Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1037
`
`. 1037
`
`

`
`C!inical and Experimental Dermatology 1987; 12: 124-125.
`
`Stevens-Johnson syndrome due to tetracyclines-a case
`report ( doxycycline) and review of the Iiterature
`
`R.K.CURLEY AND J.L.VERBOV St George's Hospital, Tooting and *Royal Liverpool Hospital, Prescot
`Street, * Liverpool L7 8XP, UK
`
`Accepted for publication 26 September 1986
`
`Summary
`A young adult female with Stevens-Johnson syndrome
`due to doxycycline is described. Other reports ofStevens-
`J ohnson syndrome due to tetracyclines are also reviewed.
`
`Erythema multiforme is an inflammatory skin reaction
`often recurrent and of unknown cause. It may be
`precipitated by various agents, in~luding drugs a~d
`infections and occur at any age, but ts most common m
`young adults. The lesions present may be of many t~pes
`but usually one type predominates. lt was first descnbed
`by Hebra in 1860.1 The most severe form of erythema
`multiforme was described in 1922 by Stevens and
`J ohnson2 as an eruptive fever associated with Stomatitis
`and severe conjunctivitis. The best-documented drug
`association with Stevens-J ohnson syndrome is long-
`acting sulphonamides. 3'4
`
`Case Report
`A 34-year-old woman who had been treated 6 years
`previously for late secondary syphilis but had n?t
`received a full course of treatment because of an allergtc
`reaction to penicillin, was given a 15-day course ?f
`doxycycline 300 mg daily, as a precautionary measure m
`late November-December 1985, in view of unchanged
`raised serology titres. The titres had been checked during
`routine pregnancy screening in October 1985. The
`patient requested a termination of. pregnancy ~nd
`received a 5-day course of tetracyclme at th~t ttme
`without ill-effect (the routine post-abortion procedure for
`all patientsatthat hospital). The day after completi~g the
`15-day course of doxycycline she developed burnmg of
`her eyes and dysuria and, after a further 2 days,. the
`eruption of erythema multiforme. She was admttted
`urgently to hospital five days after discontinuati?n.oft~e
`drug. Large bullae appeared soon after admtsswn 1.n
`addition to widespread small discrete papular and vesl-
`cular skin lesions and extensive mouth, genital, and eye
`
`Correspondence: Dr J.L.Verbov, Consultant Dermatologist, Royal
`Liverpool Hospital, Prescot Street, Liverpool L7 8XP.
`
`involvement. Investigations revealed anormal full blood
`count and serum electrolytes, and a normal CXR. A skin
`biopsy confirmed the diagnosis of erythema multiforme.
`Paired sera for Herpes simplex, Mycoplasma pneumo-
`niae and Psittacosis showed no significant increase in
`'
`titres.
`She was treated with intravenous fluid replacement
`oral erythromycin, intravenous hydrocortisone 400 m~'
`daily, followed by a tapering course of oral prednisolone,
`and was nursed on a ripple bed. Eye lesions were treated .
`with chloramphenicol eye ointment and prednisolonei ·
`neomycin (Predsol-N) eye drops. Mouth lesions were
`treated initially with benzydamine hydrochloride oral
`rinse (Diffiam) and later chlorhexidine gluconate (Cor- 1
`sodyl) mouth wash. She made a gradual recovery, and was
`discharged home 25 days after admission, receiving a
`mouth wash containing triamcinolone 1 mg t.d.s. for
`persistent gingival and buccal ulceration. At th.e time of
`discharge she showed guttate macular hypoptgmented
`areas over the backs of both forearms, and post-
`inflammatory hyperpigmentation over her cheeks and
`back. This was improving when seen at follow-up one,
`and three months later. She had residual mild conjunc-
`tival scarring, and epiphora affecting both eyes due to
`scarring of the puncta: the latter required minor ophthal-
`mological surgery.
`
`Discussion
`Tetracyclinesare widely used in dermatology patients in
`the management of acne and rosacea. Severe _ adve~se
`reactions are uncommon. The principal side-eftects, t.e.
`nausea, vomiting, and sometimes diarrhoea, are due to
`retention of the antibiotic in the bowel. 5 Other effects
`include deposition in calcifying bone, and staining of the
`deciduous teeth6, liver dam~ge 7,. renal to~icitr'·'~, oes~~
`phageal ulceration 10 and ratsed mtracramal pr~ssure.
`Skin reactions are relatively rare. Arndt and J 1ck pre~
`dicted a cutaneous reaction rate of not greater than 0· 3%
`for tetracycline (upper confidence limit 95%) compared
`with an observed rate of 5·9o/0 for co-trimoxaz()le, an.d
`5·2% for ampicillin. 12 In addition to erythemJ multi~
`
`124
`
`Exh. 1037
`
`

`
`[! me fixed drug eruption 13'1\ toxic epidermal necro-
`10r·51s' exanthematic eruptions, urticaria, angioedema
`ys~ p~rpura16 have been reported. Dimethylchlortetra-
`an cline and, to a lesser degree, other tetracyclines, are
`cy
`· 17 18
`phototoXIC.
`'
`There are scanty reports in the Iiterature of tetra-
`yclines causing Stevens-Johnson syndrome. Up to
`~ebruary 1986 the Committee on Safety of Medicines
`had reports of five cases of Stevens-J ohnson syndrome
`due to tetracyclines, but this is, of course, likely tobe an
`underestimate because of Iack of reporting of adverse
`effects. Caldwell and Cluff19, in a 3-year prospective
`study of adverse reactions to antimicrobial agents, de-
`scribed six cases of Stevens-J ohnson ~yndrome of which
`two were caused by tetracycline. Ting and Adam20
`reported 34 cases occurring over a 16-year period of
`which four were attributed to tetracycline. Tetracycline
`has, in some reports, been given in addition to other
`drugs. Of the two patients reported by Claxton21, who had
`the development of
`received
`tetracycline prior
`to
`Stevens-J ohnson syndrome, one had also received
`sulphamethoxypyridazine: whether the other patient had
`, also received further drugs is not stated. Gorbachev and
`colleagues22 described a patient who developed Stevens-
`Johnson syndrome after a combination of tetracycline;
`penicillin, and Streptomycin. In addition, patients are
`often prescribed antibiotics for pre-existing infection,
`and it is not always possible to decide which is the
`aetiological factor. Wasserman and Glass23 described a
`patient who developed Stevens-J ohnson syndrome after
`taking tetracycline phosphate capsules, but were also able
`to dernarrstrate an eight-fold rise in titre of antiborlies to
`type A Influenza virus. Ström2\
`in a survey of 266
`patients with febrile mucocutaneous syndromes, identi-
`fied one patient who was treated for an infection with a
`tetracycline, and two patients who were treated with
`tetracycline in combination with penicillin or sulphona-
`mide. Prusek and colleagues25 described a case of
`Stevens-Johnson syndrome associated with hone marrow
`aplasia occurring in a child treated for bronchitis with
`methacycline (Rondomycin).
`Doxycycline (6-Deoxy-Sß-hydroxytetracycline mono-
`hydrate), is a long-acting tetracycline which is readily
`absorbed from the gastro-intestinal tract and has adverse
`effects similar to the other tetracyclines. We are unaware
`of any published reports, in the English literature, of
`Stevens-Johnson syndrome following use of this anti-
`biotic. Albengres and co-workers26 described a case of
`' recurrent Stevens-Johnson syndrome which occurred
`after taking doxycyline which was also precipitated by
`hexacycline (tetracycline phosphate complex).
`References
`1. Hebra F. In: R. Virchow, ed. Handbuch der Speciellen Pathologie
`und Therapie 1860; Vol. 3, Erlangen: Enke, p 198.
`2. Stevens AM, Johnson FC. A new eruptive fever associated with
`
`STEVENS-JOHNSON SYNDROME
`
`125
`
`Stomatitis and ophthalmia. American Journal of Diseases of
`Children 1922; 24: 526-533.
`3. Carroll OM, Bryan PA, Robinson RJ. Stevens-Johnson syndrome
`associated with long-acting sulf onamides.Journal ofthe A11zerican
`Medical Association 1966; 195: 691-693.
`4. Böttiger LE, Strandberg I, Westerholm B. Drug-induced febrile
`mucocutaneous syndrome. Acta Medica Scandinavica 1975; 198:
`229-233.
`5. Verbov JL. Tetracyclines in Dermatology. Transactions ofthe St
`John's Hospital Dermatological Society 1969; 1: 78-84.
`6. Stewart DJ. Tetracyclines: their prevalence in children's teeth.
`British Dental Journa/1968; 124: 318.
`7. Peters RL, Edmondson HA, Mikkelsen WP, Tatter D. Tetracyc-
`line-induced fatty liver in nonpregnant patients: a report of six
`cases. American Journal of SU1·gery 1967; 113: 622-632.
`8. Lew HT, French SW. Tetracycline nephro-toxicity and non-
`oliguric acute renal failure. Archives of Interna! Medicine 1966;
`118: 123-128.
`9. Phillips ME, Eastwood JB, Curtis JR, Gowe, PE, De Wardener
`HE. Tetracycline poisoning in renal failure. British Medical
`Journal 1974; 2: 149-151.
`10. Crowson TD, Head LH, Ferrante WA. Esophagea1 ulcers
`associated with tetracycline therapy. Journal of the American
`Medical Association 1976; 235: 2747-2748.
`11. Bhowmick BK. Benign intracrania1 hypertension after antibiotic
`therapy. British Medical Journal1972; 3, 30-30.
`12. Arndt KA, Jick H. Rates of cutaneous reactions to drugs.Journal
`ofthe A11zerican Medicctl Association 1976; 235: 918-923.
`13. Pasricha JS. Drugs causing fixed eruptions. British' Journal of
`Dermatology 1979; 100: 183-185.
`14. Jolly HW, Sherman IJ, Carpenter CL, Nesbitt LT, Meek TJ.
`Fixed drug eruptions to tetracyclines. Archives of Dermatology
`1978; 114: 1484-1485.
`15. Lowney ED, BaublisJV, Kreye GM, Harreil ER, McKenzie AR.
`The scaled skin syndromein small children. Archives of Dermato-
`to/gy 1967; 95: 359-369.
`16. Bruinsma W. Adverse reaction profiles of drug eruptions.
`Dermatologica 1972; 145: 377-388.
`17. Cullen SI, Catalano PM, Helfman RJ. Tetracycline sun sensi-
`tivity. Archives of Dermatology 1966; 93: 77.
`18. Epstein JH, Tuffanelli DL, Seibert JS, Epstein WL. Porphyria-
`like changes induced by tetracycline hydrochloride photosensi-
`tization. Archives of Dermatology 1975; 112: 661-666.
`19. Caldwell JR, CluffLE. Adverse reactions to antimicrobial agents.
`Journal of the American Medical Association 1974; 230: 77-80.
`20. Ting HC, Adam BA. Stevens-Johnson Syndrome: A review of34
`cases. International Journal of Dermatology 1985; 24: 587-591.
`21. Claxton RC. A review of31 cases ofStevens-Johnson syndrome.
`The Medical Journal of Australia 1963; 50: 963-967.
`22. Gorbachev VV, Bronovets IN, Vetokhin VI, Chugunkina SB,
`Karachan NZ. Stevens-Johnson syndrome as a complication of
`antibacterial therapy. Terapevticheskii Arkhiv ( Moskva) 1972; 44:
`106-108. (Original paper in Russian.)
`23. Wasserman E, Glass WI. Stevens-Johnson syndrome. Archives of
`Intemal Medicine 1959; 104: 125-130.
`24. Ström ]. Aetiology of febrile muco-cutaneous syndromes with
`special reference to the provocätive role of infections and drugs.
`Acta Medica Scandinavica 1977; 201: 131-136.
`25. Prusek W, Nawrocka E, Kozierowska B, Kosinski S. Exudative
`erythema with hone marrow aplasia after treatment with rondo-
`mycin. (Original paper in Polish.) Polski Tygodnik Lekarski 1980;
`35: 503-504.
`26. Albengres E, Guillaume JC, Chevais M, Riant P, Touraine R,
`Tillement JP. Ectodermose pluriorificielle repetitive lors de
`traitments successifs par des tetracyclines: A propos d 'un cas.
`Therapie 1983; 38: 577-579.
`
`Exh. 1037