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Current
Drug Safety
ISSN: 1574-8863
Current Drug Safety
Volume 3, Number 2, May 2008
Contents
Managing Safety Signals in Large Endpoint Trials
Pp. 86-90
Demissie Alemayehu
[Abstract]
Immune Monitoring to Predict the Development
of Infections After Immunosuppression for Solid Organ Transplantation
and Autoimmune Diseases Pp. 91-99
Javier Carbone, Nallibe Lanio, Antonio Gallego and Elizabeth
Sarmiento
[Abstract]
Advances in Machine Learning Prediction of Toxicological
Properties and Adverse Drug Reactions of Pharmaceutical Agents
Pp. 100-114
Xiao Hua Ma, Rong Wang, Yin Xue, Ze Rong Li, Sheng Yong
Yang, Yu Quan Wei and Yu Zong Chen
[Abstract]
Side Effects of Clozapine and Some Other Psychoactive
Drugs Pp. 115-122
Robert J. Flanagan
[Abstract]
The Effect of Pharmacotherapy for Attention Deficit
Hyperactivity Disorder on Risk of Seizures in Pediatric Patients
as Assessed in an Insurance Claims Database Pp. 123-131
Andrew T. McAfee, Karen C. Holdridge, Catherine B. Johannes,
Kenneth Hornbuckle and Alexander M. Walker
[Abstract]
Hepatic Effects of Duloxetine-I: Non-Clinical and
Clinical Trial Data Pp. 132-142
Joachim Wernicke, Beth Pangallo, Fujun Wang, Isabelle
Murray, Judith W. Henck, Mary Pat Knadler, Deborah N. D’Souza
and Jack P. Uetrecht
[Abstract]
Hepatic Effects of Duloxetine-II: Spontaneous Reports
and Epidemiology of Hepatic Events Pp. 143-153
Joachim Wernicke, Nayan Acharya, Indiana Strombom, James
L. Gahimer, Deborah N. D’Souza, Natalie DiPietro and
Jack P. Uetrecht
[Abstract]
Hepatic Effects of Duloxetine-III: Analysis of Hepatic
Events Using External Data Sources Pp. 154-162
Indiana Strombom, Joachim F. Wernicke, John Seeger, Deborah
N. D’Souza and Nayan Acharya
[Abstract]
Laboratory Monitoring of Hematological and Hepatic
Parameters in Ambulatory Patients Receiving Alpha-Methyldopa
in a Nigerian Tertiary Care Setting Pp. 163-166
Kazeem Babatunde Yusuff, Adeola Ajayi and Yunana Bonatson
Joseph
[Abstract]
Abstracts
[Back to top]
Managing Safety Signals in Large Endpoint Trials
Demissie Alemayehu
We consider the management of safety signals that arise
in the context of endpoint trials. Such trials have design
features which permit the detection of signals that otherwise
may be missed in more traditional settings. However, the approaches
that are typically employed to address them are less than
satisfactory in terms of both the analytical techniques and
the communication of the findings. In this paper, alternative
approaches are evaluated, and recommendations are given for
a comprehensive strategy that involves appropriate use of
study data as well as information external to the study. It
is emphasized that formulation and implementation of an effective
communication plan that enables informed decision making should
be an integral component of the strategy.
[Back to top]
Immune Monitoring to Predict the Development
of Infections After Immunosuppression for Solid Organ Transplantation
and Autoimmune Diseases
Javier Carbone, Nallibe Lanio, Antonio Gallego and Elizabeth
Sarmiento
Infections are relevant complications that cause morbidity
in solid organ transplantation and autoimmune diseases. Infection
represents a leading single cause of death in these patients.
Identification of patients at risk for development of infections
and specific intervention to decrease infection risk might
lead to better outcomes, though one needs first to evaluate
the presence of risk factors for infection.
Underlying disease itself, activity of the disease, presence
of co-morbidities, transplantation procedures along with immunosuppressive
and immunomodulatory therapies may be associated with an increased
risk of infections.
Among host factors, there are no reliable immunological markers
to predict infections. Immune monitoring (assessment of immunocompetence)
to estimate the risk of infection has so far not been performed
routinely, with the only exception of neutrophil counts, tuberculin
skin testing and serological evaluation of donor and recipients
of transplants for anti-cytomegalovirus IgG antibodies. However,
alterations of specific and non specific humoral and cellular
immunity may be associated with a higher risk of infection
among immunosuppressed patients.
We review studies that have been designed to assess immune
monitoring for prediction of infections in patients with selected
solid organ transplantations and systemic autoimmune diseases.
[Back to top]
Advances in Machine Learning Prediction of Toxicological
Properties and Adverse Drug Reactions of Pharmaceutical Agents
Xiao Hua Ma, Rong Wang, Yin Xue, Ze Rong Li, Sheng Yong
Yang, Yu Quan Wei and Yu Zong Chen
As part of the intensive efforts in facilitating drug discovery,
computational methods have been explored as low-cost and efficient
tools for predicting various toxicological properties and
adverse drug reactions (ADR) of pharmaceutical agents. More
recently, machine learning methods have been applied for developing
tools capable of predicting diverse spectrum of compounds
of different toxicological properties and ADR profiles. Based
on the results of a number of studies, these methods have
shown promising potential in predicting a variety of toxicological
properties and ADR profiles. This article reviews the strategies,
current progresses, underlying difficulties and future prospects
in using machine learning methods for predicting compounds
of specific toxicological property or ADR profile.
[Back to top]
Side Effects of Clozapine and Some Other Psychoactive
Drugs
Robert J. Flanagan
The recognition, management, and if possible prevention, of
major cardiovascular, central nervous system, haematological,
and metabolic adverse effects, including diabetes mellitus
and weight gain, of antipsychotics and some other drugs used
to treat mental illness is a topic of much debate. However,
a wide range of other adverse effects, some of which may be
life-threatening, may also be encountered. Side-effects reviewed
here include: gastrointestinal-associated effects (constipation,
hyper¬salivation, oro¬pharyngeal lesions, nasal congestion,
nausea, nocturnal enuresis, and urinary retention), metabolic
effects (obesity, insulin resistance, dyslipidemia, impaired
glucose tolerance, and hyper¬tension), neuromuscular effects
(extrapyramidal side effects, myoclonus, and neuroleptic malignant
syndrome, and pleurothotonus), thermoregulatory effects, effects
on the liver, pancreas, and kidney, sexual side effects, and
effects on skin and bone. Metabolic factors affecting the
incidence of adverse effects to clozapine especially are also
discussed.
The increasing use of atypical (second generation) antipsychotics
and indeed of selective serotonin reuptake inhibitors has
led to a greater appreciation of not only the benefits of
these drugs, but also of the spectrum of toxicity that may
occur in clinical practice. The adverse effects of antipsychotics
are a major factor in promoting poor adherence to, and even
discontinuation of, antipsychotic treatment on the one hand,
and increasing the risk of cardiovascular and metabolic disease
on the other. As such they merit recognition and either harm
minimization strategies (use of the minimum effective dose,
or use of lower doses of combinations of antipsychotics),
or in extreme cases discontinuation of the offending drug(s).
[Back to top]
The Effect of Pharmacotherapy for Attention Deficit
Hyperactivity Disorder on Risk of Seizures in Pediatric Patients
as Assessed in an Insurance Claims Database
Andrew T. McAfee, Karen C. Holdridge, Catherine B. Johannes,
Kenneth Hornbuckle and Alexander M. Walker
Purpose: To estimate the rate of new-onset seizure
in ADHD patients in relation to ADHD pharmacotherapy.
Methods: A retrospective cohort study of 34,727 patients,
ages 6 to 17, with at least two insurance claims bearing ADHD
diagnoses during 2003 in the UnitedHealthcare database. Incidence
of seizure was calculated for observation time during treatment
with atomoxetine and stimulants/bupropion.
Results: Seizure incidence among ADHD patients was
4.5/1,000 person-years (p-y; 95% confidence interval 3.7 –
5.5). ADHD patients who received any ADHD medication had an
incidence of 3.8/1,000 p-y (3.0 – 4.8) compared to 8.7
(5.8 –12.4) for patients who did not receive any ADHD
medication. The relative risk (RR) for current vs non-use
of atomoxetine was 1.1 (0.6 – 2.1). For stimulants and
bupropion, the RR for current vs non-use was 0.8 (0.6 –
1.3). Elevated seizure risks were found in association with
central nervous system (CNS) disease (OR 3.9, 1.2 –
10.9), CNS medications (OR 2.2, 1.3 – 3.6), metabolic
disease (OR 2.9, 1.1 – 6.8), and psychiatric disease
risk factors (OR 1.7, 1.1 – 2.6).
Conclusions: In this study, there was no statistically
significant association between use of atomoxetine or stimulants
and seizure risk in children ages 6 to 17 years with ADHD
and without prior seizure disorder.
[Back to top]
Hepatic Effects of Duloxetine-I: Non-Clinical and
Clinical Trial Data
Joachim Wernicke, Beth Pangallo, Fujun Wang, Isabelle
Murray, Judith W. Henck, Mary Pat Knadler, Deborah N. D’Souza
and Jack P. Uetrecht
Objective: Review nonclinical and clinical trial
data for hepatic effects of duloxetine.
Methods: Review studies of toxicology, metabolism,
mitochondrial effects, and clinical trials.
Results: Nonclinical studies revealed no treatment-related
transaminase elevations and no effects of duloxetine on mito-chondrial
beta-oxidation in rat hepatocytes. In patients with a normal
baseline alanine transaminase (ALT), duloxetine was associated
with elevated transaminases >3X ULN in about 1% of patients.
ALT and aspartate transaminase values peaked at 8 weeks, alkaline
phosphatase steadily increased to maximum value at Week 52
and mean total bilirubin values were not increased. Hepatic-related
treatment-emergent adverse events were uncommon. Seven of
23,000 duloxetine- and 2/6000 placebo-treated patients met
criteria for modified Hy’s rule (significant elevation
of both ALT and total bilirubin) but were complicated by contributing
factors such as excessive alcohol consumption (n=3), gall
stones, common bile duct calculus, hepatitis C, and liver
adenocarcinoma (n=1 each).
Conclusions: Duloxetine has an effect on the liver,
manifested by transient, self-limiting transaminase elevations.
Rare events characterized as hepatocellular injury, cholestatic
injury, or mixed type of hepatic injury have been reported.
The pattern of liver effects was different from that in laboratory
animals.
[Back to top]
Hepatic Effects of Duloxetine-II: Spontaneous Reports
and Epidemiology of Hepatic Events
Joachim Wernicke, Nayan Acharya, Indiana Strombom, James
L. Gahimer, Deborah N. D’Souza, Natalie DiPietro and
Jack P. Uetrecht
Objective: Review spontaneous reports and epidemiology
of hepatic events associated with duloxetine.
Methods: Spontaneous reports of adverse events potentially
associated with hepatic injury were identified. Classification
schemes were Clinical Significance and Etiologic Category
relative to likelihood of being related to duloxetine.
Results: Duloxetine has been taken by an estimated
5,083,000 patients, representing approximately 1,551,000 person-years
(PY) of worldwide exposure. In the Etiologic categorization
of the 406 cases containing event terms potentially related
to the liver that have been reported to the manufacturer,
26 were deemed Probable and 127 Possible. Because of scantly-reported
information, 182 cases were considered Indeterminate. For
Severe Hepatic Injury, the observed spontaneous reporting
rate was 0.7/100,000 persons exposed. Of the 406 cases, 225
experienced enzyme elevations to values <500 U/L, most
with concentrations well below this level. The calculated
cumulative spontaneous reporting rate of all duloxetine hepatic-related
events combined was 0.00799%, in the context of other drug-induced
hepatic injury rates reported in the literature of 0.7 to
40.6 per 100,000 PY of observation.
Conclusions: There were few cases of true hepatic
injury possibly or probably related to duloxetine. The calculated
cumulative reporting rate is consistent with very rarely reported
per the Council for International Organizations of Medical
Sciences.
[Back to top]
Hepatic Effects of Duloxetine-III: Analysis of Hepatic
Events Using External Data Sources
Indiana Strombom, Joachim F. Wernicke, John Seeger, Deborah
N. D’Souza and Nayan Acharya
Objective: Present results from two hepatic safety
studies conducted within 20 months after duloxetine launch.
Methods: Signal detection based on spontaneous reports
to the FDA adverse event reporting system (AERS) and on a
comparison of duloxetine and venlafaxine in the i3 Drug Safety
Aperio claims database, using measures of disproportionality
and incidence rate ratio, respectively.
Results: In AERS all antidepressants had some degree
of association with hepatic injury, in that at least one hepatic
event was disproportionately represented for each drug. Signals
were detected for duloxetine cases analyzed against full and
antidepressant-only backgrounds. These signals corresponded
to labeled events or events investigated during ongoing surveillance.
Using a duloxetine fatal-case series, disproportional representation
of clinically serious events was detected relative to both
backgrounds, but the signals were refuted upon independent
expert panel case review. The Aperio study showed no difference
in hepatic injury between duloxetine and venlafaxine initiators
after proper control for baseline risks, suggesting differential
prescribing of duloxetine, perhaps preferentially as second-line
therapy in some initiators.
Conclusions: No new signals were identified in Aperio.
New signals detected through AERS were refuted upon independently
conducted case-level investigation. Hepatic signals arising
from spontaneously reported data must be clarified through
subsequent systematic investigation.
[Back to top]
Laboratory Monitoring of Hematological and Hepatic
Parameters in Ambulatory Patients Receiving Alpha-Methyldopa
in a Nigerian Tertiary Care Setting
Kazeem Babatunde Yusuff, Adeola Ajayi and Yunana Bonatson
Joseph
The objective of the study is to assess the frequency and
comprehensiveness of laboratory monitoring of hematological
and hepatic parameters in ambulatory Nigerian hypertensive
patients on methyldopa therapy.
A retrospective cross sectional study was conducted between
1st February and 31st March 2007 at
the Medical Outpatient Clinic of a 900-bed premier teaching
hospital located in Ibadan, Nigeria. 260 case notes of hypertensive
patients, out of the 1178 case notes of patients who had been
prescribed at least 250mg of methyldopa for at least 2 months,
were reviewed.
22.1% of the hypertensive patients were on methyldopa alone
or in combination with other anti-hypertensives for a mean
period of 26.8±2.3 months (Range: 2-36 months). Overall,
red cell count was prescribed and conducted in only 15.4%
(40) of cohort. Only 4.2% (11) of patients had follow-up red
cell count done after one month of methyldopa therapy; 9 out
of these patients had marked reduction of red blood cells.
Only 2.3% of cohort had baseline Liver Function Test (LFT)
before start of methyldopa therapy and Alanine Transaminases
and Aspartate transaminases levels were elevated in all patients.
No patient had subsequent LFT prescribed and conducted particularly
within 6-12 weeks of use of methyldopa. Direct Anti-Globulin
Test was neither prescribed nor conducted in any of the cohort
before and after commencement of methyldopa therapy.
In conclusion, laboratory monitoring of ambulatory hypertensive
patients on methyldopa therapy particularly for possible hematological
and hepatic toxicities is less than optimal. The consequent
therapeutic benefit of continuing considerable prescription
and use of methyldopa in Nigeria is less likely to be realized
without proper monitoring to preclude possible methyldopa-use
related harms.
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