Transcript BETA-LACTAM ANTIBIOTICS

ADVERSE EFFECTS
OF DRUGS
Phase II
May 2014
Adverse Drug Reaction
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An adverse reaction to a drug is a harmful or unintended
response.
ADRs are claimed to be the 4th leading cause of death,
exceeding pulmonary disease, AIDS, accidents, and
automobile deaths.
The FDA has further estimated that 300,000 preventable
adverse events occur in hospitals, many as a result of
confusing medical information.
Some adverse reactions, such as overdose, excessive
effects, and drug interactions, may occur in anyone.
Adverse reactions occurring only in susceptible patients
include intolerance, idiosyncrasy (frequently genetic in
origin), and allergy (usually immunologically mediated).
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During the IND and clinical phase 1-3 trials and before FDA
approval, all adverse events (serious, life-threatening, disabling,
reasonably drug-related, or unexpected) must be reported.
Following FDA approval to market, surveillance, evaluation, and
reporting must continue for any adverse events in patients that are
related to use of the drug, including overdose, accident, failure of
expected action, events occurring from drug withdrawal, and
unexpected events not listed in labeling.
Events that are both serious and unexpected must be reported to
the FDA within 15 days.
In January 2006, the FDA announced a new prescription drug
information format to improve patient safety by implementing
improvements in prescription drug labels and inserts so they are
less confusing and more concise with respect to prescribing
information aiding both patients and health care professionals.
Adverse Drug Reaction (ADR)
1.1 Adverse Drug Reaction (ADR)
 In the pre-approval clinical experience with a new medicinal product
or its new usages, particularly as the therapeutic dose(s) may not be
established: all noxious and unintended responses to a medicinal
product related to any dose should be considered adverse drug
reactions.
 The phrase responses to a medicinal product means that a causal
relationship between a medicinal product and an adverse event is at
least a reasonable possibility, i.e. the relationship cannot be ruled
out.
 Regarding marketed medicinal products: a response to a drug which
is noxious and unintended and which occurs at doses normally used
in man for prophylaxis, diagnosis, or therapy of diseases or for
modification of physiological function (see the ICH Guideline for
Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting).
Adverse Event (AE)
1.2 Adverse Event (AE)
 Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical
product and which does not necessarily have a causal
relationship with this treatment.
 An adverse event (AE) can therefore be any
unfavourable and unintended sign (including an
abnormal laboratory finding), symptom, or disease
temporally associated with the use of a medicinal
(investigational) product, whether or not related to the
medicinal (investigational) product (see the ICH
Guideline for Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting).
Classification
Onset of event:
 Acute within 60 minutes
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Sub-acute 1 to 24 hours
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Latent > 2 days
Classification
Severity of reaction:
 Mild: bothersome but requires no
change in therapy
 Moderate: requires change in therapy,
additional treatment, hospitalization
 Severe: disabling or life-threatening
FDA Serious ADR
 Result in death
 Life-threatening
 Require hospitalization
 Prolong hospitalization
 Cause disability
 Cause congenital anomalies
 Require intervention to prevent permanent
injury
Type A
extension of pharmacologic effect
 often predictable and dose dependent
 responsible for at least two-thirds of ADRs
 e.g., propranolol and heart block,
anticholinergics and dry mouth
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Type B
idiosyncratic or immunologic reactions
 rare and unpredictable
 e.g., chloramphenicol and aplastic anemia
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Type C
 associated
with long-term use
 involves dose accumulation
 e.g., phenacetin and interstitial nephritis or
antimalarials and ocular toxicity
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Type D
delayed effects (dose independent)
 Carcinogenicity (e.g., immunosuppressants)
 Teratogenicity (e.g., fetal hydantoin syndrome)
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Types of allergic reactions
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Type I - immediate, anaphylactic (IgE)e.g., anaphylaxis
with penicillins
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Type II - cytotoxic antibody (IgG, IgM)e.g., methyldopa
and hemolytic anemia
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Type III - serum sickness (IgG, IgM)antigen-antibody
complex
e.g., procainamide-induced lupus
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Type IV - delayed hypersensitivity (T cell)e.g., contact
dermatitis
Common Causes of ADRs
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Antibiotics
Antineoplastics*
Anticoagulants
Cardiovascular drugs*
Hypoglycemics
Antihypertensives
NSAID/Analgesics
Diagnostic agents
CNS drugs*
*account for 69% of fatal ADRs
ADR Frequency by Drug Use