SOPI January-March 2015

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site of oral vestibule. On examination there was mucosal discrete ulceration. The medication of ornidazole was stopped. The condition was diagnosed as FDE ...

Case Reports

Ornidazole induced adverse drug effects – Our experience Rubia Siddiqui1, S. S. Ahmad1, S. Z. Rahman2



Department of Oral and Maxillofacial Surgery, Dr. Z.A. Dental College and Hospital, 2 Department of Pharmacology, J.N. Medical College, AMU, Aligarh Correspondence to: Rubia Siddiqui

Ornidazole-induced Fixed drug eruption (FDE) as mucosal or mucocutaneous adverse effects are rarely seen and very few reports on this aspect are available. However the reaction with ornidazole may occur in the form of central nervous system,gastrointestinal system,skin and appendages related adverse effects. This drug is a nitroimidazole in nature, having antibacterial and antiprotozoal properties, is used to treat anaerobic enteric protozoa. It also a commonly used drug to treat oro-dental infections in isolation or in combination with some other antibiotics. In the present paper we have reported a case of FDE due to ornidazole while treating oro-dental infection.

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Introduction FDE is very common type and can be seen as cutaneous or mucocutaneous lesions which recurs at FDE is very common type and can be seen as cutaneous or mucocutaneous lesions which recurs at the same anatomic site(s) upon repeated exposures to an offending agent [1, 2]. The importance of FDE is because of the fact that it occurs with drugs prescribed in routine. Ornidazole is a commonly prescribed drug and its side effects in the literature have been shown as drowsiness, dizziness, headache, tremor, rigidity, poor coordination, epilepsy, tiredness, temporary loss of consciousness and fainting, nausea, vomiting, taste disturbances, liver impairment, skin reactions like rash, itching and inflammation. Case reports on FDE are relatively less available. Here we are reporting a case of FDE due to Ornidazole which presented as a severe mucosal hemorrhagic ulceration of oral cavity.

Case Report A 35 year old man attended the OPD of Department of Oral and Maxillofacial Surgery with chief complaint of severe spontaneous gingival bleeding. The history of the present illness revealed that he was otherwise well except there was gingival bleeding after tooth brushing for about a year and sometimes spontaneous bleeding also which stopped after rinsing or by applying some pressure on gums or by some locally available medication. However, he never consulted any dentist for this problem. This time again spontaneous bleeding occurred like before but did not stop by measures that gave him relief on earlier occasions. On examination there was deposition of plaque, gingiva was

severely inflamed and blood was seen oozing out from crevicular areas of many teeth. There was severe halitosis and it bleeded severely on probing. Blood pressure of the patient was 130/80mm of Hg. All the systemic causes of gingival bleeding were ruled out through haematological investigation. The bleeding was controlled by application of hot water cotton pressure pack and no other hemostatic agent was prescribed. On the basis of clinical findings the disease was diagnosed as acute gingivitis. The cause was considered as anaerobic infection and ornidazole in 500 mg b.i.d. dose was prescribed. A drug history was taken with any previous history of drug reaction which was negative. However, there was no previous history of taking ornidazole or metronidazole. Considering its first exposure, the patient was well informed about the possibility of side effect and was asked to report in case it happens. On the day of prescription of patient first dose but there was no adverse effect. However, on next morning about 45 minutes after taking the medication he developed sudden severe erythematous ulceration with discrete areas of bleeding and burning sensation in the right buccal vestibule (Fig. 1). The patient was in severe discomfort and he was immediately rushed to our hospital. The lesion was examined and it was diagnosed as ADR due to ornidazole. The patient was treated with proper therapy to manage the drug reaction and patient got significant relief by evening and he was well after continuation of treatment for 5 days. The ornidazole was stopped and other treatment was rendered to address his main problem. After three months the patient again came with same

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Siddiqui R et al : Ornidazole induced adverse drug effects – Our experience

problem of spontaneous bleeding on brushing. He gave the history of previous drug reaction. But it was again decided to treat with ornidazole, as it was considered as most suitable drug but to start with very small dose. The ornidazole was prescribed to start with 50 mg b.i.d. on the first day but to increase the dose progressively by adding 50 mg /day. When the dose reached 300 mg , the patient complained of burning sensation and ulceration on same site of oral vestibule. On examination there was mucosal discrete ulceration. The medication of ornidazole was stopped. The condition was diagnosed as FDE and treated accordingly. The patient improved with discontinuation of

Fig.1: Photograph showing ulcerated and hemorrhagic patches in the right vestibule after drug reaction the drug. As the patient had similar episode of reaction to the same drug before, there were no alternative explanations for the reaction.

Causation Analysis Since the challenge, de-challenge and rechallenge were all positive along with previous history of exposure to the same drug. On Naranjo ADR algorithm scale, the ADR lying under definite (>9) category, which is highest degree of Naranjo ADR scale. Moreover by WHO classification it is classified as mild and type B of ADR.

Discussion FDEs are one of the most common cutaneous or mucosal adverse reaction, which a clinician experiences in day to day practice. FDE though not fatal, can cause enough embarrassment if it recurs after taking any medication, however they are one of the major obstacles in successful pharmacotherapy. FDE is delayed type hypersensitivity mediated by CD8+ T cells. The drug acts as hapten that binds to basal

keratinocytes and then lymphokines and antibodies release that in turn damage the basal cell layer [2]. On drug intake CD8+ are reactivated to release IFN and cytotoxic granules into the local microenvironment. Mast cells are also believed to contribute to activation of intraepidermal CD8+ cells through the induction of cell adhesion molecules [3]. Cutaneous lesions of FDE are manifested as single erythematous pigmented macule, evolving into an edematous plaque or rarely bullous form. These lesions typically recur at exactly the same site with each frequency of drug. The same after discontinuation of the drug, lesion resolves spontaneously, leaving hyperpigmentation. However, the effect on mucosal regions is different. It present as severe erythematous bleeding ulcerations involving large area accompanied by burning or itching sensation. These lesions become more relentless with frequent exposures and new lesions also develop on the previously uninvolved areas. Systemic symptoms such as fever and malaise are generally absent. The diagnosis of FDE is generally thought to be straightforward, but due to varied clinical manifestations, it is often can be misdiagnosed as Erythema multiforme [4], Stevens-Johnson syndrome, Lichen planus and parapsoriasis en plaques[5], Herpes labialis[6]and Discoid lupus ertyhematosus [7]. Careful history taking about drug intake and a previous history of recurrent lesions in the same sites are essential for the diagnosis of FDE. Oral challenge test is done to confirm the diagnosis of FDE. It is generally done with one-tenth the therapeutic dose of the offending drug [3]. If the reaction is not perceived at the site of FDE, a gradual increase (e.g. 1/8, 1/4, 1/2) is undertaken until the full therapeutic dose is achieved. The appearance of erythema, edema, vesicles and bullae, accompanied by burning sensation, is indicative of positive test. A positive topical provocation test confined to previously involved site is suggestive of FDE. However a negative test does not excludes FDE. Topical provocation test has however got certain limitations, like sensitivity of the patient to metabolite but not to the drug and low concentrations of drug used in patch testing may yield false negative tests. False negative tests may also be caused by the limited penetrability of the drug [8].Oral Challenge test is most reliable test for FDR and has got ethical acceptance [3]. In our reported case the diagnosis of FDE was confirmed by oral challenge test that showed the presence of similar erythematous macules on using subtherapeutic dose of

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Siddiqui R et al : Ornidazole induced adverse drug effects – Our experience

ornidazole. Oral challenge test remains so far the only reliable method of confirmatory diagnosis of FDE [9]. The patient had reported an improvement in symptoms after withdrawal of the drug and was not willing for biopsy procedure so histopathological examination was not conducted. Nitroimidazoles are commonly the first line drugs used in treatment of anaerobic infections of oral cavity. Ornidazole is a commonly prescribed drug to treat anaerobic infections of any origin including oral infection. All the nitroimidazoles, metronidazole, tinidazole, satranidazole, ornidazole and secnidazole, have a similar nitroimidazole group but different side chains [2]. Only metronidazole and tinidazole have been known to cause FDE and have been included in the list of drugs causing FDE [1]. Thus our case was unique case FDR in which ornidazole was used to treat gingival infection.

localised skin or oral mucosal lesion should not be neglected and possibility of FDE should be considered. If FDE is suspected then the offending drug should immediately be withdrawn and supportive treatment with oral and topical steroids should be started.

References 1. 2.

3. 4. 5. 6.

Conclusion FDE is a potential side effect, which may occur due to many drugs and can be seen in patients receiving nitroimidazoles. Sometime such ADRs go unreported due to lack of knowledge of reporting of such effects by a clinician or a patient. It is necessary for the health care providers to be trained and sensitized to diagnose, treat and report such cases for the benefit of patients. Any recent

7. 8.


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