Thrombocytopaenia Associated with Loxoprofen Sodium

Asian Thrombocytopaenia J Oral Maxillofac Associated Surg. 2007;19:226-9. with Loxoprofen

CASE REPORT

Thrombocytopaenia Associated with Loxoprofen Sodium Jun Sato, Jun Goto, Takumi Kato, Michiko Terada, Akira Satoh, Yoshimasa Kitagawa Oral Diagnosis and Medicine, Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan

Abstract Loxoprofen sodium is a phenyl propionic acid non-steroidal anti-inflammatory drug with a very good safety record. An unusual case of thrombocytopaenia most likely induced by loxoprofen sodium is reported. An 82-year-old woman developed thrombocytopaenia after taking loxoprofen sodium (180 mg/day) during treatment for trigeminal neuralgia and hip bone contusion. The patient’s platelet count fell to 24,000/mm3, but her condition improved after discontinuing loxoprofen sodium. Key words: Anti-inflammatory agents, non-steroidal, Loxoprofen, Thrombocytopenia, Trigeminal neuralgia

Introduction Loxoprofen sodium (LOX) is one of the most commonly used non-steroidal anti-inflammatory drugs (NSAIDs) in Japan. LOX has an excellent record of both safety and efficacy.1-5 As with other NSAIDs, LOX can cause gastroduodenal mucosal damage,1-3,5 but is not generally thought to cause blood toxicity. Here, we report a rare case of thrombocytopaenia probably induced by LOX.

Case Report An 82-year-old woman presented with the chief complaint of severe pain on the left side of her face. The pain had persisted for 5 days, and was causing difficulty in eating and drinking. With the exception of hypertension, which had been managed well with felodipine and metoprolol tartrate, the patient’s medical and family histories were non-contributory, with no known food or drug allergies. On admission, the patient’s general condition was poor (body temperature, 36.9°C; blood pressure, 184/87 mm Hg; pulse rate, 104 beats per minute). The patient had no definite facial asymmetry. Her facial skin was moderately dry, and severe pain occurred suddenly while speaking or eating. The patient experienced severe lancing pain lasting for about 5 seconds when touched on the left side of the lower lip. Examination of the oral cavity revealed no abnormalities. Panoramic radiography of the left maxilla and mandible also showed no abnormalities, except for a small apical lesion Correspondence: Jun Sato, DDS, PhD, Oral Diagnosis and Medicine, Department of Oral Pathobiological Science, Hokkaido University Graduate School of Dental Medicine, North 13, West 7, Kita-ku, Sapporo 060-8586, Japan. Tel: (81 11) 706 4280; Fax: (81 11) 706 4280; E-mail: [email protected]

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of the upper first premolar. Computed tomography and magnetic resonance imaging of the intracranial region also showed no abnormalities. Blood chemistry was normal, except for elevated white blood cell count (12,900/mm3) and blood urea nitrogen (39 mg/dL). The patient’s platelet count (258,000/mm3) and serum C-reactive protein levels (0.3 mg/dL) were within normal range. A clinical diagnosis of idiopathic trigeminal neuralgia of the left third branch was made, and oral carbamazepine (CBZ) [200 mg/day] was prescribed, which relieved much of the pain; however, as the patient suffered a hip bone contusion in a fall on hospital day 4, LOX (180 mg/day) was prescribed for lower back pain on the following day (hospital day 5) by an orthopaedist. During hospital days 8 to 10, the patient received cefcapene pivoxil hydrochloride (CFPN-PI) [3 × 100 mg tablets/day] for shallow erosion of the lower lip caused by mastication, which healed quickly by hospital day 10. Although laboratory tests on hospital day 11 showed a normal platelet count (225,000/mm3), the platelet levels fell to 48,000/mm3 on hospital day 16; however, the patient did not reveal any leukocytopaenia or anaemia (Figure 1), there was no clinical haemorrhagic diathesis, and the bone marrow puncture revealed no abnormalities. At this time, the patient’s body temperature and serum C-reactive protein level were normal. She had no symptoms of severe infection or neoplastic disease, and serum antinuclear antibody was not detected. Disseminated intravascular coagulation (DIC) was excluded because serum levels of fibrinogen, fibrinogen degradation products, and prothrombin time-international normalised ratio were all normal. From these findings, a clinical diagnosis of drug-induced thrombocytopaenia was made. Apart from the antihypertensives mentioned above, the patient had been taking oral LOX, CBZ, and teprenone (Figure 1), and it was suspected that either CBZ or LOX may have caused the thrombocytopaenia. As CBZ was considered © 2007 AsianAsian Association J Oral Maxillofac of Oral andSurg. Maxillofacial Vol 19, No Surgeons. 4, 2007

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9000 6000

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Hb 0

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Loxoprofen sodium Carbamazepine CFPN-PI Teprenone Acetaminopohen Felodipine Metoprolol tartrate

Figure 1. Timeline of changes in the platelet and white blood cell (WBC) counts, haemoglobin (Hb) levels, and drug administration (duration shown by horizontal arrows). Thrombocytopaenia occurred from hospital days 11 to 16 and improved after discontinuation of loxoprofen sodium. Abbreviation: CFPN-PI = cefcapene pivoxil hydrochloride.

necessary for the treatment of trigeminal neuralgia, LOX was stopped on the same day (hospital day 16) and acetaminophen was prescribed instead. Although the patient’s platelet count fell to 24,000/mm3 on the following day (hospital day 17), it began increasing from hospital day 18 (27,000/mm3) and reached 205,000/mm3 on hospital day 28 (Figure 1). During this period, the patient only experienced slight back pain. With the thrombocytopaenia resolved, alcohol was injected into the left foramen mentale to block the nerves. The patient was discharged on hospital day 28. Three months after discharge, drug lymphocyte stimulation tests (DLST) against LOX, CBZ, teprenone, and CFPN-PI were performed with the patient’s consent. Although the results were negative for all drugs, responses for LOX and CBZ were stronger than the control (Table 1), while those for CFPN-PI and teprenone were weaker than the control. The patient was able to stop taking CBZ 3 months after discharge. One year after discharge, there has been no recurrence of thrombocytopaenia or facial pain, and no symptoms of neoplastic diseases or autoimmune disorders.

urine within 8 hours of administration,8,9 and similar to other NSAIDs, its main side effect is gastroduodenal mucosal damage.1-4 Cases of drug eruption,2,3 colonic ulceration,1 and acute lung injury10 have been associated with LOX, and although severe adverse reactions, such as acute renal dysfunction, liver dysfunction, and anaemia associated with LOX are listed in the manufacturer’s reports, these reactions are extremely rare and their incidence is unknown. In a prospective study of the side effects of LOX performed in Thailand, 102 of 1206 patients (8.4%) revealed side effects, of which gastroduodenal disturbance was the most common, as with other NSAIDs.5 Other side effects, such as kidney and dermatology disturbance, were rare in the study, and there were no cases of thrombocytopaenia associated with LOX. According to a manufacturer’s report, there has been no case of thrombocytopaenia among 12,895 patients prescribed LOX.4 No reports of LOX-induced thrombocytopaenia were found in a literature search based on a MEDLINE search from 1966 to 2006.

Discussion

Table 1. Results of drug lymphocyte stimulation test.

LOX is a phenyl propionic acid NSAID, first marketed in Japan in 1986.1-3 The drug has a very good safety record, with almost 1 billion tablets being used in Japan every year for pain caused by a wide variety of diseases, including arthritis and cancer.1,5,6 LOX is used in more than 20 countries around the world. LOX is a prodrug that shows anti-inflammatory activity by inhibiting prostaglandin E2 production after conversion to its active metabolite form, SRS trans-OH.7-9 More than 50% of the dosage administered is excreted in the Asian J Oral Maxillofac Surg. Vol 19, No 4, 2007

Drug

Measurement (cpm)

Stimulation index* (%)

Result

LOX

519

114

Negative

CBZ

572

126

Negative

CFPN-PI

376

83

Negative

Teprenone

333

73

Negative

Control

452

*Stimulation index = (measurement with antibody/control) × 100. Abbreviations: cpm = counts per minute; LOX = loxoprofen sodium; CBZ = carbamazepine; CFPN-PI = cefcapene pivoxil hydrochloride. 227

Thrombocytopaenia Associated with Loxoprofen

Thrombocytopaenia may result from numerous severe infections, DIC, neoplastic diseases, autoimmune disorders, hereditary conditions, environmental toxins, and drugs.11 Therefore, the diagnosis of drug-induced thrombocytopaenia should be based on clinical findings and the confirmation that there are no other causes for the condition, in addition to the resolution of thrombocytopaenia after discontinuation of the causative drugs.11-13 In the present case, severe infectious disease, DIC, neoplastic diseases, and autoimmune diseases were ruled out by laboratory data, the results of bone marrow aspiration, clinical findings, and the patient’s clinical course 1 year after discharge. Elderly patients tend to become dehydrated easily, especially when they have difficulty in eating and drinking for several days. The elevated white blood cell count, and blood urea nitrogen and haemoglobin levels noticed in the patient initially may have been influenced by such dehydration. Hereditary causes of thrombocytopaenia were excluded based on the patient’s family history, and possible effects of exposure to environmental toxins at the hospital were ruled out. As the patient was prescribed multiple drugs, including CBZ, teprenone, and 2 types of antihypertensive drugs, at the time when thrombocytopaenia occurred, a diagnosis of drug-induced thrombocytopaenia was made. Many researchers have suggested that the diagnosis of drug-induced thrombocytopaenia should be confirmed by symptoms resolving within a few days of discontinuing the causative drug;11-14 however, identifying the causative drug is sometimes difficult in patients taking multiple drugs that can induce thrombocytopaenia.15,16 In patients taking several drugs, clinicians need to be aware of the probability of a causal role for each drug.12 In the present case, CBZ was strongly suspected as a causal agent, especially as it is known to induce thrombocytopaenia, in addition to LOX.12,17 As sudden discontinuation of CBZ in patients with trigeminal neuralgia results in severe worsening of pain, it was decided, in consultation with internal medicine specialists, to stop LOX first in this case. With no discontinuation of CBZ, and administration of teprenone and the antihypertensive drugs during the entire period of hospitalisation, the likelihood of these drugs contributing to the development of thrombocytopaenia would be reduced.11 This was a very challenging decision to make, as there was no conclusive evidence that LOX was the causative drug. Therefore, changes in the platelet count were observed very carefully, with the intention of stopping CBZ next in case of no improvement. Gales et al11 have reported that platelet counts typically start to rise within 24 hours of the discontinuation of the causative drug and return to normal levels within 1 week.11,13,14 The platelet count increased within 48 hours of stopping LOX medication, and the time course of change in the platelet count in our patient suggested that thrombocytopaenia was probably induced by LOX (Figure 1). 228

It has been suggested that a recurrence of thrombocytopaenia following a rechallenge test with the suspected drug would provide strong additional evidence of a druginduced reaction;11 however, there are ethical difficulties in performing such tests. As the patient was not rechallenged with LOX in the present case, we cannot conclusively exclude other possible causes of thrombocytopaenia.11 Pellock18 has reported that the common side effects of CBZ include nausea, drowsiness, vertigo, and ataxia, while haematological adverse reactions to CBZ are reportedly very rare.18 Among the 80 significant CBZ-associated haematological reactions reported by the manufacturer over a 12-year period from 1975 to 1986, thrombocytopaenia was ranked first (31 cases), followed by aplastic anaemia (27 cases), agranulocytosis (10 cases), and pancytopaenia (8 cases).18 Drug information published by the manufacturer gave the main side effects of felodipine as glow, headache, and palpitation, and those of metoprolol tartrate as bradycardia, dizziness, nausea, and thrombocytopaenia (less than 0.1%). Teprenone was reported to show liver dysfunction, gastric symptoms, headache, and thrombocytopaenia (frequency unknown). In a systemic review of drug-induced thrombocytopaenia, George et al12 listed 63 kinds of drugs as level I (definite) and level II (probable) causes of thrombocytopaenia. Drug-induced thrombocytopaenia can result from either direct suppression of platelet production or by immunological mechanisms.11 The mechanisms of NSAID-induced thrombocytopaenia may be related to immunological reaction.19,20 Although LOX was not listed in this review, CBZ was as a level II (probable) drug. The review also listed diclofenac and ibuprofen as level I and level II drugs, respectively.12 NSAIDs are a widely used class of drugs.1 In a prospective study by Jick et al,20 only 3 patients among 102,644 individuals receiving at least 1 of 3 NSAIDs (diclofenac, naproxen, and piroxicam) were diagnosed as having thrombocytopaenia, indicating that NSAID-induced thrombocytopaenia is a rare condition. In another study based on hospital data gathered from Denmark,21 the incidence of thrombocytopaenia due to therapy with non-cytotoxic drugs was 35 per 100,000 patients. The most commonly reported categories of drugs were NSAIDs (14.5%), followed by anticonvulsants (11.2%), sulfonamides (10.9%), and gold salts (10.6%). Some NSAIDs, such as ibuprofen, indomethacin, naproxen, ketoprofen, and piroxicam, were listed in this report.21 Although LOX, ibuprofen, naproxen, ketoprofen, and piroxicam are categorised as propionic acid NSAIDs, LOX was not associated with thrombocytopaenia. It is also necessary to consider the possible contribution of CFPN-PI to thrombocytopaenia because of the timeframe of our case. Cephalosporin antibiotics, such as CFPN-PI, are among the safest and most frequently used drugs for oral outpatient antimicrobial therapy;19 however, Alanis and Weinstein19 reported that acute immune thrombocytopaenia may develop in patients receiving some cephalosporins.22,23 Asian J Oral Maxillofac Surg. Vol 19, No 4, 2007

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Although we found no previous reports of CFPN-PIinduced thrombocytopaenia in the literature, we did find cases of carbenicillin- and ticarcillin-induced thrombocytopaenia.19,22 Our patient was prescribed CFPN-PI for 3 days (hospital days 8 to 10), and although CFPN-PI was discontinued on hospital day 10, the platelet count continued to decrease until hospital day 17. The platelet counts would have recovered more rapidly in the present case had CFPN-PI been the causative drug of thrombocytopaenia. Moreover, DLST revealed that the response to CFPN-PI was less than that of the control. These findings suggest that thrombocytopaenia was probably induced by LOX rather than CFPN-PI. The presence of drug-dependent antiplatelet antibodies has beentaken asevidence of a drug-induced adverse reaction in some studies,13,24 and DLST is often used as evidence of drug allergies;3 however, these criteria are not widely accepted for diagnosing drug-induced thrombocytopaenia because there are no standardised criteria for distinguishing between positive and negative results.12 In the present case, DLST was performed 3 months after discharge, as we were unable to obtain patient consent prior to this, and this may have influenced the results. In conclusion, a rare case of drug-induced thrombocytopaenia probably caused by LOX is reported here. This occurrence of thrombocytopaenia, probably associated with LOX, has been reported to the manufacturer, and underlines the importance of clinicians understanding the possible side effects of common drugs such as LOX, and being aware of their adverse effects.

Acknowledgement

7.

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Matsuda K, Tanaka Y, Ushiyama S, Ohnishi K, Yamazaki M. Inhibition of prostaglandin synthesis by sodium 2-[4-(2-oxocyclopentylmethyl)phenyl] propionate dihydrate (CS-600), a new anti-inflammatory drug, and its active metabolite in vitro and in vivo. Biochem Pharmacol. 1984;33:2473-8.

9.

Sugimoto M, Kojima T, Asami M, Iizuka Y, Matsuda K. Inhibition of prostaglandin production in the inflammatory tissue by loxoprofen-Na, an anti-inflammatory prodrug. Biochem Pharmacol. 1991;42:2363-8.

10. Tanaka T, Suzuki K, Shibata K, Shigemori K, Yamada H. Drug-induced acute lung injury caused by loxoprofen; a case report following muscle and radial nerve ruptures at the upper arm [article in Japanese]. Orthop Surg Traumatol. 2003;46:1611-5. 11. Gales BJ, Sulak LB. Severe thrombocytopenia associated with alatrofloxacin. Ann Pharmacother. 2000;34:330-4. 12. George JN, Raskob GE, Shah SR, Rizvi MA, Hamilton SA, Osborne S, et al. Drug-induced thrombocytopenia: a systemic review of published case reports. Ann Intern Med. 1998;129:886-90. 13. Warkentin TE, Trimble MS, Kelton JG. Thrombocytopenia due to platelet destruction and hypersplenism. In: Hoffman R, Benz EJ, Shattil S, Furie B, Cohen HJ, Silberstein LE, editors. Hematology: basic principles and practice. New York: Churchill Livingstone; 1995:1889-909. 14. Gernsheimer T, Stratton J, Ballem PJ, Slichter SJ. Mechanisms of response to treatment in autoimmune thrombocytopenic purpura. N Engl J Med. 1989;320:974-80. 15. Kodjikian L, Durand B, Burillon C, Rouberol F, Grange JD, Renaudier P. Acetazolamide-induced thrombocytopenia. Arch Ophthalmol. 2004; 122:1543-4. 16. Watson TD, Stark JE, Vesta KS. Pantoprazole-induced thrombocytopenia. Ann Pharmacother. 2006;40:758-61.

This study was partially supported by a Scientific Researcher (No. 17390527) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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