NEWS
Smokeless Tobacco Linked to Subtherapeutic INR in Warfarin-Treated Patient
Failure to achieve a therapeutic international normalized ratio ( INR ) with warfarin was associated with chronic exposure to vitamin K-rich smokeless chewing tobacco in a recent case report published in the
YESCARTA and TECARTUS REMS Program : Because of the risk of CRS and neurologic toxicities , TECARTUS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the YESCARTA and TECARTUS REMS Program . The required components of the YESCARTA and TECARTUS REMS Program are :
• Healthcare facilities that dispense and administer TECARTUS must be enrolled and comply with the REMS requirements . Certified healthcare facilities must have on-site , immediate access to tocilizumab , and ensure that a minimum of two doses of tocilizumab are available for each patient for infusion within two hours after TECARTUS infusion , if needed for treatment of CRS .
• Certified healthcare facilities must ensure that healthcare providers who prescribe , dispense , or administer TECARTUS are trained in the management of CRS and neurologic toxicities .
Further information is available at www . YescartaTecartusREMS . com or 1-844-454-KITE ( 5483 ).
Hypersensitivity Reactions : Serious hypersensitivity reactions , including anaphylaxis , may occur due to dimethyl sulfoxide ( DMSO ) or residual gentamicin in TECARTUS .
Severe Infections : Severe or life-threatening infections occurred in patients after TECARTUS infusion . In ZUMA-2 , infections ( all grades ) occurred in 56 % of patients . Grade 3 or higher infections , including bacterial , viral , and fungal infections , occurred in 30 % of patients . TECARTUS should not be administered to patients with clinically significant active systemic infections . Monitor patients for signs and symptoms of infection before and after TECARTUS infusion and treat appropriately . Administer prophylactic antimicrobials according to local guidelines . Febrile neutropenia was observed in 6 % of patients after TECARTUS 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 . Viral Reactivation : 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 . Perform screening for HBV , hepatitis C virus ( HCV ), and human immunodeficiency virus ( 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 TECARTUS infusion . In ZUMA-2 , Grade 3 or higher cytopenias not resolved by Day 30 following TECARTUS infusion occurred in 55 % of patients and included thrombocytopenia ( 38 %), neutropenia ( 37 %), and anemia ( 17 %). Monitor blood counts after TECARTUS infusion .
Hypogammaglobulinemia : B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with TECARTUS . In ZUMA-2 , hypogammaglobulinemia occurred in 16 % of patients . Monitor immunoglobulin levels after treatment with TECARTUS and manage using infection precautions , antibiotic prophylaxis , and immunoglobulin replacement . The safety of immunization with live viral vaccines during or following TECARTUS treatment has not been studied . Vaccination with live virus vaccines is not recommended for at least six weeks prior to the start of lymphodepleting chemotherapy , during TECARTUS treatment , and until immune recovery following treatment with TECARTUS .
Secondary Malignancies : Patients treated with TECARTUS may develop secondary malignancies . Monitor life-long for secondary malignancies . In the event that a secondary malignancy occurs , contact Kite at 1-844-454-KITE ( 5483 ) to obtain instructions on patient samples to collect for testing .
Effects on Ability to Drive and Use Machines : Due to the potential for neurologic events , including altered mental status or seizures , patients receiving TECARTUS are at risk for altered or decreased consciousness or coordination in the eight weeks following TECARTUS 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 .
ADVERSE REACTIONS : The following clinically significant adverse reactions are described in Warnings and Precautions : Cytokine Release Syndrome , Neurologic Toxicities , Hypersensitivity Reactions , Severe Infections , Prolonged Cytopenias , Hypogammaglobulinemia .
Clinical Trials Experience : Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice . Patients with Relapsed / Refractory Mantle Cell Lymphoma ( MCL ): The safety of TECARTUS was evaluated in a Phase 2 single-arm , clinical study ( ZUMA-2 ) in which a total of 82 patients with relapsed / refractory MCL received a single dose of CAR-positive viable T cells ( 2 × 10 6 or 0.5 × 10 6 anti-CD19 CAR T cells / kg ) that was weight-based . The most common adverse reactions ( incidence ≥ 20 %) were pyrexia , CRS , hypotension , encephalopathy , fatigue , tachycardia , arrhythmia , infection – pathogen unspecified , chills , hypoxia , cough , tremor , musculoskeletal pain , headache , nausea , edema , motor dysfunction , constipation , diarrhea , decreased appetite , dyspnea , rash , insomnia , pleural effusion , and aphasia . Serious adverse reactions occurred in 66 % of patients . The most common serious adverse reactions (> 2 %) were encephalopathy , pyrexia , infection – pathogen unspecified , CRS , hypoxia , aphasia , renal insufficiency , pleural effusion , respiratory failure , bacterial infections , dyspnea , fatigue , arrhythmia , tachycardia , and viral infections . The most common ( ≥ 10 %) Grade 3 or higher reactions were anemia , neutropenia , thrombocytopenia , hypotension , hypophosphatemia , encephalopathy , leukopenia , hypoxia , pyrexia , hyponatremia , hypertension , infection-pathogen unspecified , pneumonia , hypocalcemia , and lymphopenia .
Summary of Adverse Reactions Observed in at Least 10 % of Patients Treated with TECARTUS in ZUMA-2 ( N = 82 )
Blood and lymphatic system disorders
Cardiac disorders
Gastrointestinal disorders
General disorders and administration site conditions
Immune system disorders
Adverse Reaction
Any Grade (%)
Grade 3 or Higher (%)
Coagulopathy 10 2
Tachycardias Bradycardias Non-ventricular Arrhythmias
Nausea Constipation Diarrhea Abdominal pain Oral pain Vomiting Dysphagia
Pyrexia Fatigue Chills Edema Pain
Cytokine release syndrome Hypogammaglobulinemia
45 10 10
35 29 28 17 16 13 10
94 48 41 35 17
91 16
0 0 4
1 0 5 0 0 0 2
15 1 0 2 2
18 1
Journal of Thrombosis and Haemostasis . These findings suggest that tobacco cessation is an important additional treatment target to consider when prescribing the anticoagulant .
Infections and infestations
Metabolism and nutrition disorders
Musculoskeletal and connective tissue disorders
Nervous system disorders
Psychiatric disorders
Renal and urinary disorders
Respiratory , thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Vascular disorders
Adverse Reaction
Infections – pathogen unspecified Viral infections Bacterial infections
Any Grade (%)
43 18 13
Grade 3 or Higher (%)
24 4 6
Decreased appetite 26 0
Musculoskeletal pain Motor dysfunction
Encephalopathy Tremor Headache Aphasia Dizziness Neuropathy
Insomnia Delirium Anxiety
Renal insufficiency Urine output decreased
Hypoxia Cough Dyspnea Pleural effusion
For a complete list of events that contributed to the incidence of certain adverse reactions , please see footnote below Table 3 in Section 6.1 of the Full Prescribing Information .
Other clinically important adverse reactions that occurred in less than 10 % of patients treated with TECARTUS include the following : gastrointestinal disorders : dry mouth ( 7 %); infections and infestations disorders : fungal infections ( 9 %); metabolism and nutrition disorders : dehydration ( 6 %); nervous system disorders : ataxia ( 7 %), seizure ( 5 %), increased intracranial pressure ( 2 %); respiratory , thoracic and mediastinal disorders : respiratory failure ( 6 %), pulmonary edema ( 4 %); skin and subcutaneous tissue disorders : rash ( 9 %); vascular disorders : hemorrhage ( 7 %).
Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10 % of Patients in ZUMA-2 Following TECARTUS Infusion ( N = 82 ): leukopenia 95 %, neutropenia 95 %, lymphopenia 86 %, thrombocytopenia 63 %, anemia 55 %, hypophosphatemia 30 %, hypocalcemia 21 %, blood uric acid increased 17 %, hyponatremia 16 %, aspartate aminotransferase increased 15 %, alanine aminotransferase increased 15 %, hypokalemia 10 %.
Immunogenicity : TECARTUS has the potential to induce anti-product antibodies , which has been evaluated using an enzyme-linked immunosorbent assay ( ELISA ) for the detection of binding antibodies against FMC63 , the originating antibody of the anti-CD19 CAR . To date , no anti-CAR T-cell antibody immunogenicity has been observed . Based on an initial screening assay , 17 patients tested positive for antibodies ; however , a confirmatory orthogonal cell-based assay demonstrated that all 17 patients were antibody negative at all time points tested . There is no evidence that the kinetics of initial expansion and persistence of TECARTUS , or the safety or effectiveness of TECARTUS , was altered in these patients .
USE IN SPECIFIC POPULATIONS
Pregnancy : Risk Summary : There are no available data with TECARTUS use in pregnant women . No animal reproductive and developmental toxicity studies have been conducted with TECARTUS to assess whether TECARTUS can cause fetal harm when administered to a pregnant woman . It is not known if TECARTUS has the potential to be transferred to the fetus . Based on the mechanism of action of TECARTUS , if the transduced cells cross the placenta , they may cause fetal toxicity , including B cell lymphocytopenia . Therefore , TECARTUS is not recommended for women who are pregnant . Pregnancy after TECARTUS infusion should be discussed with the treating physician . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 % - 4 % and 15 % - 20 %, respectively .
Lactation : Risk Summary : There is no information regarding the presence of TECARTUS in human milk , the effect on the breastfed infant , and the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for TECARTUS and any potential adverse effects on the breastfed infant from TECARTUS or from the underlying maternal condition .
Females and Males of Reproductive Potential : Pregnancy Testing : Pregnancy status of females with reproductive potential should be verified . Sexually active females of reproductive potential should have a negative pregnancy test prior to starting treatment with TECARTUS . Contraception : See the prescribing information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy . There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with TECARTUS . Infertility : There are no data on the effect of TECARTUS on fertility .
Pediatric Use : The safety and efficacy of TECARTUS have not been established in pediatric patients .
Geriatric Use : Of the 82 patients treated with TECARTUS , 42 were ≥ 65 years of age and 40 were < 65 years of age . No overall differences in safety or effectiveness were observed between patients ≥ 65 years of age and younger patients .
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TECARTUS is a trademark of Kite Pharma , Inc . All other trademarks referenced herein are the property of their respective owners .
© 2020 Kite Pharma , Inc . All rights reserved . | 07 / 2020
37 17
51 38 35 20 18 13
21 18 16
18 11
40 38 24 21
Rash 22 4
Hypotension Hypertension Thrombosis
57 18 17
2 4
24 2 1 7 6 2
0 5 0
9 1
20 0 6 5
27 11 4
“ To our knowledge … this is the second case report of warfarin failure during exposure to smokeless tobacco ,” Diala Nicolas , PharmD , of St . Elizabeth ’ s Medical Center in Brighton , Massachusetts , and colleagues , wrote . Warfarin dosing can be challenging and subtherapeutic INR can be caused by a variety of factors , so “ multiple causes need to be considered and ruled out before attributing warfarin resistance to chronic accumulation of vitamin K resulting from smokeless tobacco .”
In their report , the investigators described the patient as a 33-yearold man who had a history of intravenous ( IV ) drug use . The patient also had a history of infective endocarditis , which had required placement of a mechanical mitral valve – one of the few remaining indications for which warfarin is the firstline therapy ( there are fewer data for novel anticoagulants ).
Warfarin treatment was prescribed with an INR goal between 2.5 and 3.5 . While the patient did not smoke cigarettes , he admitted to using chewing tobacco daily for the past 16 years . On admission to the hospital for detox after a 4-week , warfarin-free period of heavy drinking , the patient ’ s INR was 0.9 . Clinicians subsequently started an IV heparin drip to bridge the patient to warfarin therapy .
The clinicians were unable to determine whether INR had been therapeutic , as the patient had an inconsistent follow-up history with his warfarin clinic . Treatment of warfarin doses of up to 30 mg per day were unable to achieve therapeutic INR during his hospitalization . Warfarin nonadherence , diet , genetic factors , and drug interactions were considered causes of subtherapeutic INR , but were later considered unlikely for this patient ’ s case .
Excessive alcohol consumption also was considered as a risk factor for this patient ’ s reduced INR levels . However , heavy alcohol intake was felt to be a less likely cause of increased requirements for warfarin after his liver function tests were only mildly elevated , with a normal bilirubin , and warfarin resistance remained despite reduction of alcohol consumption .
The team then performed a literature review to identify potential
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