1.10(1.06)	2.14(2.09)
	Disease progression*	1648	4.99(4.75–5.24)	4.96(1401.22)	2.27(2.20)	4.84(4.64)
	Illness*	649	3.03(2.81–3.28)	3.03(152.76)	1.58(1.47)	2.99(2.80)
Immune system disorders	Immune system disorder*	224	5.19(4.54–5.93)	5.18(26.42)	2.34(2.15)	5.05(4.52)
Immune system disorders	Decreased immune responsiveness*	375	12.02(10.82–13.35)	12.00(95.51)	3.49(3.34)	11.22(10.28)
Injury, poisoning and procedural complications	Product dose omission issue*	1770	2.59(2.47–2.72)	2.58(952.81)	1.35(1.28)	2.55(2.46)
Injury, poisoning and procedural complications	Product dose omission in error*	196	5.15(4.47–5.94)	5.15(20.16)	2.33(2.13)	5.02(4.45)
Investigations	Tumour marker increased*	478	34.62(31.35–38.22)	34.53(174.12)	4.83(4.70)	28.52(26.25)
	White blood cell count decreased*	8257	28.46(27.79–29.15)	27.30(51225.58)	4.55(4.52)	23.43(22.97)
	Full blood count decreased*	1149	17.47(16.44–18.58)	17.38(947.97)	3.98(3.89)	15.76(14.97)
	Haemoglobin decreased*	1035	3.49(3.28–3.71)	3.48(439.94)	1.78(1.69)	3.42(3.25)
	Neutrophil count decreased*	1447	12.86(12.19–13.57)	12.77(1438.39)	3.57(3.50)	11.89(11.37)
	Red blood cell count decreased*	1195	14.55(13.71–15.44)	14.47(1000.42)	3.74(3.65)	13.34(12.69)
	Blood count abnormal*	1177	16.28(15.33–17.29)	16.19(985.89)	3.89(3.80)	14.78(14.05)
	Body height decreased*	129	3.03(2.55–3.61)	3.03(6.04)	1.58(1.34)	2.99(2.59)
	Blood test abnormal*	322	6.98(6.24–7.80)	6.97(61.48)	2.75(2.59)	6.72(6.12)
	Haematocrit decreased*	164	3.31(2.83–3.86)	3.30(10.57)	1.70(1.48)	3.26(2.86)
	Laboratory test abnormal*	336	2.95(2.65–3.29)	2.95(39.89)	1.54(1.39)	2.91(2.66)
	Blood calcium decreased*	107	3.06(2.53–3.70)	3.06(4.19)	1.59(1.32)	3.02(2.57)
	White blood cell count abnormal*	302	14.28(12.7-16.07)	14.26(63.74)	3.72(3.55)	13.17(11.93)
	Full blood count abnormal*	762	29.89(27.66–32.3)	29.78(438.31)	4.66(4.55)	25.22(23.63)
Musculoskeletal and connective tissue disorders	Musculoskeletal chest pain*	173	3.66(3.15–4.25)	3.66(12.77)	1.85(1.63)	3.60(3.17)
Musculoskeletal and connective tissue disorders	Bone pain*	782	4.10(3.81–4.40)	4.08(282.04)	2.00(1.90)	4.01(3.77)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Neoplasm progression*	7697	89.49(87.01–92.05)	86.01(46801.68)	5.81(5.77)	56.06(54.75)
	Neoplasm recurrence*	133	14.57(12.20–17.40)	14.56(12.40)	3.75(3.49)	13.42(11.56)
	Second primary malignancy*	405	12.88(11.64–14.26)	12.86(112.75)	3.58(3.44)	11.97(10.99)
	Breast cancer metastatic*	225	8.74(7.64–9.99)	8.73(32.08)	3.06(2.87)	8.32(7.44)
	Cancer pain*	89	10.59(8.54–13.13)	10.59(5.25)	3.32(3.01)	9.98(8.34)
Nervous system disorders	Neuropathy peripheral*	886	2.87(2.69–3.07)	2.86(269.04)	1.50(1.40)	2.83(2.68)
Nervous system disorders	Ageusia*	199	2.70(2.35–3.11)	2.70(12.70)	1.42(1.22)	2.67(2.38)
Psychiatric disorders	Eating disorder*	202	2.82(2.45–3.24)	2.82(13.72)	1.48(1.28)	2.78(2.48)
Reproductive system and breast disorders	Breast pain*	126	3.76(3.15–4.49)	3.76(6.91)	1.89(1.64)	3.70(3.19)
Respiratory, thoracic and mediastinal disorders	Pulmonary oedema*	316	2.44(2.18–2.72)	2.43(28.02)	1.27(1.11)	2.41(2.20)
	Pleural effusion*	462	2.62(2.39–2.87)	2.62(65.91)	1.37(1.24)	2.59(2.40)
	Pulmonary thrombosis*	133	3.69(3.11–4.38)	3.69(7.59)	1.86(1.62)	3.63(3.14)
Skin and subcutaneous tissue disorders	Onychoclasis*	191	8.13(7.03–9.41)	8.13(22.67)	2.96(2.75)	7.78(6.89)
	Nail disorder*	177	7.43(6.39–8.64)	7.43(18.96)	2.84(2.62)	7.14(6.29)
	Night sweats*	234	2.42(2.12–2.75)	2.41(15.19)	1.26(1.08)	2.39(2.15)
Surgical and medical procedures	Therapy cessation*	542	2.53(2.33–2.76)	2.53(86.86)	1.32(1.20)	2.50(2.33)
Surgical and medical procedures	Therapy change*	192	5.87(5.08–6.78)	5.86(20.50)	2.51(2.30)	5.69(5.04)
Vascular disorders	Hot flush*	1243	5.68(5.37–6.01)	5.65(846.74)	2.46(2.38)	5.49(5.24)
Vascular disorders	Lymphoedema*	193	9.32(8.06–10.77)	9.31(23.98)	3.14(2.94)	8.85(7.83)
*Emerging findings of palbociclib associated AEs from FAERS database.
ROR, reporting odds ratio; CI,confidence interval; PRR, proportional reporting ratio; χ, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean.

In addition, 13 PTs were reported in the package insert but did not meet at least one of the four algorithms, including interstitial lung disease (PT: 10022611), anemia (PT:10002034), diarrhea (PT:10012735), rash (PT:10037844), vomiting (PT:10047700), weakness (PT:10003549), fever (PT:10037660), elevated alanine aminotransferase (PT:10 001551), dry skin (PT:10013786), elevated aspartate aminotransferase (PT:10003481), dry eye (PT:10013774), blurred vision (PT:10047513) and febrile neutropenia (PT:10016288).

Because FAERS includes all medically relevant PTs, some non-drug-related signals need to be eliminated (Supplementary Table S3), mainly in injury, poisoning, and procedural complications (SOC:10022117) and surgical and medical procedures (SOC:10042613).

Time to Onset of Palbociclib-Associated Adverse Events

Excluding incorrect, missing, or unknown onset time data, 15709 AEs provided onset time, with a median time to onset of 79 days (interquartile range [IQR] 20–264 days). As shown in Fig. 3, the majority of palbociclib onsets occurred during the 1st month (n = 5294, 33.70%), 2nd (n = 1801, 11.46%), 3rd (n = 1217, 7.75%), and 4th (n = 917, 5.84%) of palbociclib administration. 18.49% (n = 2905) of AEs occurred one year later.

Stratification analysis

To focus on less frequent but more harmful AEs, we made stratification analysis about pulmonary toxicity (pneumonitis, pulmonary oedema and pulmonary thrombosis) by gender, age and reporting year (Fig. 4). The strongest signal in pneumonitis was 18 ≤ and < 40 years old: ROR 8.1 (2.02–32.46), the strongest signal in pulmonary oedema was 18 ≤ and < 40 years old: ROR 38.3 (21.14–69.38), the strongest signal in pulmonary thrombosis was 18 ≤ and < 40 years old: ROR 92.23 (34.36-247.57).

To the best of our knowledge, our mining of AEs to palbociclib used more algorithms, and described more comprehensively^19–23. Compared with MGPS, PRR has higher sensitivity but lower specificity²⁴. Compared with ROR, BCPNN has a higher specificity and will detect fewer signals²⁵. Different countries or organizations may adopt different algorithms, but there is no one gold standard²⁶. For example, the European Medicines Agency uses reported odds ratios (ROR), and the Uppsala Monitoring Center (WHO) uses Bayesian confidence propagation neural networks (BCPNN)²⁷. Because disclosuring pharmacovigilance information requires sufficient evidence, the four methods were used simultaneously to obtain more conservative and reliable results in our study.

At the SOCs level, 3 SOCs showed positive signals with four algorithms simultaneously, including gastrointestinal disorders (SOC: 10017947, 25566), musculoskeletal and connective tissue disorders (SOC: 10028395, 9622), and blood and lymphatic system disorders (SOC: 10005329, 8539). A total of 13 SOCs showed positive signals with at least one algorithm result. Eight of these 13 SOCs were reported in the package insert. The other five SOCs not reported in the package insert included musculoskeletal and connective tissue disorders ROR 2.18 (2.13–2.22), ear and labyrinth disorders ROR 1.40 (1. 32-1.48), vascular diseases ROR 1.29 (1.25–1.34), neoplasms benign, malignant, and unspecified tumors (including cysts and polyps) ROR 1.27 (1.25–1.30), immune system disorders ROR 1.11 (1.05–1.18)^{8, 14}. Moreover, we found that these 13 SOCs with significant signals included a total of 12 PTs (Meet four algorithms) that were not reported in the package insert, including musculoskeletal chest pain, bone pain, hypoacusis, hot flush, lymphoedema, neoplasm progression, neoplasm recurrence, second primary malignancy, breast cancer metastatic, cancer pain, a disorder of the immune system and decreased immune responsiveness (Table 3). Our results show that the signals of these 12 PTs are significant, in particular, neoplasm progression has the strongest signal [ROR 89.49(87.01–92.05), PRR 86.01(46801.68), IC 5.81(5.77), EBGM 56.06(54.75)]. However, further analysis did not find evidence of a direct correlation between these 12 PTs and palbociclib. Instead, we found that most of these 12 PTs were directly or indirectly associated with breast cancer. For example, musculoskeletal chest pain is most likely due to surgery²⁸. Although bone pain has a significant signal, it is most likely not related to palbociclib but to breast cancer metastasis. The mechanism of metastasis is very complex, involving various interactions between tumor cells, bone cells, and activated inflammatory cells²⁹. Our search also did not find reports of an association between palbociclib and hypoacusis. An observational study suggests hypoacusis in breast cancer patients may be related to a drop in oestrogen levels³⁰. The mechanism of hypoacusis may be due to a decrease in oestrogen levels, which in turn leads to a change in the electrolyte balance within the inner ear fluid, resulting in a higher hearing threshold (hypoacusis)³¹. Therefore, we believe that despite using four algorithms to minimize the occurrence of false positives, disease progression still results in some positive signals unrelated to the drug. It seems more scientific to judge this positive signal by combining clinical cases.

In the SOC of blood and lymphatic system disorders, we found four positive signals that were not reported in the package insert, including bone marrow failure [ROR 12.66(11.83–13.56), PRR 12.61(552.62), IC 3.55(3.46), EBGM 11.75(11.10)], pancytopenia [ROR 2.31(2.08–2.57), PRR 2.31(32.35), IC 1.19(1.04), EBGM 2.29(2.10)], white blood cell disorder [ROR 9.97(8.05–12.33), PRR 9.96(5.30), IC 3.24(2.93), EBGM 9.43(7.89)], and myelosuppression [ROR 4.98(4.4–5.64), PRR 4.97(33.82), IC 2.28(2.10), EBGM 4.85(4.37)]. The underlying mechanism of myelosuppression may be cytostatic effects in the bone marrow, such as cell cycle arrest without apoptosis³². Regular blood routine test is one of the methods to prevent bone marrow suppression.

In the SOC of gastrointestinal disorders, we found constipation [ROR 2.79(2.67–2.93), PRR 2.78(1139.85), IC 1.46(1.39), EBGM 2.75(2.64)], a positive signal not reported in the package insert. In addition, some improvement in constipation has been reported when palbociclib is combined with fulvestrant, as compared with palbociclib plus placebo, due to drug interactions³³. This suggests that drug combination may be a way to overcome some AEs.

Pneumonitis was an adverse effect not reported in the phase 3 trials of palbociclib, but that has been reported in the literature^34–37. The incidence of pulmonary toxicity is about 1%³⁸. Our results showed three positive signals for pneumonitis [ROR 2.10(1.81 to 2.43), PRR 2.10(7.09), IC 1.06(0.85), EBGM 2.08(1.84)] (Meet 3 algorithms). An animal experiment showed that palbociclib could alleviate bleomycin-induced pulmonary fibrosis in mice. Still, it did not improve lung function and led to the accumulation of inflammatory factors (including macrophages and T cells) in the lung³⁹. The same phenomenon has been observed in clinical cases^{40, 41}. In the event of pneumonia that is suspected to be due to palbociclib, palbociclib should be discontinued, and glucocorticoids and oxygen therapy should be used as appropriate⁴¹. In the SOC of respiratory, thoracic, and mediastinal disorders, we found another important positive signal, which was pulmonary thrombosis [ROR 3.69(3.11–4.38), PRR 3.69(7.59), IC 1.86(1.62), EBGM 3.63(3.14)] (Meet four algorithms). Although pulmonary thrombosis is not described in the package insert, it has been reported in some relevant case reports. The occurrence of pulmonary thrombosis may be due to the self-reduction of anticoagulant dose in patients receiving anticoagulant therapy during palbociclib treatment, or the overexpression of cyclin D1, CDK 4 and loss of CDKN2A in breast cancer patients⁴². In addition, the thrombotic risks associated with tamoxifen and aromatase inhibitors themselves need to be considered⁴³. Its mechanism is not clear, but this should raise enough attention. Severe pulmonary thrombosis can lead to death⁴⁴. Therefore, it is necessary to monitor patients with cardiovascular risk factors, including hypertension, coronary heart disease, and a history of thrombosis. Patients with sudden leg swelling, thrombophlebitis, shortness of breath, hypoxia, chest pain, tachypnea, and tachycardia should be evaluated promptly. This would help reduce the risk of death due to pulmonary thrombosis⁴⁵. Among respiratory, thoracic, and mediastinal disorders, we also identified another two PTs not reported in the package insert including pulmonary oedema [ROR 2.44(2.18–2.72), PRR 2.43(28.02), IC 1.27(1.11), EBGM 2.41(2.20)], pleural effusion [ROR 2.62(2.39–2.87), PRR 2.62(65.91), IC 1.37(1.24), EBGM 2.59(2.40)].

Figure 4 shows the stratified analysis for pulmonary toxicity (pneumonitis, pulmonary oedema, and pulmonary thrombosis). The results showed positive signals for pneumonitis, pulmonary oedema and pulmonary thrombosis in women but negative signals in men. This suggests that pulmonary toxicity (pneumonitis, pulmonary oedema and pulmonary thrombosis) may be more common in women taking palbociclib. Nevertheless, the results should be treated with caution because this method does not exclude bias arising from breast cancer itself. According to Fig. 4, it can also be found that the signal strength of all three AEs is stronger in those aged 18 ≤ and < 40 years than in those aged < 18 years and ≥ 40 years. This result suggests that female patients with breast cancer should be closely monitored for lung function while using palbociclib to prevent serious lung-related AEs. Similarly, women with breast cancer and comorbid lung disease should remain cautious when choosing to use palbociclib.

Three PTs were found with significant signals in general disorders and administration site conditions and not in the package insert: death [ROR 2.19(2.13–2.25), PRR 2.15(8577.46), IC 1.10(1.06), EBGM 2.14(2.09)], disease progression [ROR 4.99(4.75–5.24), PRR 4.96(1401.22), IC 2.27(2.20), EBGM 4.84(4.64)], and illness [ROR 3.03(2.81–3.28), PRR 3.03(152.76), IC 1.58(1.47), EBGM 2.99(2.80)]. However, death and disease progression is likely to be caused by the breast cancer disease itself rather than by palbociclib. In investigations, we identified a total of 14 PTs not reported in the package insert, including white blood cell count decreased [ROR 28.46(27.79–29.15), PRR 27.30(51225.58), IC 4.55(4.52), EBGM 23.43(22.97)], neutrophil count decreased [ROR 12.86(12.19–13.57), PRR 12.77(1438.39), IC 3.57(3.50), EBGM 11.89(11.37)], and red blood cell count decreased [ROR 14.55(13.71–15.44), PRR 14.47(1000.42), IC 3.74(3.65), EBGM 13.34(12.69)], etc. Among nervous system disorders, we identified a total of 2 PTs, including neuropathy peripheral [ROR 2.87(2.69–3.07), PRR 2.86(269.04), IC 1.27(1.11), EBGM 2.41(2.20)] and ageusia [ROR 2.70(2.35–3.11), PRR 2.70(12.70), IC 1.42(1.22), EBGM 2.67(2.38)] not reported in the package insert. Among psychiatric disorders, it was found that eating disorder [ROR 2.82(2.45–3.24), PRR 2.82(13.72), IC 1.48(1.28), EBGM 2.78(2.48)] was not reported in the package insert. Among reproductive system and breast disorders, breast pain [ROR 3.76(3.15–4.49), PRR 3.76(6.91), IC 1.89(1.64), EBGM 3.70(3.19)] was found not reported in the package insert.

Interestingly, onychoclasis [ROR 8.13(7.03–9.41), PRR 8.13(22.67), IC 2.96(2.75), EBGM 7.78(6.89)], nail disorder [ROR 7.43(6.39–8.64), PRR 7.43(18.96), IC 2.84(2.62), EBGM 7.14(6.29)], night sweats [ROR 2.42(2.12–2.75), PRR 2.41(15.19), IC 1.26(1.08), EBGM 2.39(2.15)], and hypoacusis [ROR 3.40(3.12–3.71), PRR 3.40(117.39), IC 1.74(1.62), EBGM 3.35(3.11)] were found to have positive signals, which were not reported in the package insert. Although the hypothesis of onychoclasis is the same as that of the other study, there is a lack of evidence-based evidence, so further prospective trials are needed to verify whether there is a causal relationship between onychoclasis and palbociclib⁴⁶.

We also found a lot of signals that were consistent with the package insert. For example, in the SOC of blood and lymphatic system disorders, the PT that conforms to all four algorithms and is reported in the drug package includes neutropenia [ROR 8.04(7.76–8.33), PRR 7.92(6673.17), IC 2.92(2.87), EBGM 7.59(7.37)], leukopenia [ROR 5.28(4.91–5.67), PRR 5.26(301.53), IC 2.36(2.25), EBGM 5.12(4.82)], and cytopenia [ROR 5.38(4.69–6.17), PRR 5.37(24.29), IC 2.39(2.19), EBGM 5.23(4.66)]. Moreover, Stefanie L. Groenland, who developed a drug metabolism model, found that palbociclib-induced neutropenia was proportional to drug exposure and suggested that in some patients with neutropenia, appropriate dose reductions or longer intervals between doses of palbociclib may be necessary⁴⁷.

In the SOC of gastrointestinal disorders, nausea [ROR 2.39(2.32–2.45), PRR 2.35(8798.71), IC 1.22(1.18), EBGM 2.33(2.27)], oral pain [ROR 8.36(7.70–9.09), PRR 8.34(217.98), IC 3.00(2.88), EBGM 7.97(7.44)], stomatitis [ROR 10.73(10.25–11.23), PRR 10.63(2645.13), IC 3.33(3.26), EBGM 10.03(9.65)], glossodynia [ROR 2.50(2.14–2.92), PRR 2.50(7.54), IC 1.31(1.09), EBGM 2.48(2.17)], mouth ulceration [ROR 3.02(2.61–3.49), PRR 3.02(12.10), IC 1.58(1.37), EBGM 2.98(2.64)], gingival pain [ROR 4.69(3.86–5.70), PRR 4.69(5.41), IC 2.20(1.92), EBGM 4.58(3.89)], and oral mucosal blistering [ROR 5.74(4.81–6.84), PRR 5.73(9.17), IC 2.48(2.23), EBGM 5.57(4.81)] were described in the package insert of palbociclib. Of note, a case observation found that esophageal ulcers were more severe when patients received palbociclib plus radiotherapy than when they received palbociclib alone. This suggests that more attention should be paid to the risk of esophageal ulcers when adding radiotherapy to palbociclib-treated patients⁴⁸.

In addition, there were 61,821 reports of palbociclib, with the majority of patients being women older than 40 years of age. This is consistent with the epidemiology of breast cancer⁶. The number of reported adverse effects of palbociclib in FAERS has increased yearly since its approval in 2015. This may reflect growing palbociclib prescribing or rising public concern about adverse effects. In addition, the number of AEs to palbociclib increased as the dose was administered in Fig. 2, reflecting that high doses of palbociclib are more likely to cause AEs. This suggests that physicians must have contingency plans to deal with AEs when using high doses of palbociclib.

FIGURE 3 showed that the incidence of AEs was highest within one month of taking palbociclib (33.7%). This was followed by one year after taking palbociclib (18.49%), followed by between one and two months of taking palbociclib (11.46%). This suggests that patients' indicators, especially blood count and pulmonary function, should be closely monitored during the first three months of palbociclib administration. For patients taking palbociclib for more than one year, an effective follow-up mechanism should also be established to follow up on the health status of the patients after taking the drug. In addition, we calculated the latency of AEs to help identify rare and long-latency AEs. This is also one of the characteristics of big data mining.

There are only two reports on data mining of palbociclib AEs by FAERS, one focusing on analyzing of the relationship between palbociclib and skin toxicity and the other comparing the effects of palbociclib and abemaciclib in the lung, and no comprehensive data mining reports have been seen^{22, 46}. Therefore, this study systematically analyzed of the potential AEs of palbociclib by summarizing all AE data in FAERS from the first quarter of 2015 to the present and found some AEs not reported in the description.

Although big data mining of AEs based on the real world has certain advantages, it also has some shortcomings. First, FAERS is an open system that includes many adverse-reaction reports uploaded by nonmedical professionals, which may lead to reporting bias. Second, the raw data in the FAERS database may have errors that have not been detected, which may lead to analysis bias. Third, the study did not examine the causal relationship between palbociclib and specific adverse effects, which requires further experimental verification. Fourth, the database is mainly reported from the United States, and there is a lack of data from other regions or countries. Therefore, the applicability of the assumptions derived from this study is limited. Moreover, because the study was a comprehensive data mining of adverse effects of palbociclib, rather than focusing on a few or one class of adverse effects, the study was difficult to control for bias by setting positive controls. At the same time, because this study did not exclude the interference of indications, combination drugs, complications, etc., the applicability of the hypothesis proposed in this study is limited, and prospective experimental verification or data mining for specific AEs is needed. Despite its limitations, this study can provide some reference for the pharmacovigilance of palbociclib.

From the first quarter of 2015 to the third quarter of 2022, the FAERS system collected a total of 12367994 reports, of which 61821 reported palbociclib as a “PS”. These 61821 reports included 195616 AEs associated with palbociclib. The AEs of palbociclib are concentrated in three SOCs of general disorders and administration site conditions, gastrointestinal disorders, and investigations, and therefore require extra attention. Pulmonary toxicity, hematologic toxicity, and myelosuppression are the major risk with palbociclib. The AEs mainly occurred in the first three months and one year after using palbociclib, and regular follow-up of patients using palbociclib may help to identify more potential adverse effects. At the same time, we also found some potential AEs that were not reported in the package insert, which provided a reference for the revision of the package insert in the future. In conclusion, this study provides a comprehensive overview of the reported and potential adverse effects of palbociclib and cautions against a high risk of adverse effects. However, the causal relationship between palbociclib and specific adverse effects must be further tested.

The authors have indicated that they have no conflicts of interest with regard to the content of this article.

DATA AVAILABILITY STATEMENT

The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author.

AUTHOR CONTRIBUTIONS

QC was responsible for the design of the study, data processing and the writing of the article. MHS was responsible for the guidance and design of the project. XS was responsible for the collection of data, and YZZ and SPZ were responsible for the revision of the manuscript.

FUNDING SUPPORT

None.

【AUTHOR CONTRIBUTIONS】

【Author Disclosures】

All authors disclosed no relevant relationships.

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Post-Marketing Safety Concerns With Palbociclib A Disproportionality Analysis of the FDA Adverse Event

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Abstract

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INTRODUCTION

METHODS

Data Source

Adverse Event and Drug Identification

Data Mining

RESULTS

Descriptive Analysis

Disproportionality Analysis

Signal at the SOC level

Signal at the PT level

Time to Onset of Palbociclib-Associated Adverse Events

Stratification analysis

DISCUSSION

Conclusion

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References

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