Pharmacovigilance in Dermatology

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43 IJAMSCR |Volume 1 | Issue 2 | Nov - 2013 www.ijamscr.com Review article Pharmacovigilance in Dermatology Languluri Reddenna 1 Tedlla Rama Krishna 1 Donthu Venu Gopal 1 Shaik Ayub Basha 1 Harshavardhan 2 1 Intern Department of Pharmacy Practice P.Rami Reddy Memorial College of Pharmacy Rajiv Gandhi Institute of Medical Sciences Utukur Kadapa Andhra Pradesh India-516003 2 Assistant Professor Department of Dermatology Rajiv Gandhi Institute of Medical Sciences Kadapa Andhra Pradesh India-516003. ABSTRACT Pharmacovigilance is the science and activities relating to the detection assessment understanding and prevention of adverse effects or any other possible medicine-related problems. A huge quantity of adult people suffer from undesired side effects to pharmaceutical products at some stage in the way of their lives and can be classified as expected or A-type reactions and unexpected or B type reactions. The skin is a favoured target organ for B-type reactions and these skin reactions occur in 2–3 of hospitalized patients. Morbilliform drug rashes are the generally happening skin reactions to drugs constituting up to 90 of all reactions followed by drug induced urticaria which constitutes about 6. The Council for International Organization of Medical Sciences CIOMS considers as serious ADRs that are lethal or life-threatening or need prolonged hospitalization or consequence in persistent or considerable disability or incapacity because hospitalization may depend on the socioeconomic status of the patient and on admittance to health care. The centre of attention of this summary is on pattern of cutaneous ADRs. Case evaluation must commence with a precise explanation of the skin lesions. The documentation of cases should be terminated by photographic pictures which can help for the retrospective evaluation of cases by experts. Concluded that there is a need of active Pharmacovigilance centre with intensive monitoring for drug induced reactions in the dermatology department Key words: Adverse drug reactions Cutaneous drug reactions Dermatology Pattern and Pharmacovigilance INTRODUCTION Pharmacovigilance is the science and activities relating to the detection assessment understanding and prevention of adverse effects or any other possible medicine-related problems. 1 A huge quantity of adult people suffer from undesired side effects to pharmaceutical products at some stage in the way of their lives and can be classified as expected or A-type reactions and unexpected or B type reactions. The skin is a favoured target organ for B-type reactions and these skin reactions occur in 2–3 of hospitalized patients. Morbilliform drug rashes are the generally happening skin reactions to drugs constituting up to 90 of all reactions followed by drug induced urticaria which constitutes about 6. Severe cutaneous adverse reactions SCAR to drugs include:  Anaphylaxis and angioedema  Photosensitivity  Drug-induced hypersensitivity syndrome DIHS/drug reaction with eosinophilia and systemic symptoms DRESS  B ullous drug reactions including toxic epidermal necrolysis TEN  Most often involved drugs are  Antibiotics – in particular b -lactam antibiotics sulphonamids and fluoro quinolones  Antiretroviral drugs such as abacavir and nevirapin  Allopurinol International Journal of Allied Medical Sciences and Clinical Research IJAMSCR

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Languluri Reddenna et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-12 2013 43-50  Anticonvulsants  Contrast media  NSAIDs  Cytotoxic drugs such as platinum salt hypersensitivity A-type reactions include drug toxicity for illustration over dosage or usual side effects at a dosage required to attain the desired effect as in the case of chemotherapeutic agents and drug interactions. Examples of A-type reactions: Skin diseases comprise alopecia induced by chemotherapy folliculitis induced by anti-EGF treatment or severe dryness of the skin induced by retinoid treatment. B-type reactions consequence from the particular properties of each active pharmaceutical ingredient and individual risk factors of the patient. These reaction include intolerance reactions side effects that occur at low concentrations of a drug idiosyncracy reactions reactions depending upon patient-specific genetic or pharmocokinetic characteristics as well as allergic or pseudoallergic reactions. Example: A pseudoallergic reaction to nonsteroidal anti-inflammatory drugs is implicit as an intolerance reaction since the pathophysiological origin of this reaction is based upon the ordinary pharmacological effect of COX- inhibition. 2 The Council for International Organization of Medical Sciences CIOMS considers as serious ADRs that are lethal or life-threatening or need prolonged hospitalization or consequence in persistent or considerable disability or incapacity because hospitalization may depend on the socioeconomic status of the patient and on admittance to health care. The centre of attention of this summary is on pattern of cutaneous ADRs. 3 Patterns of Cutaneous ADRs 4 Exanthematous drug eruption Exanthematous eruptions reported as ‘drug rashes’ or ‘drug eruptions’ are the majority common ADRs disturbing the skin. The key mechanism is possibly immunologic and may match up to type IV delayed cell-mediated hypersensitivity reaction. The eruption typically occurs between 4 and 14 days subsequent to commencement a new therapy and yet a few days after it has ceased. The eruption consists of erythematous macules papules often symmetric and begins on the trunk upper extremities and increasingly become confluent. Figure 1- Exanthematous morbilliform eruption Cutaneous pathological slides display an extremely gentle lymphocytic infiltrate in the region of vessels of the dermis and a little necrotic keratinocytes within the epidermis. Treatment is mainly supportive typically after the exclusion of the felonious agent associated with topical corticosteroid and systemic antipruritic agents. Most drugs can induce an erythematous eruption in about 1 of users. The following drugs had privileged risks are allopurinol aminopenicillins cephalosporins antibacterial sulphonamides and most antiepileptic agents. Urticaria and Angioedema 5 Urticaria is a transitory eruption of erythematous and oedematous papules and plaques habitually coupled with pruritus. When dermal and subcutaneous tissues are concerned this reaction is known as Angioedema. Urticaria Angioedema and anaphylaxis might be a type I hypersensitivity

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Languluri Reddenna et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-12 2013 43-50 www.ijamscr.com 45 reaction mediated by IgE antibodies. They are localized anywhere on the body including the palm soles and scalp. They normally last a few hours and wane within 24 hours. Angioedema is related with urticaria consisting of pale or pink swellings which affect the face but also buccal mucosa the tongue larynx pharynx and so on. Urticaria is histologically non-specific with a surface and deep limited infiltrate of mononuclear cells accompanied by eosinophils neutrophils oedematous reticular dermis vascular and lymphatic dilatation. Figure 2-Urticaria with oedematous papules and plaques The two most frequent causes of drug-induced non- IgE-mediated urticaria and Angioedema are NSAIDs and angiotensin-converting enzyme ACE inhibitors. Angioedema occurs in 2 to 10 per 10 000 new users of ACE inhibitors a rate that is almost certainly higher than the risk allied with penicillins about 1 per 10 000 courses. Withdrawal of the causative agent is the main treatment. Photosensitivity 6 Cutaneous photosensitivity diseases may be idiopathic produced by endogenous photosensitizers or associated with exogenous photosensitizers like drugs. The relationship of light and a drug can be accountable for acute inflammation of the skin. The photosensitivity reactions are divided into two types like phototoxicity and photoallergy was displayed in table 1. Table-1- Differences between phototoxicity and photoallergy Phototoxicity Photoallergy Results directly from photochemistry involving the skin Result of cell-mediated hypersensitivity Exaggerated sunburn occurring in sun-exposed areas only hyperpigmentation Mainly eczematous pruritic erythematous scaling and lichenification dominate Histologically characterized by epidermal cell degeneration with necrotic keratinocytes oedema sparse dermal lymphocytic infiltrate and vasodilatation ------ Minimal dose of UV UVA more often than UVB inducing an erythema will be decreased in all subjects during treatment Removal of the offending agent and/or avoidance of sun exposure. Topical corticosteroid systemic antipruritic agents may be useful Antibiotics sulphonamides pyrimethamine fluoroquinolones fragrances NSAIDs phenothiazine thiazide diuretics

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Languluri Reddenna et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-12 2013 43-50 Figure 3- Bullous eruption of the arm phototoxic eruption on a sun-exposed area Vasculitis Vasculitis corresponds to immune-mediated inflammation and injure to a blood vessel’s wall. Direct drug toxicity aligned with a vessel’s wall auto-antibodies reacting with endothelial cells and cell-mediated cytotoxic reactions aligned with vessels were projected as explanations. The specific mechanism is still unknown. It consists of palpable purpuric papules which preponderate on the lower extremities. Figure 4- Cutaneous necrotizing vasculitis consisting of purpuric papules The histology of small blood vessels exhibits necrotizing and/or leukocytoclasic vasculitis. Vasculitis occurs 7 to 21 days subsequent to drug administration and less than 3 days after rechallenge. Withdrawing the drug generally leads to a quick decree. A systemic corticosteroid may benefit some patients. The main drugs concerned are allopurinol NSAIDs cimetidine penicillin hydantoin sulphonamides and propylthiouracil. Acute generalized Exanthematous pustulosis 7 AGEP is considered by fever which usually begins the same day as the pustular rash. Abundant tiny chiefly non-follicular pustules happen on a extensive oedematous erythema burning pruritic or both. Oedema of the face and the hands purpura vesicles blisters erythema multiforme-like lesions and mild involvement of mucous membrane also allied. Pustules are primarily restricted on the main folds trunk and upper extremities. The histopathology shows spongiform pustules positioned beneath the stratum corneum the mainly superficial layer of the epidermis. Papillary dermal oedema and perivascular polymorphous infiltrate are generally present. The eruption lasts 1 to 2 weeks and is followed by a superficial desquamation. The removal of the liable drug is the foremost treatment allied with a topical corticosteroid and occasionally a systemic antipruritic agent. Antibiotics béta-lactam some macrolides and quinolones are the major drugs concerned in AGEP.

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Languluri Reddenna et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-12 2013 43-50 www.ijamscr.com 47 Figure 5- Acute generalized Exanthematous pustulosis DRESS/Hypersensitivity The short form of DRESS for Drug Reaction with Eosinophilia and Systemic Symptoms had projected as more precise than hypersensitivity which would be suitable for generally types of drug reaction. It was approximate to happen in between one in 1000 and one in 10 000 exposures with drugs such as antiepileptics and sulphonamides. This syndrome is normally considered by a severe eruption lymphadenopathy fever hepatitis interstitial nephritis pulmonary infiltrates and occasionally arthralgias. They commence 2 to 6 weeks after the first drug use. Fever and skin rash are the mainly general symptoms. Liver abnormalities with elevated aminotransferase alkaline phosphatase bilirubin levels and irregular prothrombin time are present in about 50 of patients. Histopathology exhibits a quite thick lymphocytic infiltrate in the superficial dermis and/or perivascular coupled with dermal oedema. Topical high-potency corticosteroids could supportive in skin manifestations. Systemic corticosteroids are frequently planned when internal organ contribution exists. The aromatic antiepileptic agents phenobarbital carbamazepine phenytoin minocycline and sulphonamides are the common causes of hypersensitivity syndrome. Figure 6- DRESS syndrome presenting as exfoliative dermatitis Fixed drug eruption 8 Clinically considered by an introverted or few round sharply demarcated erythematous and oedematous plaques occasionally with a central blister. The lesions extend usually less than 2 days after the drug intake. Histopathology reveals a superficial and deep dermal and perivascular infiltrate composed of lymphocytes eosinophils and sometimes neutrophils linked with necrotic keratinocytes. The drugs linked with fixed drug eruption are phenazone derivates barbiturates tetracycline sulphonamides and carbamazepine .

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Languluri Reddenna et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-12 2013 43-50 Figure 7- Fixed drug eruption round sharply demarcated erythematous plaques Drug-induced Pemphigus 9 10 Pemphigus is a continual autoimmune blistering disease aggravated by autoantibodies reacting with ordinary constituents of desmosomes the structures that afford addition between epidermal cells. Clinically flaccid intra-epidermal blisters and erosions of the skin and mucous membranes. The histology exhibits impassiveness of epidermal cells accountable for intra-epidermal blisters positioned sub-corneally or in the lower epidermis. It begins several weeks or months after drug therapy are started. The main drugs accountable are d-penicillamine captopril and piroxicam. Figure 8- Drug-induced Pemphigus with erosion of mucous membrane Steven Johnson syndrome and Toxic epidermal necrolysis 12 13 The incidence of TEN is evaluated to 0.4 to 1.2 cases per million person-years and of SJS from 1 to 6 cases per million person-years. The immune- pathologic outline of early lesions suggests a cell- mediated cytotoxic reaction aligned with epidermal cells. SJS is considered by small blisters arising on purple macules. Toxic epidermal necrolysis is considered by the same lesions as SJS but with a convergence of blisters important to a positive Nikolski sign and to the objectivity of huge epidermal sheets on more than 30 of the body surface area. Skin pathology displays necrosis of full-thickness epidermis and negative immunofluorescence. Death occurs in 10 of patients with SJS and more than 30 of patients with TEN primarily from sepsis or pulmonary participation. SJS and TEN characteristically begin within 4 weeks of starting therapy generally 7 to 21 days after the first drug exposure and occasionally a few days after the drug has been withdrawn. It happens more rapidly with rechallenge. The treatment is mostly symptomatic consisting of nursing care safeguarding of fluid and electrolyte balance and nutritional support. Untimely withdrawal of all potentially accountable drugs is necessary. Antibacterial sulphonamides anticonvulsants oxicam and pyrazolone NSAIDs allopurinol and chlormezanone are the drugs allied with the privileged risks.

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Languluri Reddenna et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-12 2013 43-50 www.ijamscr.com 49 Figure 9- Toxic epidermal necrolysis Serum sickness-like eruption This condition is mainly reported in children and characteristically includes fever arthralgias and rash and lymphadenopathy. It occurs 1 to 3 weeks subsequent to drug coverage and occurs as regards 1 in 2000 children given cefaclor which along with minocycline penicillins and propranolol are the chief drugs accountable for eruption. Anticoagulant-induced skin necrosis Usually begins 3 to 5 days after therapy is started. Red painful plaques develop to necrosis hemorrhagic blisters ulcers and as a result of occlusive thrombi in vessels of the skin and subcutaneous tissue. Of the persons who take warfarin 1 in 10 000 will build up skin necrosis. People with a hereditary lack of protein C are at the utmost risk. Therapy includes discontinuing warfarin administering vitamin K giving heparin as an anti-coagulant and purified protein C concentrate. 19-22 Case evaluation must commence with a precise explanation of the skin lesions. Appropriate clinical information includes: 1. Distribution of lesions • Face hands feet vs. thorax and abdomen • Photo-exposed vs. covered areas 2. Number of lesions 3. Outline of individual lesions macules purpura blisters pustules etc. 4. Mucous membrane contribution. 5. Period of the eruption 6. Allied symptoms/signs • Fever • Pruritis • Lymph node swelling. CONCLUSION Case evaluation must commence with a precise explanation of the skin lesions. The documentation of cases should be terminated by photographic pictures which can help for the retrospective evaluation of cases by experts. Concluded that there is a need of active Pharmacovigilance centre with intensive monitoring for drug induced reactions in the dermatology department. REFERENCES 1 The importance of pharmacovigilance safety monitoring of medicinal products. Geneva World Health Organization 2002. 2 Weiss ME 1992 Drug allergy. Med.Clin.North Am 76: 857–882. 3 Council for International Organization of Medical Sciences CIOMS 1997 Harmonizing the use of adverse drug reaction terms definition of terms and minimum requirements for their use: respiratory disorders and skin disorders. Pharmacoepidemiol and Drug Saf 6: 115–27. 4 Arndt KA and Hershel J 1976 Rates of cutaneous reactions to drug. J Am Med Assoc 235: 918–23. 5 Hedner T Samuelsson O Lunde H et al. 1992 Angiooedema in relation to treament with angiotensin converting enzyme inhibitors. Br Med J 304: 941–5. 6 Gould JW Mercurio MG and Elmets CA 1995 Cutaneous photosensitivity diseases induced by exogenous agents. JAAD 33: 551–73. 7 Roujeau J-C Bioulac-Sage P Bourseau C et al. 1991 Acute generalized exanthematous pustulosis analysis of 63 cases. Arch Dermatol 127: 1333–8.

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Languluri Reddenna et al / Int. J. of Allied Med. Sci. and Clin. Research Vol-12 2013 43-50 8 Kauppinen K and Stubb S 1984 Drug eruptions: causative agents and clinical types. Acta Derm Venereol Stockh 64: 320–4. 9 Knowles SR Uetrecht J and Shear NH 2000 Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet 356: 1587–91. 10 Roujeau J-C and Stern RS 1994 Severe cutaneous adverse reactions to drugs. New Engl J Med 331: 1272–85. 11 Auquier-Dunant A Mockenhaupt M Naldi L et al. 2002 Correlations between clinical patterns and causes of erythema multiforme majus Stevens–Johnson syndrome and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 138: 1019–24. 12 Bastuji-Garin S Rzany B Stern RS et al. 1993 A clinical classification of cases of toxic epidermal necrolysis Stevens–Johnson syndrome and erythema multiforme. Arch Dermatol 129: 92–6. 13 Beylot C Bioulac P and Doutre MS 1980 Pustuloses exanthématiques aigues généralisées A propos de 4 cas. Ann Dermatol Venereol 107: 37–48. 14 Callot V Roujeau J-C Bagot M et al. 1996 Drug-induced pseudolymphoma and hypersensitivity syndrome: two different clinical entities. Arch Dermatol 138: 1315–21. 15 Descamps V Valance A Edlinger C et al. 2001 Association of human herpesvirus 6 infection with drug reaction with eosinophilia and systemic symptoms. Arch Dermatol 137: 301–4. 16 Hunziker T Kunzi UP Braunschweig S et al. 1997 Comprehensive hospital drug monitoring CHDM: adverse skin reactions a 20-year survey. Allergy 52: 388–93. 17 Kano Y Inaoka M and Shiohara T 2004 Association between anticonvulsant hypersensitivity syndrome and human herpesvirus 6 reactivation and hypogammaglobulinemia. Arch Dermatol 140: 183–8. 18 Roujeau J-C Kelly JP Naldi L et al. 1995 Medication use and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis. New Engl J Med 333: 1600–7. 19 Shear NH and Spielberg SP 1988 Anticonvulsant hypersensitivity syndrome. J Clin Invest 82: 1826– 32. 20 Staughton RCD Rowland-Payne CME Harper JI et al. 1984 Toxic pustuloderma: a new entity. J R Soc Med 77 Suppl 4: 6–8. 21 Van Rijnsoever EW Kwee-Zuiderwijk WJ and Feenstra J 1998 Angioneurotic edema attributed to the use of losartan. Arch Intern Med 158: 2063–5. 22 Wolkenstein P Latarget J Roujeau JC et al. 1998 Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 352:1586–9.

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