DERMATOLOGY
`
`OCTOBER 1997
`
`Unht. of Minn.
`Bio-Medical
`Library
`
`Question: What do these 3 individuals have in common? See page 1311 .
`
`THE AGING ISSUE
`
`DEATH FROM SKIN CANCER AMONG THE
`ELDERLY: EPIDEMIOLOGICAL PATTERNS
`
`GENETIC SKIN DISEASES
`WITH ALTERED AGING
`
`AGING OF THE SKIN: IMPLICATIONS FOR
`, CUTANEOUS SURGERY
`
`PIGMENTARY CHANGES IN AGED
`AND PHOTOAGED SKIN
`
`PHOTOAGING AND TOPICAL TRETINOIN:
`THERAPY, PATHOGENESIS,
`AND PREVENTION
`
`AGING AND THE SKIN IMMUNE SYSTEM
`
`American Medical Association
`Physicians dedicated to the health of America
`
`~BXHBBCLitllftitilte~lti****·3-D:tG:tT 554
`· adto4-sos~s~2toii!'"·r ---'---------'-------.,
`Bl:O~D:tCAL · L:tBRA Dr. Reddy's Laboratories, Ltd., et al.
`.
`v.
`i.JHI:~~:it'l' .(ri::.· .• 111:
`Galderma Laboratories, Inc.
`.
`IPR2015-__
`32Sf'l t>l:'e.HL HALL
`Exhibit 1039
`So'S ESSEX si .SE
`M'l:NHEA'PoLl:S MH S54SS-0350.
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`
`

`
`E ATOLO
`
`OCTOBER 1997
`
`Question: What do these 3 individuals have in common? See page 1311 .
`
`THE AGING ISSUE
`
`DEATH FROM SKIN CANCER AMONG THE
`ELDERLY: EPIDEMIOLOGICAL PATTERNS
`
`GENETIC SKIN DISEASES
`WITH ALTERED AGING
`
`AGING OF THE SKIN: IMPLICATIONS FOR
`- CUTANEOUS SURGERY
`
`PIGMENTARY CHANGES IN AGED
`AND PHOTOAGED SKIN
`
`PHOTOAGING AND TOPICAL TRETINOIN:
`THERAPY, PATHOGENESIS,
`AND PREVENTION
`
`AGING AND THE SKIN IMMUNE SYSTEM
`
`American Medical Association
`Physicians dedicated to the health of America
`
`1a1t1tileltthalaltlula{illtittillttlt1tHiaaltilt1
`ttBXHBBCL!It***jk***** 3-D:tG:tT 554
`atl10460SSSOS2tt04t> 1712 001070 00053 **
`**
`B:tOMED:tCAL L:tBRARY
`lJH:tt.JERS:tT"r' OF. tttHHESOTA
`325A t>:tEHL HALL
`505 ESSEX ST SE
`M:t:HHEAl='OL:tS MH 55455-~350
`
`Exh. 1039
`
`

`
`Comparative Safety of Tetracycline,
`Minocycline, and Doxycycline
`
`Lori E. Shapiro, MD, FRCPC; Sandra R. Knowles, BScPhm; Neil H. Shear, MD, FRCPC
`
`Background: Because minocycline can cause serious ad-
`verse events including hypersensitivity syndrome reac-
`tion (HSR), serum sicknesslike reaction (SSLR), and drug-
`induced lupus, a follow-up study based on a retrospective
`review of our Drug Safety Clinic and the Health Protec-
`tion Branch databases and a literature review was con-
`ducted to determine if similar rare events are associated
`with tetracycline and doxycycline. Cases of isolated single
`organ dysfunction (SOD) attributable to the use of these
`antibiotics also were identified.
`
`Observations: Nineteen cases of HSR due to minocy-
`cline, 2 due to tetracycline, and 1 due to doxycycline were
`identified. Eleven cases of SSLR due to minocycline, 3
`due to tetracycline, and 2 due to doxycycline were iden-
`tified. All33 cases of drug-induced lupus were attribut-
`
`able to minocycline. Forty cases of SOD from minocy-
`cline, 3 7 cases from tetracycline, and 6 from doxycycline
`were detected. Hypersensitivity syndrome reaction, SSLR,
`and SOD occur on average within 4 weeks of therapy,
`whereas minocycline-induced lupus occurs on average
`2 years after the initiation of therapy.
`
`Conclusions: Early serious events occurring during the
`course of tetracycline antibiotic treatment include HSR,
`SSLR, and SOD. Drug-induced lupus, which occurs late
`in the course of therapy, is reported only with minocy-
`cline. We theorize that minocycline metabolism may ac-
`count for the increased frequency of serious adverse events
`with this drug.
`
`Arch Dermatol. 1997;133:1224-1230
`
`INOCYCLINE HAS been
`reported to cause seri-
`ous, rare adverse
`events including the
`hypersensitivity syn-
`drome reaction (HSR), serum sickness-
`like reaction (SSLR), and drug-induced lu-
`pus (DIL). 1•2 We conducted a review to
`determine if similar events are associated
`with other tetracycline antibiotics, namely,
`tetracycline and doxycycline. We also at-
`tempted to identify serious single organ
`dysfunction (SOD) attributable to these an-
`tibiotics.
`
`Review of the Drug Safety Clinic data-
`base, Health Protection Branch data, and
`MEDLINE search produced 19 reports of
`HSR, 11 reports of SSLR, 40 reports of
`SOD, and 32 reports of DIL attributable
`to minocycline (Table 1 ) . 2"34 Table 2
`shows data on the mean patient age, mean
`interval to onset of the reaction, and sex
`distribution of these reactions. We found
`no difference in the average daily doses of
`minocycline in causing the different re-
`
`ARCH DERMATOUVOL 133, OCT 1997
`1224
`
`action patterns. The most common pat-
`terns of internal organ involvement seen
`with minocycline HSR were hepatitis in 15
`(79%), lymphadenopathy in 14 (74%), he-
`matologic annormalities in 13 (68%), and
`renal and pulmonary abnormalities in 5
`(26%) patients each. Three case fatalities
`have been described.2·11 Three patients who
`were rechallenged redeveloped symp-
`toms within 48 hours.
`Reports of SOD attributable to min-
`ocycline include 17 of pneumonitis,6.18-23
`4 ofhepatitis,3·24·25 2 of antineutrophil cy-
`toplasmic antibody-positive polyarthri-
`tis,26·27 1 of nephritis,28 1 of both fulmi-
`nant hepatic failure and necrotizing
`pancreatitis,29 and 1 of severe cutaneous
`adverse reaction. 30
`The patients with minocycline-
`induced lupus erythematosus presented
`with malaise that was accompanied by my-
`algia, arthralgia, or arthritis. Eighty-eight
`percent of cases occurred in women. Ten
`patients developed elevated serum he-
`patic transaminase levels. Two patients had
`livedo reticularis and antineutrophilic cy-
`toplasmic antibodies, and in 2 other pa-
`tients, precise descriptions of their erup-
`
`From the Divisions of
`Dermatology (Drs Shapiro
`and Shear) and Clinical
`Pharmacology (Drs Shapiro
`and Shear and Ms Knowles),
`Drug Safety Research Group
`(Drs Shapiro and Shear and
`Ms Knowles), Departments of
`Medicine (Drs Shapiro and
`Shear), Pharmacology
`(Dr Shear), and Pharmacy
`(Ms Knowles), Sunnybrook
`Hospital, University ofT oronto
`Medical School,
`Toronto, Ontario.
`
`Exh. 1039
`
`

`
`MATERIALS AND METHODS
`
`DEFINITIONS OF ADVERSE EVENTS
`
`Specific reaction patterns were identified for inclu-
`sion. Hypersensitivity syndrome reaction was de-
`fined by fever, skin eruption, and internal organ in-
`volvement developing within 8 weeks of initiation of
`therapy; SSLR was defined by fever, skin eruption
`(most commonly urticarial or erythema multi-
`forme), arthralgia with or without lymphadenopa-
`thy occurring within 6 weeks of treatment; and DIL
`was defined by the presence of antinuclear antibod-
`ies, the presence of at least 1 clinical feature of sys-
`temic lupus erythematosus (SLE) that resolves with
`drug discontinuation, and the absence of idiopathic
`SLE. Single organ dysfunction was defined as the pres-
`ence of severe disease in a major organ, eg, pancre-
`atitis, hepatitis.
`
`SOURCES OF CASES
`
`Drug Safety Clinic
`
`We reviewed the records of all patients referred to the
`Glaxo Wellcome-Sunnybrook Drug Safety Clinic,
`Toronto, Ontario, from january 1985 through October
`1996 who possibly had adverse events attributable to
`the use of minocycline, tetracycline, or doxycycline.
`
`Health Canada
`
`Reports from the Adverse Drug Reaction Monitor-
`ing Division of the Health Protection Branch, Ot-
`tawa, Ontario, were requested regarding adverse
`events possibly attributable to the use of minocy-
`cline, tetracycline, or doxycycline from 1966 through
`October 1996. Cases were classified as HSR, SSLR,
`DIL, or isolated SOD.
`
`Literature Search
`
`A thorough computer-based MEDLINE search of
`articles published from 1966 to October 1996 was
`conducted. Search terms included drug hypersensi-
`tivity, tetracycline antibiotics, and liver, kidney, skin,
`and joint diseases. The reference lists of all perti-
`nent articles also were reviewed to identify any
`additional articles that might have been missed or that
`predated the computer search.
`
`Utilization Data
`
`The Institute of Medical Statistics, Toronto, pro-
`vided us with the most recent statistics from 1994
`to identify prescribing patterns for tetracycline
`antibiotics.
`
`tion were lacking. No patient had renal, neurologic, or
`vasculitic involvement. All patients' symptoms had im-
`proved after discontinuation of the minocycline. Twenty-
`one patients who were rechallenged with minocycline de-
`veloped a recrudescence of their DIL. One patient in whom
`
`symptoms developed with minocycline rechallenge re-
`mained asymptomatic after doxycycline exposure.31
`Review of the Drug Safety Clinic database, Health
`Protection Branch data, and MEDLINE search pro-
`duced 2 reports of HSR, 3 reports of SSLR, 3 7 reports of
`SOD, and no reports of DIL attributable to tetracy-
`cline.35-41
`Review of the Drug Safety Clinic database, Health
`Protection Branch data, and MEDLINE search pro-
`duced 1 report of HSR, 2 reports of SSLR, 6 reports of
`SOD, and no reports of DIL attributable to doxycy-
`clineY-45
`
`PRESCRIBING DATA
`
`The Institute of Medical Statistics provided the most re-
`cent (ie, 1994) Canadian national statisitics regarding the
`use of tetracycline antibiotics. In 1994, 1 866 000 pre-
`scriptions for tetracycline antibiotics were filled
`(Table 3).
`
`Minocycline has been used as successful, safe, long-
`term therapy for patients with acne vulgaris. However,
`there are concerns about the safety of minocycline based
`on recent reports of serious adverse events.1·2 These re-
`ports of minocycline-induced side effects prompted a com-
`plete review of the literature to determine whether these
`reactions occur with other tetracycline antibiotics:
`Twenty-two patients with HSRs attributable to the
`3 tetracycline antibiotics were identified, of which min-
`ocycline was implicated in 86%. Reports of hepatotoxic
`effects from excessive serum levels of tetracycline are not
`included in this report as the mechanism of these reac-
`tions is associated with suprapharmacologic doses. 49-53
`Of note are additional references in the literature per-
`taining to tetracycline antibiotic-induced severe iso-
`lated SOD. These cases may represent a forme fruste of
`HSRs. For example, critical detailed information in
`case reports is often lacking so that the defining criteria
`of an HSR may not be fulfilled (eg, presence of fever).
`Another shortcoming with extracting data from case re-
`ports is that patients are often taking multiple medica-
`tions and exact details of timing are missing. Therefore,
`an accurate assessment of drug causation is more
`difficult and less reliable. 54
`Isolated SOD attributable to tetracycline and doxy-
`cycline is manifest most commonly as severe cutaneous
`adverse reaction (30% and 71%, respectively), whereas
`SOD related to minocycline most commonly is manifest
`as pneumonitis (45%).
`Based on the available information, there are more
`reports of serious adverse events from minocycline use
`than from the use of other tetracycline antibiotics. We
`acknowledge that the sources from which we collected
`our data rely on voluntary reporting, and therefore only
`a fraction of the true number of reactions are known. Al-
`though it is unclear why there are more serious adverse
`events reported with the use of minocycline, we theo-
`rize that this may relate to its unique metabolism.
`Tetracycline antibiotics all possess the same basic
`
`ARCH DERMATOUVOL 133, OCT 1997
`1225
`
`Exh. 1039
`
`

`
`Table 1. Summary of Adverse Events to Tetracycline Antibiotics
`
`Drug
`Safety
`Clinic
`166
`
`66
`35
`II
`4
`23
`
`0
`
`0
`
`0
`
`2
`
`I
`0
`0
`0
`0
`0
`0
`0
`
`No. referred
`Mild
`Rash
`Urticaria
`Angioedema
`Photosensitivity
`Vomiting/diarrhea
`Severe
`Hypersensitivity
`syndrome
`reaction
`Serum sicknesslike
`syndrome
`Drug-induced
`lupus
`Single organ
`dysfunction
`Severe cutaneous
`adverse reaction
`Hepatitis
`Pneumonitis
`Pancreatitis
`Nephritis
`Hematologic
`Parotitis
`Myocarditis
`Arthritis
`
`Tetracycline
`Health
`Protection
`Branch
`
`Literature
`
`Minocycline
`
`Drug
`Safety
`Clinic
`17
`
`Health
`Protection
`Branch
`160
`
`Literature
`
`Doxycycline
`
`Health
`Protection
`Branch
`145
`
`I
`Drug
`Safety
`Clinic
`39
`
`Literature
`
`406
`138
`8
`10
`159
`
`3
`
`0
`
`26
`
`9
`
`7
`0
`3
`2
`4
`I
`0
`0
`
`0
`0
`0
`0
`0
`
`146
`
`0
`
`0
`
`9
`
`135
`
`0
`138
`436,41,48
`0
`239,40
`0
`137
`0
`
`I
`6
`I
`0
`2
`
`2
`
`2
`
`0
`
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`
`52
`7
`8
`0
`53
`
`4
`
`4
`
`0
`
`14
`
`2
`
`7
`0
`I
`0
`4
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`132,6·10,42,47
`
`54,34
`
`322,3,5,12-17,27,31,32
`
`26
`
`130
`
`43,24,25
`176,18-23,33
`129
`128
`0
`0
`0
`226,27
`
`15
`II
`3
`3
`3
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`
`38
`0
`I
`4
`17
`
`0
`
`0
`
`3
`
`0
`0
`I
`I
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`
`142
`
`0
`
`0
`
`3
`
`343-45
`
`0
`0
`0
`0
`0
`0
`0
`0
`
`4-ring carbocyclic structure but differ in the substitu-
`ents on the ring55 (Figure). Doxycycline has a hydroxyl
`side chain distinguishing this congener from tetracy-
`cline.56 Minocycline shares the basic 4-ring structure of
`the other commonly used tetracyclines having a substi-
`tution of a dimethylamino group in the 7 position. 57
`Whether minocycline metabolism produces a reactive me-
`tabolite is unknown, although an iminoquinone deriva-
`tive may be generated that is a potential reactive electro-
`philic intermediate. Neither tetracycline nor doxycycline
`contains this amino acid side chain that has the poten-
`tial to form this reactive metabolite.
`Black pigmentation in the thyroid gland has been
`seen in patients receiving long-term minocycline treat-
`ment and is not seen with other tetracyclines. One ex-
`planation for this effect of minocycline is that its strongly
`electron-donating dimethylamino group possibly in-
`creases its reactivity to oxidation. In support of this theory,
`treatment of minocycline-induced black pigmentation
`with thyroid peroxidase resulted in the formation of a
`black product, whereas other members of the tetracy-
`cline family were not oxidized to dark products by the
`same system.58
`In vitro studies have demonstrated the presence of
`a minocycline-glutathione conjugate when minocycline
`is incubated with hypochlorous acid, as is found in neu-
`trophils. This in vitro system serves as a surrogate for oxi-
`dation reactions that take place in the liver. These reac-
`tions are most commonly mediated by the cytochrome
`P450 family of heme-containing enzymes. When a reac-
`
`tive metabolite is generated, there are several cellular
`mechanisms that detoxify this product. One such sys-
`tem is glutathione transferase; therefore, the presence of
`minocycline-glutathione conjugates implies the forma-
`tion of potentially toxic metabolites. When tetracycline
`or doxycycline were incubated in the same system, no
`glutathione conjugates were detected 0. Uetrecht, per-
`sonal communication, 1996).
`The potential reactive metabolites generated by min-
`ocycline may bind to tissue macromolecules thereby caus-
`ing cell damage directly, or they may act as haptens, elic-
`iting an immune response secondarily.59 This "hapten
`hypothesis" is thought to explain HSRs seen with aro-
`matic anticonvulsants, sulfonamide antibiotics, allopu-
`rinol, and dapsone, as well as SSLRs due to cefaclor.60
`Minocycline causes DIL and appears to be most com-
`mon in young women. We found no reports of either tet-
`racycline- or doxycycline-induced lupus. There has been
`a misperception that tetracycline causes DIL based on a
`misinterpretation of the 1959 article by Domz et al.61 In
`that article, 1 of the 3 case reports describes aminoglu-
`tethimide-induced lupus erythematosus and another de-
`scribes positive lupus erythematosus cells without clini-
`cal symptoms after tetracycline and penicillin were
`separately administered. The third case report describes
`a patient with active SLE whose underlying disease con-
`tinued to progress after tetracycline was prescribed and
`in whom a severe cutaneous adverse reaction, possibly
`from tetracycline, developed. These cases do not sup-
`port the concept of tetracycline causing DIL.
`
`ARCH DERMATOUVOL 133, OCT 1997
`1226
`
`Exh. 1039
`
`

`
`Table 2. Descriptive Data
`
`Mean:tSE
`Interval to Onset,
`Mean:tSE
`d (Range)
`PatientAge,y
`Hypersensitivity Syndrome Reaction
`11 (1-21)
`54
`21.2±1.8
`24.4±1.5 (4-30)
`15 (2-37)
`18
`Serum Sicknesslike Reaction
`11±3 (8-14)
`16.2±2. 7 (8-35)
`25±3
`24.5 (21-28)
`35.3±12.3
`Drug-Induced Lupus
`
`Sex, No.
`
`2M
`13 F, 6 M
`1 F
`
`1 F, 1 M
`6 F, 5 M
`2 F, 1M
`
`21.9±1.5
`
`632.6± 1 04.8 (3-2190)
`
`28 F, 4 M
`
`Single Organ Dysfunction
`41.8±8.0*
`5± 1.8 (1-90)*
`42.9±4.7t
`18.3±6.6 (1-720)t
`13.8±8.5 (1-1 O):t:
`39.8±10.3:t:
`
`17F, 18M
`18 F, 9 M
`3 F, 3M
`
`Group
`
`Tetracycline
`Minocycline
`Doxycycline
`
`Tetracycline
`Minocycline
`Doxycycline
`
`Tetracycline
`Minoyycline
`Doxycycline
`
`Tetracycline
`Minocycline
`Doxycycline
`
`*Denotes values for tetracycline-induced severe cutaneous adverse
`reactions.
`tDenotes values for minocycline-induced pneumonitis.
`:t:Denotes values for doxycycline-induced severe cutaneous adverse
`reactions.
`
`Table 3. Prescribing Data for Tetracycline Antibiotics, 1994*
`
`No.
`Total No. prescriptions
`(%of total)
`New prescriptions, %
`Repeated prescriptions, %
`
`Tetracycline Minocycline Doxycycline
`855 000 (45.8) 369 000 (19.8) 642 000 (34.4)
`
`68.2
`31.8
`
`37.2
`62.8
`
`91.3
`8.7
`
`*From the Institute of Medical Statistics, Toronto, Ontario.
`
`Several mechanisms for DIL have been suggested and
`include the possibility that a reactive metabolite binds to
`the class II major histocompatibility antigen and induces
`an autoimmune reaction analogous to a graft vs host re-
`action.62 A drug or its potentially reactive metabolites may
`bind direcdy to his tones and act as hap tens, producing an
`antigenic complex capable of stimulating autoantibody for-
`mation.63 Factors that have been implicated in causing DIL
`include the use of the drug for long-term therapy, dose
`dependency, and the presence of a functional group that
`is easily oxidized to a reactive metabolite such as what we
`hypothesized occurs with minocycline.
`The frequency of these reactions attributable to tet-
`racycline antibiotics remains unknown. The incidence
`or prevalence cannot be estimated without knowing the
`denominator, ie, the number of patients receiving each
`of the tetracycline antibiotics. However, the risk of de-
`veloping symptomatic hepatotoxic effects from tetracy-
`clines has been estimated to be between 1.6 per million
`and 2.1 per 100 000 treated patients.64-66
`In Canada, tetracycline has been licensed since 1959,
`doxycycline since 1969, and minocycline since 1972. Re-
`view of the Institute of Medical Statistics data reveals that
`although minocycline is the least frequently prescribed
`
`OH
`
`OH
`
`OH
`0
`Tetracycline
`
`0
`
`~ Doxycycline
`
`Minocycline
`
`Structure of tetracycline antibiotics.
`
`of the 3 tetracycline congeners, it is the tetracycline an-
`tibiotic with the largest fraction of repeated prescrip-
`tions. This prescribing pattern likely reflects the fact that
`minocycline is more commonly used as long-term therapy,
`particularly in the treatment of acne vulgaris. This may
`help explain the sole association of minocycline with DIL.
`Doxycycline and tetracycline are more likely to be pre-
`scribed for acute infections in which the duration of treat-
`mentis relatively brief. This assumes that prescribing pat-
`terns in Canada reflect patterns in other geographic
`locales. It also assumes that the reason for the long-term
`use of minocycline is not explained by better tolerance
`compared with tetracycline and doxycycline.
`The diagnosis of these specific reaction patterns rests
`largely on the presence of a symptom complex. In a re-
`cent report of minocycline-induced SSLRs, a migration
`inhibitory factor assay and mast cell degranulation test
`were positive in 4 of 5 patients.4 No skin, patch, or lym-
`phocyte transformation testing was documented in any
`of the published reports.
`To evaluate the safety of high-dose long-term min-
`ocycline therapy, researchers in England studied 700 pa-
`tients with acne vulgaris treated with 100 mg/d or more
`of minocycline for a mean of 10.5 months.67 Although
`no laboratory abnormalities were noted, the study popu-
`lation was too small to detect the severe but rare reac-
`tions that can occur. A study sample would need to be 3
`to 4 times larger to detect hepatitis and DIL that occur
`in less than 1 in 10 000 patients.68
`Blood samples from more than 3000 patients re-
`ceiving minocycline showed no abnormalities in he-
`patic transaminase levels. 69 In the United Kingdom, 6.5
`million patients have been treated with minocycline on
`average for 9 months during the last 26 years, and in 1996,
`28 million tablets a year of minocycline were taken. The
`conclusion is that these serious side effects are ex-
`tremely rare.
`Risk management strategies can be applied to vari-
`ous phases of prescribing. These include pretreatment
`identification of risk factors, risk communication of po-
`tential adverse events to patients when the medication
`is prescribed, monitoring and ascertainment of adverse
`
`ARCH DERMATOUVOL 133, OCT 1997
`1227
`
`Exh. 1039
`
`

`
`Table 4. Risk Management Strategy
`for Tetracycline Antibiotics*
`
`Table 4. Risk Management Strategy
`for Tetracycline Antilbiotics* (cont)
`
`Minocycline
`Common and dose-dependent side effects: gastrointestinal upset,
`vestibular dysfunction, headache, localized pigmentary disturbances
`Serious, rare side effectst: HSR; SSLR; isolated SOD, most commonly
`manifest as pneumonitis; OIL; and hepatitis
`Early reaction patterns: HSRs, SSLRs, and SOD occur on average
`within 2 mo of treatment and are characterized by fever, malaise,
`arthralgia with or without major organ involvement.
`Late reaction pattern: OIL occurs on average after 2 y of therapy but
`may be delayed up to 6 y. Occurs predominantly in females,
`presents with a symmetrical polyarthritis or polyarthralgia in the
`small joints of the hands and wrists. Some of these patients have
`concomitant liver disease with biopsy specimens disclosing chronic
`active hepatitis. Phototoxicity is rare. Benign intracranial
`hypertension is rare.
`Recommendations
`• Minocycline should be avoided in patients with systemic lupus
`erythematosus (SLE) or in those with a history of SLE in a
`first-degree relative.
`• Relative contraindications to the use of minocycline include
`underlying hepatic or renal disease.
`• Patients receiving chronic minocycline therapy should have
`antinuclear antibody and hepatic transaminase levels assessed only
`if symptoms develop during the course of treatment.
`• Routine monitoring of patients receiving chronic minocycline
`therapy is not recommended.
`• Any patient with a serious adverse event such as HSR, SSLR, or OIL
`should be advised to avoid the class of tetracycline antibiotics.
`• First-degree relatives of patients with a tetracycline-induced HSR
`may be at higher risk for similar reaction patterns and should avoid
`tetracycline antibiotics.
`• In patients presenting with an early reaction pattern, the following
`laboratory values should be assessed: complete blood cell count,
`hepatic transaminases, urinalysis, urea and creatinine, chest
`radiograph, thyroid function tests at 3 mo
`• There is no standardized treatment for early reaction patterns.
`Discontinuation of the offending drug is mandatory. Symptomatic
`treatment with nonsteroidal anti-inflammatory drugs or
`corticosteroids may be required.
`• In patients presenting with a late reaction pattern, the following
`laboratory values should be assessed: antinuclear antibody, hepatic
`transaminases
`• Treatment of OIL includes discontinuation of the offending drug.
`Symptomatic treatment with nonsteroidal anti-inflammatory drugs
`or corticosteroids may be required.
`• Severe adverse reactions should be reported to the appropriate
`agency such as the US Food and Drug Administration or Canadian
`Health Protection Branch.
`
`events during therapy, and management of adverse events
`when they occur (Table 4).
`Before physicians prescribe tetracyclines, identifi-
`cation of patients who are at risk for adverse reactions is
`required. The recent publications of minocycline-
`induced lupus have prompted a change in the US prod-
`uct labeling adverse reactions section from "transient lu-
`pus-like syndrome" to "lupus-like syndrome. "70 Because
`minocycline is clearly associated with DIL, prudence
`would dictate avoidance in patients with underlying SLE
`or a history of SLE in a first-degree relative. Few data are
`available to support or negate the use of drugs known to
`cause DIL in patients with spontaneous lupus. 71 There
`are no data to support that the natural history of lupus
`erythematosus is worsened by use of such a drug even if
`symptoms develop; however, the standard of practice for
`
`Tetracycline
`Common and dose-dependent side effects: nausea, vomiting,
`epigastric burning, photosensitivity, vaginal candidiasis
`Serious, rare side effects: HSR, SSLR, benign intracranial hypertension
`Recommendations
`• No baseline or periodic investigations are required.
`• Investigations should be done if symptoms develop.
`• Any patient with a serious adverse event such as HSR or SSLR
`should be advised to avoid the class of tetracycline antibiotics.
`Doxycycline
`Common and dose-dependent side effects: nausea, vomiting,
`epigastric burning, photosensitivity, vaginal candidiasis
`Serious, rare side effects: HSR, SSLR, benign intracranial hypertension
`Recommendations
`• Warn patients about ph ototoxic potentiaL
`• No baseline or periodic investigations are required.
`• Investigations should be done if symptoms develop.
`• Any patient with a serious adverse event such as HSR or SSLR
`should be advised to avoid the class of tetracycline antibiotics.
`
`*Appropriate risk communication for each drug requires (1) informing
`patients about minor side effects if they are relatively common (> 2% of
`exposed patients) or may be dose dependent; and (2) warning patients about
`rare side effects that are serious, such as hypersensitivity syndrome reaction
`(HSR}, serum sickness/ike reaction (SSLR), single organ dysfunction (SOD},
`and drug-induced lupus (OIL).
`t These reactions can be divided into 2 groups according to the average
`time to onset after initiation of therapy, early and late.
`
`rheumatologists is avoidance of drugs that can cause a
`lupuslike reaction in patients with definite SLE. 72
`Appropriate risk communication imparts informa-
`tion to the patient about minor side effects that are com-
`mon and about rare side effects that are serious. It is clear
`that the serious reaction patterns to tetracycline antibi-
`otics can be categorized into 2 groups-early and late.
`Early reactions include HSRs, SSLRs, and isolated SOD
`that occur on average within 2 months of treatment. They
`are characterized by fever, malaise, and arthralgia with
`or without major organ involvement. Late reactions in-
`clude DIL, which occurs on average 2 years after initia-
`tion of therapy but may be delayed even up to 6 years.
`These patients, predominantly female, present with a sym-
`metrical polyarthritis or polyarthralgia in the small joints
`of the hands and wrist. It is important to recognize this
`group as it is believed that there is no sex predilection to
`DIL when compared with idiopathic SLE. This belief
`comes from earlier reports of antiarrythmic-induced lu-
`pus erythematosus where the population treated re-
`flects the population afflicted with the disease in ques-
`tion.63 Minocycline-induced lupus erythematosus afflicts
`the same population as idiopathic lupus, and there may
`be a long interval before onset. Some of these patients
`had concomitant liver disease with biopsy specimens dis-
`closing chronic active hepatitis. 2 In these patients, all
`symptoms and signs promptly resolved with drug dis-
`continuation. To avoid unnecessary interventions, such
`as liver biopsy or immunosuppressive therapy, this re-
`action pattern must be promptly recognized.
`Appropriate investigations of an early reaction in-
`clude complete blood cell count to identify an atypical
`lymphocytosis or eosinophilia, hepatic transaminase lev-
`
`ARCH DERMATOUVOL 133, OCT 1997
`1228
`
`Exh. 1039
`
`

`
`els, urinalysis, urea and creatinine levels, chest radio-
`graph, and thyroid function test 3 months after the acute
`event.59·73 Further evaluation of internal organ involve-
`ment will be determined by the patient's history and physi-
`cal examination findings.
`Extrapolating from the literature pertaining to aro-
`matic anticonvulsant HSRs, we suggest that patients with
`a tetracycline antibiotic-induced HSR and their first-
`degree relatives avoid the class of tetracycline antibot-
`ics. 59 A medical alert bracelet should document allergy
`to the tetracycline antibiotics.
`For late reactions, tests for antinuclear antibody and
`hepatic transaminase levels are appropriate. Based on the
`rarity of DIL and the lack of large prospective trials, it is
`not justified to routinely monitor patients receiving long-
`term minocycline therapy. In one prospective study, ll
`patients treated with minocycline showed no difference
`between pretreatment hepatic transaminase levels and
`those measured 6 months later. 74 A recent literature re-
`view did not support the practice of routine laboratory.
`monitoring in healthy young patients with acne treated
`with oral tetracycline or minocycline. 75 Prospective tri-
`als to assess liver function in a large cohort of patients
`receiving minocycline for acne are under way? Patients
`receiving long-term minocycline therapy should have an
`antinuclear antibody test and hepatic transaminase lev-
`els assessed only if symptoms develop during their course
`of treatment.
`Treatment for these serious adverse reactions is not
`standardized. Corticosteroid therapy has been widely used
`without confirmation of its efficacy by controlled stud-
`ies. Anecdotal experience suggests that treatment with
`systemic corticosteroids in doses of 0.5 to l.O mg!kg im-
`proves symptoms and laboratory measurements. 76 A slow
`taper over several weeks is suggested as relapses of HSR
`are common. 76 Severe adverse reactions should be re-
`ported to the appropriate agency such as the Canadian
`Health Protection Branch or the US Food and Drug Ad-
`ministration.
`Reports of idiosyncratic adverse events with tetra-
`cycline, doxycycline, and minocycline are infrequent. Al-
`though there are published reports stating that patients
`with serious adverse reactions to minocycline can be sub-
`sequently treated with tetracycline, there is minimal evi-
`dence to support this claim.77 One patient who devel-
`oped a minocycline-induced pneumonitis on 2 occasions
`was able to tolerate doxycycline with no relapse. 6 An-
`other patient who developed minocycline-induced lu-
`pus was able to tolerate doxycycline without an adverse
`event.31 Because of the severity of these reactions, pa-
`tients who experience a serious adverse event while re-
`ceiving l of these tetracycline antibiotics should be ad-
`vised to avoid all tetracyclines until more information
`regarding potential cross-reactivity is known.
`
`Accepted for publication june 12, 1997.
`This work was supported in part by agrant-in-aidfrom
`Medicis Pharmaceutical Corporation, Phoenix, Ariz.
`The interpretation of the results does not reflect the opin-
`ions or policies of Health Canada. The reproduced infor-
`mation from the Health Protection Branch is raw informa-
`tion and has not been scientifically verified.
`
`Presented at the Canadian Pharmacoepidemiology
`Forum, Hamilton, Ontario, April28 and 29, 1997.
`We thank the Drugs Directorate, Health Protection
`Branch, Ottawa, Ontario, for providing the data.
`Reprints: Neil H. Shear, MD, FRCPC, Drug Safety Re-
`search Group, Sunnybrook Health Science Centre, Room
`E240, 2075 Bayview Ave, Toronto, Ontario, Canada M4N
`3M5.
`
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