RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

BANGALORE, KARNATAKA-560041

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the candidate and address
(in block letters) / Dr. S G S RAJESH REDDY V, MBBS
PG IN PHARMACOLOGY
KARNATAKA INSTITUTE OF MEDICAL SCIENCES (KIMS), HUBLI-580021
2. / Name of the Institution / KARNATAKA INSTITUTE OF MEDICAL SCIENCES (KIMS),
HUBLI-580021
3. / Course of study and subject / M.D ( PHARMACOLOGY)
4. / Date of admission to the course / 31st AUGUST,2013
5. / Title of the Topic / “MONITORING AND EVALUATION OF ADVERSE DRUG REACTIONS IN ANTIRETROVIRAL THERAPY CENTRE AND DERMATOLOGY DEPARTMENT IN A TERTIARY HOSPITAL”
6. / BRIEF RESUME OF INTENDED WORK
6.1. NEED FOR THE STUDY:
Adverse drug reactions (ADRs) are inevitable consequences of drug therapy. Incidence of ADR in Indian population is 1.75% to 25.1%. ADRs cause 3-7% of hospital admissions and account for 5-9% of hospital inpatient costs. The overall incidence of serious ADRs is 6.7% & of fatal ADRs is 0.32% in hospitalized patients making these reactions between fourth and sixth leading cause of death respectively. So ADRs are major contributors for mortality, morbidity and hospitalization in world. Reporting of ADR in India is poor and inadequate. ADR monitoring forms an integral part of pharmacovigilance. ADRs commonly manifest with dermatological symptoms. The Incidence of cutaneous adverse drug reactions in developed countries is 1 to 3%1 and in developing countries it is much higher 2 to 6%. Different types of skin reaction are morbiliform, fixed drug eruptions, phototoxic, urticaria, exfoliative dermatitis, Steven Johnson syndrome and toxic epidermal necrolysis. In India 2.4 million people are infected with HIV till 2009. India has third highest population of HIV/AIDS2. HAART is cornerstone in management of HIV/AIDS2.With availability of HAART there has been decline in mortality and morbidity. Although HAART to a great extent has excluded the mortality and morbidity associated with HIV it cannot eradicate virus. Since these drugs have to be taken lifelong and adherence of >95% is required for effective outcome. These patients are exposed to this drugs for longer periods of time. These drugs are highly toxic and associated with many ADRs due to which many patients require withdrawal of drug or even discontinuation of treatment3.The overall incidence of ADRs is 100 to 1000 times more in HIV patients compared to immunocompetent people. Hence monitoring and reporting of ADRs in HIV/AIDS patients assumes great importance. So the current study was designed to monitor and evaluate adverse drug reactions in ART centre and Dermatology department of tertiary care hospital.
6.2. REVIEW OF LITERATURE:
According to WHO Adverse drug reaction is defined as "Any response to drug which is noxious or unintended and occurs at a dose normally used in man for prophylaxsis, diagnosis or therapy of disease, or for modification of physiological function4” .
Laurence definition: A harmful or significantly unpleasant effect caused by a drug at dose intended for therapeutic effect which warrants reduction of dose or with drawl of drug & foretells hazards from future administration5.
New EU Pharmacovigilance Legislation: The definition of term adverse reaction should be amended to ensure that it covers noxious and unintended effects not only from authorized use of medicinal products at normal doses but also from medication errors and uses outside the terms of marketing authorization including misuse & abuse of medicinal products.
Unexpected adverse reaction: An adverse reaction, nature and severity of which is not consistent with domestic labeling or market authorization or expected from characteristics of drug.
SEVERITY OF ADRs:
Mild: No therapy, antidote or prolongation of hospital stay required.
Moderate: Requires change in drug therapy ,specific treatment or prolongs hospital stay by at least 1day.
Severe: Potentially Life threatening, causes permanent damage, requires intensive medical treatment.
Lethal: Directly or indirectly contributes to death of patients.
Adverse event: An outward occurrence that may present during treatment with pharmaceutical product but which does not have casual relation to treatment.
CLASSIFICATION OF ADVERSE DRUG REACTIONS4:
Type A(Augmented): Dose related, common, related to pharmacological action of drug, predictable, low mortality eg; Anticholinergic effects of TCA. Type B(Bizarre): Non dose related, uncommon, unpredicted ,high mortality, not related to drug action eg; pencillin hypersensitivity.
Type C(Chronic): Time and dose related, related to cumulative dose eg; Hypothalamic pitutary axis suppression by steroids.
Type D(Delayed): Time related, becomes apparent sometimes after drug use eg; teratogenesis.
Type E (End of use): Withdrawal of drug eg; opiate withdrawal.
Type F(Failure of therapy): Common, dose related, often by interactions eg; oral contraceptive pills and enzyme inducers.
CAUSALITY ASSESMENT OF ADRs6:
Causality assessment is on basis of temporal relationship, previous knowledge, dechallenge, rechallange .Causality have been graded as: 1)definite: causality proven 2)probable: though not proven, drug is likely cause of event 3)possible: drugs as well as other causes could be responsible for event 4)doubtful: drug unlikely to cause, but cannot be ruled out.
Such monitoring may be useful in identifying and minimizing preventable ADRs while generally enhancing the knowledge of prescribing & to deal with ADRs more effectively. Hence impact of ADRs on patient safety, health cost and improved public health in relation to use of medication by the provision of reliable and balanced information resulting in more rational use of medicines lead to emergence of new medical discipline known as pharmacovigilance.
ADVERSE DRUG REACTIONS OF ART:
HIV/AIDS is a chronic illness since drug therapy cannot eradicate virus, cure is not possible & patient have to maintain lifelong adherence to drug toxicity, interaction, & drug resistance. ART regimen is combination of drugs selected based on side effect profile, interaction, comorbidity, cost of drug availability. A physician should be well equipped to identify and treat ART toxicity. The principle toxicities include mitochondrial toxicity ,hypersensitivity ,insulin resistance, dyslipidemia, peripheral neuropathy, lipodystrophy.
NRTIs:
All NRTIS may be associated with mitochondrial toxicity due to inhibition of mitochondrial DNA polymerase, Lactic acidosis and hepatic steatosis.
Zidovudine: Bone marrow suppression (anemia, neutropenia , thrombocytopenia).
Didanosine: Peripheral neuropathy, pancreatitis, probable increase in myocardial infraction.
Abacavir: Rash , hypersensitivity, possible increase in MI7.
NNRTIs:
Associated with skin rash, Steven-Johnson syndrome, toxic epidermal necrolysis & gastrointestinal side effects7.
Efavirenz: neuropsychiatric manifestations.
PROTEASE INHIBITORS:
A syndrome of redistribution and accumulation of fat leading to central obesity, dorsocervical fat enlargement, peripheral & facial wasting giving cushingoid appearance in patients receiving ART is associated with use of PI, results in increase of LDL & TG, hyperglycemia & insulin resistance7.
Lopinavir causes diarrohea, nausea, abdominal pain, dyslipidemias.
Ritonavir causes drug interactions, paresthesia, diarrohea and dyslipidemias.
Indinavir causes nephrolithiasis.
CUTANEOUS ADVERSE DRUG REACTIONS:
Any undesirable change in structure and function of skin, its appendages or mucous membranes different forms of skin reaction are 1)morbiliform 2)fixed drug eruptions 3)phototoxic 4)urticaria 5)exfoliative dermatitis 6)Steven-Johnson syndrome, 7)toxic epidermal necrolysis. Maculopapular rash represent majority of cutaneous drug reaction(95%) followed by urticaria8.
In a study by Thappa et al most common eruptions were fixed drug eruptions (31.1%). Although virtually any drug is capable of eliciting an adverse reaction. Most frequently elicited are antimicrobials and NSAIDs9.
The relative risk of Steven-Johnson syndrome and toxic epidermal necrolysis perhaps most important severe cutaneous reactions has been quantified in an international case control study and case series sulfonamide antibiotics, amine antiepileptic(phenytoin and carbamazepine), lamotrigine, oxicam NSAIDs are associated with highest risk10. 1 in 1000 hospitalized patients will develop severe cutaneous adverse reaction11. A study by Chaterjee et al found drug induced adverse skin reactions to be 2.6% at dermatology outpatient setting10. Mortality for erythema multiforme is higher, mortality of Steven Johnson syndrome is 5%, and mortality of TEN is 20 to 30%. Death is due to sepsis.
6.3 OBJECTIVES OF STUDY
1)To create awareness among health care professionals on ADR monitoring and to encourage reporting culture.
2)To monitor and collect ADR reports.
3)To assess casualty and severity of ADRs.
4)To evaluate management and outcome of ADR
7. / METHODS AND MATERIALS
7.1. SOURCE OF DATA:
HIV/AIDS patients of ART centre KIMS HUBLI and outpatients and inpatients of dermatology department KIMS HUBLI
7.2. METHOD OF COLLECTION OF DATA:
After obtaining approval and clearance from IEC, 100 subjects with suspected ADRS will be included in study. Written and informed consent will be obtained from all study subjects.
The demographic data of patients reporting ADR, date and time of event, brief description of event, suspected drug(s) name causing reaction, the risk factors and co morbid factors will be collected.
The pattern of ADRs reported will be analyzed .The causality of reactions will be analyzed by naranjo causality scale Severity of ADRs will be assessed using modified hatwig scale. Preventability of ADRs will be assessed by schumock and Thornton scale. Confidentiality of patients will be maintained throughout and after study.
A) INCLUSION CRITERIA:
1) All HIV/AIDS patients visiting ART centre.
2) All patients of dermatology inpatients and outpatients.
3) Willingness to give written informed consent.
B)EXCLUSION CRITERIA:
1) Reactions due to unintentional or deliberate over dose.
2) Error in prescribing and dispensing.
3) Mentally retarded or unconscious.
C) SAMPLE SIZE:
100 and more
D) SAMPLE DESIGN:
Purposive
E) STUDY DESIGN:
A prospective observational
F) STUDY PERIOD:
January 2014 To December 2014(1year).
G) PLACE OF STUDY:
KIMS Hospital, Hubli.
7.3. STATISTICAL METHODS:
Data will be analyzed using descriptive studies mean and standard deviation for quantitative variables. Chi-square test is used for comparing attributes and variables of study. p <0.05 will be considered as significant. Data will be described in form of tables and graphs.
7.4 DOES STUDY REQUIRE ANY INVESTIGATIONS OR INTERVENTIONS TO BE COUNDUCTED ON HUMANS OR ANIMALS?
YES base line investigations are required. No investigations or interventions required in animals
7.5. HAS ETHICAL CLEARENCE BEEN OBTAINED FROM INSTITUTION IN CASE OF 7.3?
YES
8 / REFERENCES:
1)  Bigby M. Rates of cutaneous reactions to drug. Arch Dermatol. 2000; 137: 765-70.
2)  Nagpal M, Tayal V, Kumar S, Gupta U. Adverse drug reactions to Antiretroviral therapy in AIDS patients at a tertiary care hospital in india: A prospective observational study. Indian J Med Sci. 2010 June; 64: 6.
3)  Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2001; 356: 1423-30.
4)  Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis and management. The Lancet.2000; 356: 1255-59.
5)  Laurence D, Carpenter J. A dictionary of pharmacology and allied topics. 2nd ed. Amesterdam: Elsevier; 1998: 8-9.
6)  Tripathi KD. Adverse drug reactions. Essentials of Medical Pharmacology. 7th ed. New Delhi: Jaypee; 2013: 83-84.
7)  Safrin S. Antiviral Agents. In: Katzung BG,Masters SB,Trevor AJ,editor. Basic and clinical pharmacology. 12thed. New Delhi: Tata Mc Graw Hill; 2012: 869-79.
8)  Alanko K, Stubb S, Kauppien K. Cutaneous drug reactions: Clinical types and causative agents a five year survey of inpatients (1981-1985). Acta Derm Venerol. 1989; 69: 223-26.
9)  Chatterjee S, Ghosh AP, Barbhuiya, Dey SK. Adverse drug reactions: A one year survey at a dermatology outpatient clinic of a tertiary care hospital. Ind J Pharmacol. 2006; 38: 429-31.
10) Chosidow OM, Stern RS, Wintroub BU. Cutaneous drug reaction.In: Kasper DL, Braunwald, editor. Harrisons principles of internal medicine. 16thed. New York: Mc Graw Hill; 2005: 318.
11) Roujeau JC, Stern RS. Severe adverse reactions to drugs. N Engl J Med. 1994; 331: 1272-85.

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