Evaluation of Serious Adverse Drug Reactions

Bennett, Charles L.; Nebeker, Jonathan R.; Yarnold, Paul R.; Tigue, Cara C.; Dorr, David A.; McKoy, June M.; Edwards, Beatrice J.; Hurdle, John F.; West, Dennis P.; Lau, Denys T.; Angelotta, Cara; Weitzman, Sigmund A.; Belknap, Steven M.; Djulbegoviĉ, Benjamin; Tallman, Martin S.; Kuzel, Timothy M.; Benson, Al B.; Evens, Andrew M.; Trifilio, Steven; Courtney, D. Mark; Raisch, Dennis W.

doi:10.1001/archinte.167.10.1041

Cited by 42 publications

(21 citation statements)

References 40 publications

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“…In interpreting our findings, several factors, particularly epidemiology of melanoma, natalizumab‐associated progressive multifocal leukoencephalopathy (PML), various aspects of the TOUCH Risk Management (RiskMAP) Action Plan, and the Safety Surveillance Program in this RiskMAP (Table 3), potential pathophysiology, and an overview of pharmacovigilance efforts for opportunistic complications of medications, should be considered 6, 7, 8, 9, 10, 11, 13, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47.…”

Section: Discussionmentioning

confidence: 99%

“…FDA case reporting is limited as only 1% of all adverse events, such as natalizumab‐associated melanoma, are included in FAERS and 25–50% completeness occurs in reporting of individual cases 6, 12, 45. Pathologic documentation was recorded in 78% of reports of melanoma cases reported to regulatory agencies versus 100% pathologic confirmation for the index case and the seven published cases.…”

Section: Discussionmentioning

confidence: 99%

“…5, 6, 10, 14. Inclusion criteria included: use of natalizumab prior to melanoma diagnosis and diagnosis of melanoma based on pathology information included in the adverse event report (as in the seven case reports and the index case) or notations in FAERS reports that melanoma had been diagnosed (there was not communication back to the reporter seeking report verification).…”

Section: Methodsmentioning

confidence: 99%

“…The most serious complication of natalizumab is progressive multifocal leukoencephalopathy (PML), an adverse drug reaction (ADR) confirmed to have been reported in 714 patients through March 6, 2017, and a risk estimate of 4.2/1000 patients (95% confidence interval, 3.89‐4.52) 5. PML is also a known complication of therapy with rituximab, an ADR initially reported in 2009 6. In 2012, receiving an immune suppressing medication prior to initiating natalizumab was identified as an additional risk factor for PML.…”

Section: Introductionmentioning

confidence: 99%

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Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

et al. 2017

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A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P < 0.0007). Clinicians should monitor existing nevi and maintain suspicion for melanoma developing in natalizumab‐treated patients. The TOUCH Safety Surveillance Program, currently focused on progressive multifocal leukoencephalopathy, should be expanded to include information on other serious complications including malignancies, particularly if they are immunologic in nature.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

et al. 2017

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“…ADRs are among the top 10 leading causes of death [1,2]. It is estimated that 100,000 deaths per year are attributed to ADRs [3].…”

Section: Introductionmentioning

confidence: 99%

Idiosyncratic Drug Reactions

Wojcinski

Uetrecht

2012

Encyclopedia of Drug Metabolism and Interactions

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Idiosyncratic drug reactions (IDRs) are adverse drug reactions that are not related to the known pharmacological properties of the drug occur in only a small percentage of the population and do not show any apparent dose–response relationship. The unpredictable nature of IDRs together with the often serious adverse effects encountered pose a major health concern in the development and clinical usage of pharmaceuticals. The mechanism of IDRs is not clearly understood, and although several theories have been proposed, IDRs can be generally categorized mechanistically as either immune mediated or non‐immune‐mediated. There is circumstantial evidence that suggests that most idiosyncratic reactions are hypersensitivity reactions initiated by the formation of chemically reactive metabolites that bind to proteins and induce an immune‐mediated response. Investigations in animal models have had limited success owing to the unpredictability of IDRs in animals, which is similar to the situation in humans. However, IDRs in animals do share some similar characteristics and mechanisms observed in humans supporting the need for further study of animal models.

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Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: A report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project

Carson

Newsome²,

Kim

et al. 2014

Cancer

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Purpose Brentuxiumab vedotin (BV) is an anti-CD30 monoclonal antibody-drug conjugate approved in 2011 for treating anaplastic large cell and Hodgkin lymphomas. The product label indicates that three BV-treated patients developed progressive multifocal leukoencephalopathy (PML), a frequently fatal JC-virus induced central nervous system infection. Prior immunosuppressive therapy and compromised immune systems were postulated risk factors. We report 5 patients who developed BV-associated PML, including two immunocompetent patients. Patients Case information was obtained from clinicians (four patients) or a Food and Drug Administration database (one patient). Results All five patients had lymphoid malignancies. Two patients with cutaneous T-cell lymphomas had not previously received chemotherapy. PML developed after a median of three BV doses (range, 2 to 6) and within a median of 7 weeks following BV initiation (range, 3 to 34 weeks). Presenting findings included aphasia, dysarthria, confusion, hemiparesis, and gait dysfunction; JC virus in cerebrospinal fluid (two patients), or CNS biopsy (three patients); and brain MRI scans with white matter abnormalities (five patients). Four patients died a median of 8 weeks (range, 6 to 16 weeks) after PML diagnosis. The sole survivor developed immune reconstitution inflammatory syndrome. Conclusion PML can develop after a few BV doses and within weeks of BV initiation. Clinicians should be aware of this syndrome, particularly when neurologic changes develop following BV initiation. The decision to administer BV to patients with indolent cutaneous lymphomas should be based on consideration of risk-benefit profiles and of alternative options.

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Evaluation of Serious Adverse Drug Reactions

Cited by 42 publications

References 40 publications

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

Melanoma complicating treatment with natalizumab for multiple sclerosis: A report from the Southern Network on Adverse Reactions (SONAR)

Idiosyncratic Drug Reactions

Progressive multifocal leukoencephalopathy associated with brentuximab vedotin therapy: A report of 5 cases from the Southern Network on Adverse Reactions (SONAR) project

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