C A S E R E P O R T

Eikenella corrodens InfectionsCase report in two adolescent females with 1DDM

RON S. NEWFIELD, MDILEANA VARGAS, MD

ZlLLA HUMA, MD

OBJECTIVE — To alert physicians caring for patients with diabetes to the microorganismEikenella corrodens and to discuss the appropriate preventive and therapeutic measures to takeagainst this potentially morbid opportunistic Gram-negative bacilli.

CASES — We present two cases of extra-oral E. corrodens infections in adolescent females with1DDM. The first patient had diabetes of 4 years' duration, which was moderately well controlled.Chronic finger biting resulted in a complex felon that evolved gradually and worsened while thepatient received cephalexin orally. Delay in seeking further intervention resulted in necrosis ofher distal fingertip and nail bed. The second patient had poorly controlled diabetes for 5 years.She developed an acute thigh abscess at an insulin injection site that resolved after drainage andintravenous antibiotics.

CONCLUSIONS — E. corrodens commonly inhabits the human oral cavity and becomes apathogen mostly when host defenses are impaired, causing abscesses and infections that are attimes fatal. Patients with IDDM are compromised hosts and with daily microtrauma to their skinvia glucose monitoring and insulin injections, are prone to develop E. corrodens infections thatcan be introduced through oral secretions by licking or biting their skin. Educational effortsaimed at preventing exposure of traumatized skin to oral secretions can minimize the risk of E.corrodens infections in compromised hosts. Early intravenous administration of antibiotics,bearing in mind E. corrodens resistance to clindamycin, metronidazole, and other antibiotics,coupled with prompt surgical intervention, is essential in successfully managing E. corrodensinfections.

Eikenella corrodens is a slow-growing fac-ultatively anaerobic Gram-negative bacil-lus. It is undoubtedly a human pathogen,displaying opportunistic characteristics.Infections in normal hosts have been re-ported but are infrequent. Most patientswith E. corrodens infections have reducedhost defenses (1-5) due to trauma, sur-gery, or chronic or debilitating illnesses,such as malignancies, or from receivingimmunosuppressive therapy. We presenttwo adolescent patients with IDDM whodeveloped E. corrodens infections (appar-ently the first report in literature in En-glish), where reduced host defenses areattributed to IDDM, the routine micro-trauma to the skin associated with insulininjections and blood glucose monitoring,

and exposure of broken skin surfaces tooral secretions. Diagnosis of E. corrodensinfection, its unusual antibiotic sensitivi-ties, and its treatment will be discussed.

CASE REPORT I— A 14-year-oldblack female with IDDM for 4 years wasadmitted in moderately good glycemiccontrol, with an HbAlc level of 8.7% (nor-mal, 4.5-6.5%). Over the 9 months pre-ceding her admission, her mean HbAlc

was 9.6% (range 8.7-11.3%). She hadbeen chronically biting her fingernailsand fingertips. Ten days before her admis-sion, the fingertip of her fourth digit onthe right hand gradually became tender,swollen, and erythematous. Four days be-

From the Department of Pediatrics, Division of Pediatric Endocrinology, The New York Hospital, CornellMedical Center, New York, New York.

Address correspondence and reprint requests to Ron S. Newfield, MD, Department of Pediatrics, Rm.N-236, The New York Hospital, Cornell Medical Center, 525 E. 68th St., New York, NY 10021.

Received for publication 27 November 1995 and accepted in revised form 18 April 1996.

fore her admission, her pediatrician hadstarted her on 500 mg of oral cephalexin,three times daily, along with hot soaks.On follow-up with the pediatrician, shedeveloped pus, bluish discoloration, anddecreased range of motion of her distalphalanx.

She was admitted (not in ketoaci-dosis) with a low-grade fever of 38.6°C.She was immediately sent to the operatingroom for a wide excision and drainage ofa complex felon, and 3 cm3 of pus wasdrained. A Gram stain showed Gram-positive cocci in pairs and chains, and cul-tures from her pus grew many E. corro-dens, Enterococcus fecaelis, and a fewcoagulase-negative staphylococci. She re-ceived two doses of unasyn before switch-ing empirically to nafcillin and clindamy-cin. E. corrodens sensitivities werechecked, according to the manual andconventional Kirby Bauer method, andthe organism was found to be sensitive tocefazolin, penicillin, ampicillin, and gen-tamicin. It was resistant to clindamycin,and sensitivity to nafcillin was not re-ported. Nafcillin was switched to penicil-lin-G, gentamicin was added for synergyfor both organisms, and ampicillin wasused a few days later as well. The patientunderwent imaging studies of the affecteddigit, such as magnetic resonance imaging(MRI), bone scan, and labeled indium-I l l , to rule out osteomyelitis, none ofwhich were conclusive. Despite initialsurgery followed by 2 weeks of intrave-nous antibiotics and daily wound care,she eventually required a second surgicalintervention. She underwent debride-ment of the distal phalangeal tip, whichinvolved removal of the nail and nail bedand resulted in shortening of the digit.

CASE REPORT II— A 13-year-oldmidpubertal black female with IDDM for5 years had multiple admissions for poorcontrol due to noncompliance and lack ofadequate parental supervision. On admis-sion, her HbAlc level was 10.2%, and overthe year preceding her admission, hermean HbAlc was 11.2% (range 9.9-12.5%). She presented at this institution'sdiabetes clinic with a 2-cm tender lesion

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Eikenella infection in diabetic adolescents

at an insulin injection site on her rightanterior thigh, judged to be a hematoma.She was admitted to this institution'sChildren's Clinical Research Center thenext day under an institutionally ap-proved protocol, and informed consentwas obtained from her legal guardian. Shehad a soft tissue infection to her thigh anda raised lesion that was nonfluctuant, ten-der, warm, and erythematous (7 cm). Shewas afebrile with no inguinal lymphade-nopathy, and her leukocyte count anderythrocyte sedimentation rate were notelevated. Her blood glucose level was25.9 mmol/1 (466 mg/dl), without keto-acidosis. She was started on intravenousnafcillin and gentamicin. After 36 h of in-travenous antibiotics, the involved areabecame larger, and fluctuance was sus-pected. A sonogram showed a 1.1 X 1.2cm abscess, and 1.5 cm3 of brown yellowputrid pus was aspirated. A Gram staindemonstrated Gram-positive cocci inpairs and clusters and also bacilli. Culturegrew £. corrodens that was sensitive to naf-cillin, penicillin, and cephalothin, but re-sistant to clindamycin. After the drainage,she continued to improve on intravenousnafcillin alone for 10 days and was dis-charged home on cephalexin, taken orallyfor an additional week.

CONCLUSIONS— In 1958, Eikenfirst characterized 21 strains of fastidiousGram-negative anaerobic rods possessinga typical colony morphology that ap-peared to corrode or pit blood agar sur-faces (6). A review by Chen and Wilson(1) of E. corrodens in human oral and non-oral infections elaborates on the morpho-logic, biochemical, serological, and geno-typic characteristics of this facultativelyanaerobic Gram-negative bacillus. SinceEiken's initial report, which concentratedon abscess isolates from the oral region,there have been many reports of E. corro-dens infections, both in adults and chil-dren. E. corrodens is a common inhabitantin the human oral cavity, with only a fewclones from this species apparently beingpathogenic (1). Therefore, E. corrodens in-fections are often due to orally contami-nated wounds (2-4,7,8) associated withfist fights, clenched fists, tooth lacera-tions, or bites. Extra-oral infections havebeen described in numerous sites ( 1 -6,9,10), including, among others, brainabscesses, subdural empyema, sinusitis,pneumonia with empyema, osteomyeli-

tis, or endocarditis. Extra-oral infectionscarry considerable morbidity and, attimes, are fatal, especially if the centralnervous system is affected. These infec-tions are explained either by bacteria(10,11) or by direct contact with oral orupper respiratory tract secretions, as inaspiration pneumonia. E. corrodens is alsopresent in the gastrointestinal and genitaltracts themselves, as evident by its isola-tion in intra-abdominal abscess often re-lated to surgery (2-5,12), or rarely, a Bar-tholin abscess (13) or intrauterine deviceinfection (14).

In review of the literature, four pa-tients with diabetes were previously re-ported to develop E. corrodens infections,all of whom were adults. The first patientwas a 66-year-old female patient withN1DDM, who also had metastatic gastriccarcinoma. She developed an abdominalabscess with E. corrodens after abdominalsurgery (5). The three other patients (typeof diabetes unspecified), aged 31,51, and52 years old, had subacute or chronic in-fections to their feet with multiple organ-isms, and failure of conventional antibiot-ics to cover E. corrodens resulted inosteomyelitis (15).

E. corrodens is mostly a pathogenwhen host defenses are compromised. In-fections are often indolent, but can beacute, with E. corrodens isolated alone, butmore commonly, in synergy with strepto-cocci, staphylococci, or other organisms.E. corrodens abscesses often mimic mixedanaerobic infections with yellow, green,or brown putrid pus. We will now discusswhat predisposed our two patients topresent with E. corrodens infections, andmost importantly, how to best treat suchinfections when they occur, as well asways to prevent infections with E. corro-dens in diabetic subjects and other suscep-tible hosts.

In the adult diabetic population,ischemic changes to the skin, primarily inthe feet, due to changes in the micro- andmacrovasculature play a major role in sus-ceptibility to infection and poor woundhealing. Unlike in adults, peripheral neu-ropathy does not contribute to the riskof infection in adolescent patients withIDDM. Ineffective phagocytosis, de-creased chemotactic activity of poly-morphonuclear leukocytes, and serumopsonizing capacity have long been rec-ognized in patients with diabetes of dif-ferent ages (16) but most likely play aminor role.

In the first patient, chronic fingerand nail biting exposed broken skin tooral secretions, which frequently harborE. corrodens. Paronychial infections withE. corrodens were reported in healthy chil-dren sucking or biting their fingers (17)and may progress to osteomyelitis (18). Itis also conceivable that pricking the skinfor blood glucose monitoring provided aport of entry.

In our second patient, the infec-tion occurred at an insulin injection site.Good cleansing of the skin before inject-ing insulin would seem crucial in prevent-ing infection, though evidence to the con-trary exists (19,20). Licking an insulininjection site, a wound, or broken skinelsewhere may be a more important factorthen previously suspected, and avoidingthat practice would prevent exposure tooral secretions and, thus, infections withE. corrodens or other oral pathogens.

The mainstays of successful treat-ment of E. corrodens infections are as fol-lows:

1. Suspect E. corrodens in any ab-scess, especially abdominal, oral, orwhere exposure to oral secretion is possi-ble. In addition, suspect E. corrodens insoft tissue infections not responding toroutine antibiotics, such as nafcillin orcephalothin. Note that a Gram stainshowing Gram-negative bacilli is an im-portant tip-off. The microbiology labshould be instructed to look for this fas-tidious organism, retaining routine aero-bic cultures for 48 h longer or growingthis organism in 5-10% CO2.

2. Suspecting E. corrodens shoulddirect antibiotic coverage before sensitiv-ities, knowing it is universally resistant toclindamycin and metronidazole (1-3)(drugs commonly used in abscesses dueto anaerobes). Brooks et al. (2) docu-mented partial resistance to methicillinand cephalothin in vitro and reported onpatients who developed E. corrodens in-fections while receiving those drugs. Ourfirst patient did not respond to oralcephalexin, in spite of organism sensitiv-ity to it in vitro. Similar findings were re-ported (15), with resistance to nafcillin,oxacillin, dicloxacillin, and cephalexin, inadult patients with diabetes; treatmentwith those antibiotics resulted in indolentchronic infections of the patients' feet andprogression to osteomyelitis. Some E. cor-rodens strains are also relatively resistantto aminoglycosides. Recommendationsfor antibiotic coverage vary. Ampicillin

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Newjield and Associates

and penicillin are generally recom-mended (1-4,12), although strains notresponding to penicillin were reported(21,22). ff. corrodens is uniformly sensi-tive to tetracycline and chloramphenicol(1-4), which are used in patients withdrug allergies. Goldstein and colleagues(23,24) have found that E. corrodens is notuniformly sensitive to all the new j3-lac-tams, second and third generations ceph-alosporins. Overall, E. corrodens showedgood susceptibility to commonly used an-tibiotics, such as cefoxitin, cefotetan, ce-fotaxime, ceftriaxone, ticarcillin, andmoxalactam. For empirical treatment ofdiabetic subjects' feet infections, somerecommend using cefoxitin or imipenem(13).

3. Early surgical drainage, whenindicated, together with appropriate anti-biotics coverage is of the utmost impor-tance in treating E. corrodens infectionssuccessfully (2,3).

Our two cases underscore theneed to educate patients with IDDM andtheir parents about the dangers associatedwith licking their wounds or fingertips af-ter blood glucose monitoring. In addition,we advocate for aggressive and early insti-tution of intravenous antibiotics in anysoft tissue infection in patients with dia-betes. We are hopeful that increasedawareness to E. corrodens will raise the in-dex of suspicion and thus contribute tooptimal management of these infections,minimizing the significant morbidity as-sociated with this organism.

Acknowledgments—This study was sup-ported in part by a grant from the NationalInstitutes of Health, Division of Research Re-sources, Award RR0620.

References

1. Chen CKC, Wilson ME: Eikenella corro-dens in human oral and non-oral infec-tions: a review. J Periodontal 63:941-953,1992

2. Brooks GF, O'Donoghue JM, RissingJP,Suapes K, SmithJW: Eikenella corrodens,a recently recognized pathogen: infec-tions in surgical patients and in associa-tion with methylphenidate abuse. Medi-cine 53:325-342, 1974

3. Marsden HB, Hyde WA: Isolation of Bac-teroides corrodens from infections in chil-dren. J Clin Path 24:117-119, 1971

4. Kaplan JM, Nelson JD, McCracken G: In-fections in children caused by the HBgroup of bacteria. J Pediatr 82:398-403,1973

5. Dor ff GJ, Jackson LJ, Ry tel MW: Infectionswith Eikenella corrodens a newly recog-nized human pathogen. Ann Intern Med80:305-309, 1974

6. Eiken M: Studies on an anaerobic, rod-shaped Gram-negative microorganism:Bacteroides corrodens sp. Ada Pathol Mi-crobiol Scand 43:404-416, 1958

7. Schmidt DR, Heckman JD: Eikenella cor-rodens in human bites infections of thehand. J Trauma 23:478-482, 1983

8. GoldsteinEJC,MillerTM,CitronMD,Fine-gold SM: Infections following clenchedfist injury: a new perspective. J Hand3:455-457, 1978

9. St. John MA, Belda AA, Matlow A, ProberCG: Eikenella corrodens empyema inchildren. Am J Dis Child 135:415-417,1981

10. Olopoenia LA, Mody V, Reynolds M:Eikenella corrodens endocarditis in an in-travenous drug user: case report and lit-erature review. J Natl Med Assoc 86:313-315,1994

11. Khairat O: Bacteroides corrodens isolatedfrom bacteriaemias. J Path Bad 95:29-40,1967

12. Danziger LH, Schoonover LL, Kale P,Resnick DJ: Eikenella corrodens as an in-

tra-abdominal pathogen. Am J Surg 60:296-299, 1994

13. Riche O, Vernet V, Megier P: Bartholinsabscess associated with Eikenella corro-dens (Letter). Lancet ii: 1089, 1987

14. Drouet E, DeMontclos H, Boude M, De-noyel GA: Eikenella corrodens and intra-uterine contraceptive device (Letter), Ixin-cetii:1089, 1987

15. Konugres GS, Goldstein EJC, Wallace SI.:Eikenella corrodens as a cause of osteo-myelitis in the feet of diabetic patients.J Bone Joint Surg 69:940-941, 1987

16. Feigin RD, Shearer WT: Opportunistic in-fection in children. JPt>tiiu(r87:(i77, W i

17. Brook 1: Bacteriologic study of paronychiain children. Am J Surg 141:703-70"),1981

18. Sagerman SD, Lourie GM: Eikenella os-teomyelitis in a chronic nail biter: a casereport. J Hand Surg 20:71-72, 1995

19. Koivisto VA, Felig P: Is skin preparationnecessary before insulin injection? Lanceti:1072-1075, 1978

20. McarthyJA, Covarrubias B, Sink P: Is thetraditional alcohol wipe necessary beforean insulin injection (Letter). Diabetes Care16:402, 1993

21. Henriksen SD: Studies on Gram-negativeanaerobes. II. Gram-negative anaerobicrods with spreading colonies. Ada PatholMicrobiol Scand 25:368-375, 1948

22. Trallero EP, Arenzana JMG, F.guilui:GC, Larrucea JT: j3-lactamase-produc-ing Eikenella corrodens in an intraab-dominal abscess (Letter). J Inject Dis153:379-380, 1986

23. Goldstein EJC, Citron DM: Susceptibilityof Eikenella corrodens to penicillin, apal-cillin and twelve new cephalsporins. An-timkrob Agents Chemother 26:947-948,1984

24. Goldstein EJC, Gombert ME., Agyare FO:Susceptibility of Eikenella corrodens tonewer j3-lactam antibiotics. AntimicrobAgents Chemother 18:832-833, 1980

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13

Diabetes on the Old Silk Road :'; /?. ihrnv. I »'*<n; f.

HLA and (ttutamtr Acid Decarboxyiase in Human Insulin-dependent DiabetesMellitus V ;? .S,?njrri<:, A. :V:';S.*,';J, I ktnUm IV, A. /uyopvrr., A. h">:::!W*.

Restitution «t Ncurophysiological functions, Performance, and Subjetlive Symptomsafter Moderate Insulin-induced Hypoglycaemia in Non-diabetic Men \J ; .('*«*:,

h i

>A 1

Correcting for Ethnicity when Defining Large for Gestational Age Infants in Diabetic:Pregnancies A, Domho^r, ;. V />. \nholk, A. WtHth, A. A!;. S P. Chin, R V. s'vau:..

Familial Aggregation of Type 2 (N'on-insulin-dependent) Diabetes Mellitus in SouthIndia; Absence of Excess Maternal Transmission \1. Vhivandth-jn, Xt. i. Xk t >.\i.vv.('. S^vk-Sui'hu, ('•. A. i:;»f**v?; A. RMI\Urranu'nin

Serum Sialtc Acid and the Long-term Complications of Insulin-dependent DiabetesMeilitus ;". i\. ftr.vriv. (.. ? ll'dity VI A. Crook, /. .V. lng!un:. \ . A l<wb, K. \?. 'shdu-..

Risk factors for lower Extremity Arterial Disease in Non-insulin-dependent DiabeticPersons \ . t. KaSiLsnthroy P. ( . Kipo&is XI P. Aiv,initi\ \ . A. .'•/*«•>, / . P. A!v\iou,t \ . . t\?.^c '*» . . . . . . .

Relative Fasting Hypoinsulinaemia and Ultrasonically Measured Early Arterial Diseasein type 2 Diabetes R. S. iJLKvs, j . R. Duirnond, X. M-Babv-hnut:, S. l)l\u:;H,

P. S-wrp, thv S$SlX'Ai* Stu<:\> (iTOUp A4VPhysical Work Capacity in Diabetic Children and Adolescents with and without

Cardiovascular Autonomic: Dysfunction /. Harkdi, Xi /V/a, *'. Y,hvo\s ). >• *Abnormal Response to Exercise in Middle-aged NIDDM Patients with and without

Autonomic Neuropathy VI Radke, A. ROUJ, I. Bvdon, \ . XUSSM < hio, A. \Uu.ihiia,(:. Sv&im . » • « )

A Novel Method for the Assessment of Autonomic Neuropathy in Type 2 DiabeticPatients: a Comparative Evaluation of 12i4l-MIBG Myocardial Scintigraphy andPower Spectral Analysis of Heart Rate Variability K. Xluhihi Y. SumkLi,S, Xiuhhhm'ti, K. Xldhutiuna, II. lakvik, L Nakagawa, 1. Shimj 'b(>

CMNICA! PRACtKTPatterns of In and Out-patient Activity for Diabetes: a District Survey C. / Cunh\

n R. K. Wil'kms, /. R. Pvlvt> »: \

CASI KH'OKIAggressive Limb Salvage Using Tibio-pedal Bypass Grafting with Free Tissue Transfer

in a Diabetic Patient 1). vViilmshy, C. /. Ingfalivhl, A, R. Njylor, I. t. XUmhhon,/'. S. Ko'hv, C.. (,, Cooper 2<S!

IIIHRSUrine Hydroxvproline Increase in Patients with Diabetes Mellitus A V7. ()lnio\

XI I t <jti ij, /. A. Amado, 1. (,<m/Ahv-\Ud<isReply from P. L. SelbySerum Sialic Acid Concentrations in Asian Diabetic Patients in the UK /. ( Pit hup.

1. (Kuuh VI ft XUtkn% A. Satnud i 1. XI XUthw

284

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INTRODUCING a new adjunct to diet and exercise

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1,2 , and 4 mgBrief SummaryDrug InteractionsThe hypoglycemic action of sulfonylureas may be potentiated by certain drugs, including nonsteroidalanti-inflammatory drugs and other drugs that are highly protein bound, such as salicylates, sulfonamides,chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blockingagents.

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include thethiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oralcontraceptives, phenytoin, nicotinic acid, sympathomimetics, and isoniazid.

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severehypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical, orvaginal preparations of miconazole is not known. Potential interactions of glimepiride with other drugsmetabolized by cytochrome P450IIC9 also include phenytoin, diclofenac, ibuprofen, naproxen, andmefenamic acid.

Although no specific interaction studies were performed, pooled data from clinical trials showed noevidence of clinically significant adverse interactions with uncontrolled concurrent administration ofcalcium-channel blockers, estrogens, fibrates, NSAIDs, HMG CoA reductase inhibitors, sulfonamides,or thyroid hormone.INDICATIONS AND USAGEAMARYL is indicated as an adjunct to diet and exercise to lower the blood glucose in patients withnoninsulin-dependent (Type II) diabetes mellitus (NIDDM) whose hyperglycemia cannot be controlled bydiet and exercise alone.

AMARYL is also indicated for use in combination with insulin to lower blood glucose in patients whosehyperglycemia cannot be controlled by diet and exercise in conjunction with an oral hypoglycemic agent.Combined use of glimepiride and insulin may increase the potential for hypoglycemia.CONTRAINDICATIONSAMARYL is contraindicated in patients with

1. Known hypersensitivity to the drug.2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.

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SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITYThe administration of oral hypoglycemic drugs has been reported to be associated with increasedcardiovascular mortality as compared to treatment with diet alone or diet plus insulin.PRECAUTIONSGeneral

Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Patients withimpaired renal function may be more sensitive to the glucose-lowering effect of AMARYL. A starting doseof 1 mg once daily followed by appropriate dose titration is recommended in those patients. Debilitated ormalnourished patients, and those with adrenal, pituitary, or hepatic insufficiency are particularlysusceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia is more likely to occurwhen caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or whenmore than one glucose-lowering drug is used.

Loss of control of blood glucose: When a patient stabilized on any diabetic regimen is exposed tostress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may benecessary to add insulin in combination with AMARYL or even use insulin monotherapy. Shouldsecondary failure occur with AMARYL monotherapy, AMARYL-insulin combination therapy may beinstituted. Combined use of glimepiride and insulin may increase the potential for hypoglycemia.Information for PatientsPatients should be informed of the potential risks and advantages of AMARYL and of alternative modesof therapy. They should also be informed about the importance of adherence to dietary instructions, of aregular exercise program, and of regular testing of blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to itsdevelopment should be explained to patients and responsible family members. The potential for primaryand secondary failure should also be explained.Laboratory TestsFasting blood glucose should be monitored periodically to determine therapeutic response. Glycosylatedhemoglobin should also be monitored, usually every 3 to 6 months, to more precisely assess long-termglycemic control.Canclnogenesis, Mutagenesis, and Impairment of FertilityStudies in rats at doses of up to 5000 ppm in complete feed (approximately 340 times the maximumrecommended human dose, based on surface area) for 30 months showed no evidence of carcinogenesis.In mice, administration of glimepiride for 24 months resulted in an increase in benign pancreatic adenomaformation which was dose related and is thought to be the result of chronic pancreatic stimulation. Theno-effect dose for adenoma formation in mice in this study was 320 ppm in complete feed, or 46-54 mg/kgbody weight/day. This is about 35 times the maximum human recommended dose of 8 mg once dailybased on surface area.

Glimepiride was non-mutagenic in a battery of in vitro and in vivo mutagenicity studies (Ames test,somatic cell mutation, chromosomal aberration, unscheduled DNA synthesis, mouse micronucleus test).

There was no effect of glimepiride on male mouse fertility in animals exposed up to 2500 mg/kg bodyweight (>1,700 times the maximum recommended human dose based on surface area). Glimepiride hadno effect on the fertility of male and female rats administered up to 4000 mg/kg body weight(approximately 4,000 times the maximum recommended human dose based on surface area).PregnancyTeratogenic EffectsPregnancy Category C. Glimepiride did not produce teratogenic effects in rats exposed orally up to 4000mg/kg body weight (approximately 4,000 times the maximum recommended human dose based onsurface area) or in rabbits exposed up to 32 mg/kg body weight (approximately 60 times the maximumrecommended human dose based on surface area). Glimepiride has been shown to be associated withintrauterine fetal death in rats when given in doses as low as 50 times the human dose based on surfacearea and in rabbits when given in doses as low as 0.1 times the human dose based on surface area. Thisfetotoxicity, observed only at doses inducing maternal hypoglycemia, has been similarly noted with othersulfonylureas, and is believed to be directly related to the pharmacologic (hypoglycemic) action ofglimepiride.

There are no adequate and well-controlled studies in pregnant women. On the basis of results fromanimal studies, AMARYL should not be used during pregnancy. Many experts recommend that insulin beused during pregnancy to maintain glucose levels as close to normal as possible.Nonteratogenic EffectsIn some studies in rats, offspring of dams exposed to high levels of glimepiride during pregnancy andlactation developed skeletal deformities consisting of shortening, thickening, and bending of the humerusduring the postnatal period. Significant concentrations of glimepiride were observed in the serum andbreast milk of the dams as well as in the serum of the pups. These skeletal deformations were determinedto be the result of nursing from mothers exposed to glimepiride.

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who

were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with theuse of agents with prolonged half-lives. Patients who are planning a pregnancy should consult theirphysician, and it is recommended that they change over to insulin for the entire course of pregnancy andlactation.Nursing MothersIn rat reproduction studies, significant concentrations of glimepiride were observed in the serum andbreast milk of the dams, as well as in the serum of the pups. Although it is not known whether AMARYLis excreted in human milk, other sulfonylureas are excreted in human milk. AMARYL should bediscontinued in nursing mothers. If AMARYL is discontinued, and if diet and exercise alone areinadequate for controlling blood glucose, insulin therapy should be considered. (See above Pregnancy,Nonteratogenic Effects)Pediatric UseSafety and effectiveness in pediatric patients have not been established.ADVERSE REACTIONSThe incidence of hypoglycemia with AMARYL, as documented by blood glucose values <60 mg/dL,ranged from 0.9-1.7% in two large, well-controlled, 1-year studies. (See WARNINGS and PRECAUTIONS)

AMARYL has been evaluated for safety in 2,013 patients in US controlled trials, and in 1,551 patients inforeign controlled trials. More than 1,650 of these patients were treated for at least 1 year.

Adverse events, other than hypoglycemia, considered to be possibly or probably related to study drugthat occurred in US placebo-controlled trials in more than 1 % of patients treated with AMARYL are shownbelow.

Adverse Events Occurring in > 1 % AMARYL PatientsAMARYL Placebo

Total TreatedDizzinessAstheniaHeadacheNausea

No.7461312118

%1001.71.61.51.1

No.294

1340

%1000.31.01.40.0

Gastrointestinal ReactionsVomiting, gastrointestinal pain, and diarrhea have been reported, but the incidence in placebo-controlledtrials was less than 1 % . Isolated transaminase elevations have been reported. Cholestatic jaundice hasbeen reported to occur rarely with sulfonylureas.Dermatologic ReactionsAllergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions,occur in less than 1 % of treated patients. These may be transient and may disappear despite continueduse of AMARYL; if skin reactions persist, the drug should be discontinued. Porphyria cutanea tarda andphotosensitivity reactions have been reported with sulfonylureas.Hematologic ReactionsLeukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopeniahave been reported with sulfonylureas.Metabolic ReactionsHepatic porphyria reactions and disulfiram-like reactions have been reported with sulfonylureas; however,no cases have yet been reported with AMARYL. Cases of hyponatremia have been reported withglimepiride and all other sulfonylureas, most often in patients who are on other medications or havemedical conditions known to cause hyponatremia or increase release of antidiuretic hormone. Thesyndrome of inappropriate antidiuretic hormone (SIADH) secretion has been reported with certain othersulfonylureas, and it has been suggested that these sulfonylureas may augment the peripheral(antidiuretic) action of ADH and/or increase release of ADH.Other ReactionsChanges in accommodation and/or blurred vision may occur with the use of AMARYL. This is thought tobe due to changes in blood glucose, and may be more pronounced when treatment is initiated. Thiscondition is also seen in untreated diabetic patients, and may actually be reduced by treatment. Inplacebo-controlled trials of AMARYL, the incidence of blurred vision was placebo, 0.7%, and AMARYL, 0.4%.0VERD0SAGEOverdosage can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness orneurologic findings should be treated aggressively with oral glucose and adjustments in drug dosageand/or meal patterns. Close monitoring should continue until the physician is assured that the patient isout of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occurinfrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemiccoma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated(50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucosesolution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should beclosely monitored for a minimum of 24 to 48 hours, because hypoglycemia may recur after apparentclinical recovery.DOSAGE AND ADMINISTRATIONThere is no fixed dosage regimen for the management of diabetes mellitus with AMARYL or any otherhypoglycemic agent.Usual Starting DoseThe usual starting dose of AMARYL as initial therapy is 1-2 mg once daily, administered with breakfast orthe first main meal. Those patients who may be more sensitive to hypoglycemic drugs should be startedat 1 mg once daily, and should be titrated carefully. (See PRECAUTIONS Section for patients at increased risk).

No exact dosage relationship exists between AMARYL and the other oral hypoglycemic agents. Themaximum starting dose of AMARYL should be no more than 2 mg.

Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do notadhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response totherapy.Usual Maintenance DoseThe usual maintenance dose is 1 to 4 mg once daily. The maximum recommended dose is 8 mg oncedaily. After reaching a dose of 2 mg, dosage increases should be made in increments of no more than 2mg at 1-2 week intervals based upon the patient's blood glucose response. Long-term efficacy should bemonitored by measurement of HbA1c levels, for example, every 3 to 6 months.AMARYL0-Insulin Combination TherapyCombination therapy with AMARYL and insulin may be used in secondary failure patients. The fastingglucose level for instituting combination therapy is in the range of >150 mg/dL in plasma or serumdepending on the patient. The recommended AMARYL dose is 8 mg once daily administered with the firstmain meal. After starting with low-dose insulin, upward adjustments of insulin can be done approximatelyweekly as guided by frequent measurements of fasting blood glucose. Once stable, combination-therapypatients should monitor their capillary blood glucose on an ongoing basis, preferably daily. Periodicadjustments of insulin may also be necessary during maintenance as guided by glucose and HbA1c levels.Specific Patient PopulationsAMARYL is not recommended for use in pregnancy, nursing mothers, or children. In elderly, debilitated,or malnourished patients, or in patients with renal or hepatic insufficiency, the initial dosing, doseincrements, and maintenance dosage should be conservative to avoid hypoglycemic reactions (SeePRECAUTIONS, General).

| HOECHST-ROUSSEL:euticals Incorporated

ISomerville, NJ0S876-1258922100-10/95

References: 1. Kramer W, Muller G, Girbig F, et al. Differential interaction of glimepiride andglibenclamide with the p-cell sulfonylurea receptor: II. photoaffinity labeling of a 65 kDa pro-tein by [3H]glimepiride. Biochim Biophys Acta. 1994,1191:278-290. 2. Muller G, Hartz D,Punter J, Okonomopulos R, Kramer W. Differential interaction of glimepiride and glibenclamidewith the p-cell sulfonylurea receptor: I. binding characteristics. Biochim Biophys Acta. 1994;1191:267-277. 3. Data on file, Hoechst Marion Roussel.

1171-96687815 ©1996, Hoechst Marion Roussel, Inc. 0313B6

Hoechst Marion RousselHoechst Marion Roussel, Inc. • Kansas City, MO 64134A member of the Hoechst Group

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