1. ADVERSE EFFECTS OF DRUGS Phase II May 2014

2. Adverse Drug Reaction 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).

3. 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.

4. 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).

5. 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).

6. Classification Onset of event: Acute within 60 minutes Sub-acute 1 to 24 hours Latent > 2 days

7. 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

8. FDA Serious ADR Result in death Life-threatening Require hospitalization Prolong hospitalization Cause disability Cause congenital anomalies Require intervention to prevent permanent injury

9. 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

10. Type B idiosyncratic or immunologic reactions rare and unpredictable e.g., chloramphenicol and aplastic anemia

11. Type C  associated with long-term use  involves dose accumulation  e.g., phenacetin and interstitial nephritis or antimalarials and ocular toxicity

12. Type D delayed effects (dose independent) Carcinogenicity (e.g., immunosuppressants) Teratogenicity (e.g., fetal hydantoin syndrome)

13. Types of allergic reactions Type I - immediate, anaphylactic (IgE)e.g., anaphylaxis with penicillins Type II - cytotoxic antibody (IgG, IgM)e.g., methyldopa and hemolytic anemia Type III - serum sickness (IgG, IgM)antigen-antibody complex e.g., procainamide-induced lupus Type IV - delayed hypersensitivity (T cell)e.g., contact dermatitis

14. Common Causes of ADRs Antibiotics Antineoplastics* Anticoagulants Cardiovascular drugs* Hypoglycemics Antihypertensives NSAID/Analgesics Diagnostic agents CNS drugs* *account for 69% of fatal ADRs

15. ADR Frequency by Drug Use