WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES
- Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH…+
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For:
Pediatric and Young Adult B-cell ALL
Efficacy
In the ELIANA trial, the majority of KYMRIAH patients attained and sustained remission
A potentially definitive treatment
ELIANA Study Design
Study characteristics of the global, phase 2 pivotal trial1,2
ELIANA was an open-label, multicenter, single-arm, global Phase II trial of tisagenlecleucel in 79 patients with B-cell ALL who were primary refractory, chemorefractory, relapsed after, or were not eligible for allogeneic SCT (NCT02228096).
ELIANA Baseline Characteristics
Inclusion/Exclusion Criteria2
• Inclusion:
– r/r B-cell ALL, aged 3-21 yearsa
– Bone marrow with ≥ 5% lymphoblasts
• Exclusion:
– Isolated extra-medullary disease relapse
– Prior CD19-directed or gene therapy
End Points1
• Primary: Overall remission rate (CR/CRi) within 3 months after infusion1
– 4-week maintenance of remission
– IRC assessment
• Secondary: CR or CRi with MRD-negative bone marrow, DOR, OS, EFS, cellular kinectics, safety1
aAge of 3 years at the time of screening to age 21 years at time of initial diagnosis.1
ALL, acute lymphoblastic leukemia; ASH, American Society of Hematology; CR, complete remission; CRi, complete remission with incomplete blood count recovery; DOR, duration of remission; EFS, event-free survival; IRC, Independent Review Committee; MRD, minimal residual disease; NEJM, New England Journal of Medicine; OS, overall survival; SCT, stem cell transplant; USPI, United States Prescribing Information.
ORR and MRD-Negative Remission
WITH KYMRIAH, THE MAJORITY OF PATIENTS ATTAINED AND SUSTAINED MRD-NEGATIVE REMISSION1
About 8/10 patients achieved minimal residual disease negative (MRD-negative) remission at 3 months after treatment with KYMRIAH® (tisagenlecleucel).1 MRD-negative status is a strong marker for positive prognosis.4
ORR, overall response rate.
bORR consisted of complete remission (CR) and complete remission with incomplete blood count recovery (CRi), defined as less than 5% of blasts in the bone marrow, no evidence of extramedullary disease, and without full recovery of peripheral blood counts with or without blood transfusion). Remission status was required to be maintained for at least 28 days without clinical evidence of relapse.2
cMRD-negative was defined as MRD by flow cytometry <0.01%.2
dFive patients who were infused with KYMRIAH were excluded from the efficacy set in the interim analysis. The efficacy analysis set (n=63) is a subset of the full analysis set (N=68), which consisted of all patients treated with KYMRIAH at least 3 months prior to data cutoff.2
eDay 28 assessment initially defined as ±7 days; definition changed to ±4 days after 1 site was enrolled, 3 patients were enrolled, and 1 patient was treated.5
REMISSION WAS ACHIEVABLE WITH KYMRIAH REGARDLESS OF CLINICAL CHARACTERISTICS5,6
KYMRIAH demonstrated consistent response rates across all subgroups evaluated, including high-risk patient subgroups
NR, not reported.
fFive patients who were infused with KYMRIAH were excluded from the efficacy set in the interim analysis. The efficacy analysis set (n=63) is a subset of the full analysis set (N=68), which consisted of all patients treated with KYMRIAH at least 3 months prior to data cutoff.2
gThe area of each box is proportional to the number of patients in the particular grouping. The 95% CIs are exact Clopper-Pearson CIs calculated for each subgroup.5
hIncludes 8 patients categorized with chemorefractory disease at study entry.6
RFS and OS
KYMRIAH DELIVERS DURABLE RESPONSES IN PATIENTS WITH R/R ALL (≤25 YEARS)1
Median relapse-free survival (RFS) was not reached at 24 months1
iRFS was defined as time since onset of CR or CRi to relapse or death due to underlying cancer, whichever is earlier, censoring for new cancer therapy including SCT.3
USPI: 4.8 MONTHS6
As reported in the USPI at 4.8 months after response, 75% of responders were estimated to still be in remission at 6 months, and 64% of responders were estimated to still be in remission at 9 and 12 months.6
KYMRIAH Persistence Based on Pharmacokinetics2
KYMRIAH was present in the blood and bone marrow, and was measurable beyond 2 years.
TWO-THIRDS OF PATIENTS TREATED WITH KYMRIAH WERE ALIVE AT 2 YEARS1
Median OS was not reached at 24 months1
- OS was a secondary efficacy end point of the global phase 2 pivotal trial1
- OS data are not in the Prescribing Information and should be interpreted with caution in a single-arm trial. The statistical significance of OS is not known
NE, not evaluable.
STEM CELL TRANSPLANT AFTER KYMRIAH DOES NOT APPEAR TO IMPROVE OVERALL SURVIVAL3,7
At a median follow-up of 13.1 months postinfusion, 87% of responders did not proceed to stem cell transplant (SCT).
No difference in OS was observed between the full patient population (including the 13% of patients who underwent SCT while in remission after KYMRIAH infusion) and those who did not receive SCT.
- OS was a secondary efficacy end point of the global phase 2 pivotal trial1
- OS data are not in the Prescribing Information and should be interpreted with caution in a single-arm trial. The statistical significance of OS is not known
Patient-reported QOL
PATIENTS REPORTED INCREASES IN QUALITY-OF-LIFE MEASURES AFTER KYMRIAH INFUSION8
KYMRIAH led to a decrease in severity of problems at Months 3 and 6 compared with baseline as assessed via the EQ-5D questionnaire.8
- The QoL study is not part of the Prescribing Information. The PedsQL, EQ VAS, and EQ-5D models were evaluated and validated in a patient population that did not include patients with pediatric ALL. The patient population decreased over time. The study’s statistical significance was not evaluated and, therefore, should be interpreted cautiously.
QOL, quality of life.
j107 patients were screened for the ELIANA trial between April 8, 2015, and April 25, 2017; 92 were enrolled, 75 received KYMRIAH, and 58 were aged 8 to 23 years and included in the analysis displayed here. Tumor response was evaluated on Day 28, every month, to Month 6, then every 3 months until Month 12. Patients are being followed for efficacy and safety for 5 years unless withdrawn from study by patient or investigator choice or lost to follow-up. The data shown are from the mixed model analysis.8
kThe 23-item PedsQL addresses the physical, emotional, social, and school functioning of healthy children and children with chronic disease (scale, 0‐100).8,10
lThe EQ-5D includes questions on the 5 dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression and a VAS that records self-rated overall health state (range, 0-100).8,11
Supporting Trial: CHP 959
CHP 959 study characteristics12,13
- • CHP 959 was an open-label, single-site, phase 1/2, supportive, proof-of-concept study of KYMRIAH in pediatric and young adult patients with r/r B-cell precursor ALL (N=62) initiated by University of Pennsylvania in 2012. These data were not included in the KYMRIAH Prescribing Information12
- • Enrolled patients aged 1-24 years (median, 11 years)12
- • Primary end point: Safety, feasibility, and duration of CAR-T cells in vivo12,m
- • Secondary end point: Anti-tumor activity, including13:
– Day 28 overall response rate (CR + CRi)
– DOR (from the date of CR/CRi to relapse or death due to underlying cancer) - • There were some differences noted between this study, and the pivotal ELIANA study, and results should be interpreted with caution
CNS, central nervous system.
mDetermined via reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of whole blood.12
Safety results from CHP 95914
The majority (89.3%) of patients with non–CNS3 ALL in CHP 959 experienced at least 1 serious adverse event any time after CTL019 infusion. The most common (incidence ≥20%, all grades) serious adverse events regardless of study drug relationship were CRS (82.1%), febrile neutropenia (71.4%), hypotension (39.3%), encephalopathy (26.8%), and pyrexia (23.2%). The most common (incidence >30%, all grades) adverse events regardless of study drug relationship in the non–CNS3 ALL group were decreased white blood cell count (WBC; 94.6%), decreased hemoglobin (92.9%), decreased neutrophil count (91.1%), CRS (89.3%), decreased platelet count (87.5%), lymphopenia (82.1%), febrile neutropenia (78.6%), vomiting (78.6%), aspartate aminotransferase (AST) increased (75.0%), headache (75.0%), nausea (75.0%), alanine aminotransferase (ALT) increased (71.4%), decreased appetite (69.6%), hypogammaglobulinemia (66.1%), diarrhea (57.1%), cough (55.4%), hypotension (51.8%), pain (48.2%), tachycardia (46.4%), fatigue (44.6%), chills (39.3%), increased blood creatinine (35.7%), pyrexia (35.7%), activated partial thromboplastin time prolonged (33.9%), hyperphosphatemia (33.9%), and abdominal pain (32.1%). The most frequently reported (in at least 30% of patients) grade 3/4 adverse events by preferred term (PT), regardless of study drug relationship, were febrile neutropenia (78.6%), decreased neutrophil count (69.6%), lymphopenia (67.9%), decreased WBC count (62.5%), decreased platelet count (48.2%), CRS (46.4%), decreased appetite (35.7%), hypotension (32.1%), decreased hemoglobin (30.4%) and increased ALT (30.4%).
Primary End Point: Safety in Non-CNS3 ALL Patients (n=56)
| Nonhematological adverse events | All Grades, (%) |
|---|---|
| Cytokine release syndrome | 91 |
| Febrile neutropenia | 80 |
| Vomiting | 79 |
| Headache | 75 |
| Nausea | 75 |
| Decreased appetite | 70 |
| Cough | 57 |
| Diarrhea | 57 |
| Hypotension | 52 |
| Pain | 48 |
| Tachycardia | 48 |
| Fatigue | 45 |
| Chills | 41 |
| Pyrexia | 36 |
| Abdominal pain | 32 |
Secondary End Point
REMISSION RATES BY BASELINE DISEASE BURDEN (N=60)14
CR, complete response.
nMRD-negative was defined as MRD by flow cytometry <0.01%.15
Patients Responded to Treatment With CTL019, Across Disease Characteristics15
- Data presented here are based on a different analysis of CHP 959 with a population of 60 patients
CNS INVOLVEMENT (N=60)14
| CNS status at infusion | Patients, n (%) |
|---|---|
| CNS1 | 54 (90) |
| CNS2o | 4 (7) |
| CNS3p | 2 (3) |
| CNS3p within 12 months of infusion | 16 (27) |
oCNS2 status defined as blast cells detected in a sample with <5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.16
pCNS3 status defined as blast cells detected in a sample with ≥5 leukocytes per cubic millimeter and <10 erythrocytes per cubic millimeter.16
Remission Rates by CNS Status15
- Experience with KYMRIAH in patients with active CNS leukemia is limited, and these data should be interpreted with caution
Persistence Based on Pharmacokinetics15
- 98% of all patients treated had detectable levels of CTL019 in cerebrospinal fluid (CSF), with lumbar puncture showing detectable CTL019 at 1 year
References: 1. Grupp SA, Maude SL, Rives S, et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia. Presented at: 60th American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 895. 2. Kymriah [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 3. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. 4. Borowitz MJ, Wood BL, Devidas M, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015;126(8):964-971. 5. Data on file. Study CTL019B2202. Novartis Pharmaceuticals Corp; Sept 2017. 6. Data on file. Study CTL019B. Novartis Pharmaceuticals Corp; Feb 2017. 7. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia [Supplemental Appendix]. N Engl J Med. 2018;378(5):1-27. 8. Laetsch TW, Myers GD, Baruchel A, et al. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial. Lancet Oncol. 2019;20(12):1710-1718. 9. Laetsch TW, Myers GD, Baruchel A, et al. Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial [Supplemental Appendix]. Lancet Oncol. 2019;20(12):1710-1718. 10. Varni JW, Burwinkle TM, Seid M, Skarr D. The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr. 2003;3(6):329-341. 11. Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ-5D utility and VAS scores in cancer. Health Qual Life Outcomes. 2007;5:70. 12. Data on file. Study CTL019B2101J. Novartis Pharmaceuticals Corp; Sept 2017. 13. Data on file. Study CTL019B2101J. Novartis Pharmaceuticals Corp; Dec 2016. 14. Data on file. CTL019B2101J First Interpretable Results, Final Analysis. Novartis Pharmaceuticals Corp; 2018. 15. Maude SL, Teachey DT, Rheingold SR, et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. Presented at: American Society of Clinical Oncology Annual Meeting; May 30, 2016; Chicago, IL. 16. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.
Indication
KYMRIAH is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse.
Important Safety Information for KYMRIAH® (tisagenlecleucel)
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGICAL TOXICITIES
- Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving KYMRIAH. Do not administer KYMRIAH to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids
- Neurological toxicities, which may be severe or life-threatening, can occur following treatment with KYMRIAH, including concurrently with CRS. Monitor for neurological events after treatment with KYMRIAH. Provide supportive care as needed
- KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS
Warnings and Precautions
Cytokine Release Syndrome: CRS, including fatal or life-threatening reactions, occurred following treatment with KYMRIAH. CRS occurred in 61 (77%) of the 79 patients with relapsed or refractory (r/r) ALL receiving KYMRIAH, including ≥ grade 3 (Penn Grading System) in 48% of patients. The median times to onset and resolution of CRS for patients with r/r ALL were 3 days (range: 1-22; 1 patient with onset after Day 10) and 8 days (range: 1-36), respectively.
Of the 61 patients with r/r ALL who had CRS, 31 (51%) received tocilizumab; 10 (16%) patients received 2 doses of tocilizumab, 3 (5%) patients received 3 doses of tocilizumab, and 17 (28%) patients received addition of corticosteroids (eg, methylprednisolone).
Two deaths occurred in patients with r/r ALL within 30 days of KYMRIAH infusion. One patient died with CRS and progressive leukemia, and 1 patient had resolving CRS with abdominal compartment syndrome, coagulopathy, and renal failure when an intracranial hemorrhage occurred. Among patients with r/r ALL who had CRS, key manifestations included fever (93%), hypotension (69%), hypoxia (57%), and tachycardia (26%). CRS may be associated with hepatic, renal, and cardiac dysfunction; and coagulopathy.
Delay KYMRIAH infusion after lymphodepleting chemotherapy if patient has unresolved serious adverse reactions from preceding chemotherapies including pulmonary toxicity, cardiac toxicity, or hypotension, active uncontrolled infection, active graft vs host disease, or worsening of leukemia burden.
Risk factors for severe CRS are high pre-infusion tumor burden (>50% blasts in bone marrow), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy, active infections, and/or inflammatory processes.
Ensure that a minimum of 2 doses of tocilizumab are available on-site prior to infusion of KYMRIAH. Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care, tocilizumab, and/or corticosteroids as indicated.
Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.
Neurological Toxicities: Neurological toxicities, including severe or life-threatening reactions, occurred in 56 (71%) of the 79 patients with r/r ALL following treatment with KYMRIAH including ≥ grade 3 in 22% of patients. Among patients who had a neurological toxicity, 84% occurred within 8 weeks after KYMRIAH infusion. Median time to the first event was 6 days from infusion (range: 1-301), and the median duration was 7 days. Resolution occurred within 3 weeks in 71% of patients. Encephalopathy lasting up to 70 days was noted. The onset of neurological toxicity can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.
The most common neurological toxicities observed in r/r ALL studies included headache (35%), encephalopathy (30%), delirium (19%), anxiety (16%), sleep disorders (11%), dizziness (5%), tremor (8%), and peripheral neuropathy (4%). Other manifestations included seizures and aphasia.
Monitor patients 2 to 3 times during the first week following KYMRIAH infusion at the REMS-certified health care facility for signs and symptoms of neurological toxicities. Rule out other causes of neurological symptoms. Monitor patients for signs or symptoms of neurological toxicities for at least 4 weeks after infusion and treat promptly. Neurological toxicity should be managed with supportive care and/or corticosteroids as needed.
Counsel patients to seek immediate medical attention should signs or symptoms of neurological toxicity occur at any time.
KYMRIAH REMS to Mitigate CRS and Neurological Toxicities: Because of the risk of CRS and neurological toxicities, KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS.
The required components of the KYMRIAH REMS are:
- Health care facilities that dispense and administer KYMRIAH must be enrolled in the program and comply with the REMS requirements
- Certified health care facilities must have on-site, immediate access to tocilizumab and ensure that a minimum of 2 doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion, if needed for treatment of CRS
- Certified health care facilities must ensure that health care providers who prescribe, dispense, or administer KYMRIAH are trained in the management of CRS and neurological toxicities
Further information is available at www.kymriah-rems.com or 1-844-4KYMRIAH (1-844-459-6742).
Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS, which can be life-threatening or fatal, has occurred following treatment with KYMRIAH. HLH was reported in 6% (5/79) of patients with r/r ALL (time to onset ranged from 3 to 18 days); all HLH events occurred during ongoing CRS and resolved. Treatment of HLH should be administered as per institutional standards.
Hypersensitivity Reactions: Allergic reactions may occur with KYMRIAH. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide or dextran 40 in KYMRIAH. Observe patients for hypersensitivity reactions during the infusion.
Serious Infections: Infections, including life-threatening or fatal infections, occurred in 125 (64%) of 194 patients after KYMRIAH infusion. Seventy-seven patients (40%) experienced ≥ grade 3 infections, including fatal infections in 2 patients (3%) with r/r ALL after KYMRIAH infusion. Prior to KYMRIAH infusion, infection prophylaxis should follow local guidelines. Patients with active uncontrolled infection should not start KYMRIAH treatment until the infection is resolved. Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately.
Febrile neutropenia (≥ grade 3) was also observed in 34% of patients with r/r ALL after KYMRIAH infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. There is no evidence with manufacturing KYMRIAH for patients with a positive test for HIV or with active HBV or active hepatitis C virus (HCV). Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.
Prolonged Cytopenias: Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion. In patients with r/r ALL, ≥ grade 3 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia (40%) and thrombocytopenia (27%) among 52 responding patients. At 56 days following KYMRIAH, 17% and 12% of responding patients had ≥ grade 3 neutropenia or thrombocytopenia, respectively. Prolonged neutropenia has been associated with increased risk of infection. Myeloid growth factors, particularly granulocyte-macrophage colony-stimulating factor, are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved.
Hypogammaglobulinemia: Hypogammaglobulinemia and agammaglobulinemia related to B-cell aplasia can occur in patients after KYMRIAH infusion. Hypogammaglobulinemia was reported in 53% of patients with r/r ALL. Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement standard guidelines.
The safety of immunization with live vaccines during or following KYMRIAH treatment has not been studied. Vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during KYMRIAH treatment, and until immune recovery following treatment with KYMRIAH.
Pregnant women who have received KYMRIAH may have hypogammaglobulinemia. Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH.
Secondary Malignancies: Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their cancer. Monitor lifelong for secondary malignancies. If a second malignancy occurs, call 1‑844‑4KYMRIAH (1-844-459-6742) to obtain instructions on patient samples to collect for testing.
Effects on Ability to Drive and Use Machines: Due to the potential for neurological events, including altered mental status or seizures, patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.
Drug Interactions
HIV and the lentivirus used to make KYMRIAH have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests may yield false positive results in patients who have received KYMRIAH.
Pregnancy, Lactation, Females and Males of Reproductive Potential
No data are available of KYMRIAH use in pregnant or lactating women. Therefore, KYMRIAH is not recommended for women who are pregnant or breastfeeding. A risk to the breastfed infant cannot be excluded. Pregnancy after KYMRIAH administration should be discussed with the treating physician. Pregnancy status of females of reproductive potential should be verified with a pregnancy test prior to starting treatment with KYMRIAH. Report pregnancies to Novartis Pharmaceuticals Corporation at 1‑888‑669‑6682.
Adverse Reactions
The most common adverse reactions (>20%) in patients with r/r ALL were CRS, infections-pathogen unspecified, hypogammaglobulinemia, fever, decreased appetite, viral infectious disorders, headache, febrile neutropenia, hemorrhage, musculoskeletal pain, vomiting, encephalopathy, diarrhea, hypotension, cough, nausea, bacterial infectious disorders, pain, hypoxia, tachycardia, edema, fatigue, and acute kidney injury.
Please see full Prescribing Information for KYMRIAH, including Boxed WARNING, and Medication Guide.
