Innovative Use
`of Dapsone
`
`V.E. Gottfried Wozel, MD
`
`KEYWORDS
` Dapsone  Dermatology  Sulfone
`
`In the past, sulfones were used preferentially as
`antimicrobial/chemotherapeutic agents to treat
`infections caused by streptococcus, mycobacter-
`iaceae, and other bacteria.1 Currently, dapsone
`(4,40 diaminodiphenylsulfone) is the only remaining
`sulfone congener used in human therapeutics.
`Because of its dual mechanism of action—antimi-
`crobial and anti-inflammatory/immunomodulatory
`effects—dapsone alone or in conjunction with
`other drugs is used worldwide for preventing and
`treating pathogen-caused diseases (eg, leprosy,
`Pneumocystis jiroveci pneumonia in individuals
`with HIV infection) or chronic inflammatory
`diseases, especially in the field of dermatology
`(eg, autoimmune bullous eruptions).
`Synthesis of dapsone was reported in 1908 by
`Emil Fromm (Fig. 1), professor of organic chem-
`istry in Freiburg/Germany, and Jakob Wittmann
`during their experiments in dye chemistry.2 When
`first synthesized, dapsone was not envisioned as
`a medical agent. In 1937, soon after the discovery
`of sulphonamides as antibiotics,
`two research
`groups (one in England and one in France) were
`the first
`to investigate dapsone. Both groups
`concurrently published the observed anti-inflam-
`matory potency of dapsone in experimentally
`induced infections in mice.3,4 In the narrowest
`sense, that marked the beginning of the sulfone
`story.
`From a historical perspective, it is remarkable
`that other sulfones, and not the so-called ‘‘parent
`sulfone’’ (dapsone), were first used to treat gonor-
`rhoea.5,6 After extensive use of with promin and
`related sulfones in the treatment of Hansen’s
`disease at the U.S. leprosarium in Carville, Louisi-
`ana early in the 1940s by Faget and coworkers,7
`
`sulfones ultimately developed from simple chemi-
`cal compounds into valuable therapeutic agents.
`In 1950, the Portuguese Esteves and Brand~ao8
`introduced sulfones (eg, Sulphetrone, Diasone)
`into dermatology through their reports of their
`successful use in treating dermatitis herpetiformis
`(Duhring’s disease), which was subsequently
`confirmed by other groups.
`Later, Sneddon and Wilkinson9 in England re-
`ported a remission in subcorneal pustulosis after
`dapsone administration. Since that time, dapsone
`has been increasingly considered effective in
`treating neutrophil-mediated processes and auto-
`immune skin diseases, and retains its place in the
`therapeutic armamentarium as a unique and
`essential agent.
`
`CHEMISTRY AND PHARMACOLOGY
`
`Chemically, dapsone is an aniline derivative. All
`sulfones share the structure of a sulfur atom linking
`to two carbon atoms (Fig. 2). The solubility of
`dapsone varies over a large range depending on
`the solvent used (eg, water, 0.2 mg/mL, methanol,
`52 mg/mL). Dapsone has been considered a diffi-
`cult-to-handle compound for experimental investi-
`gations, especially using living cell assays.10
`After oral administration, dapsone is almost
`completely absorbed from the gastrointestinal
`tract with bioavailability of more than 86%. Peak
`serum concentrations are generally attained within
`2 to 8 hours. After ingestion of a single 50- to
`300-mg dose of dapsone, maximal serum con-
`centrations are reached between 0.63 and
`4.82 mg/L.10–12 Under steady-state conditions,
`the most frequently used dosage of 100 mg/d
`
`derm.theclinics.com
`
`Department of Dermatology, University Hospital Carl Gustav Carus, Technical University of Dresden,
`Fetscherstr. 74, D-01307 Dresden, Germany
`E-mail address: Verena.Huebner@uniklinikum-dresden.de
`
`Dermatol Clin 28 (2010) 599–610
`doi:10.1016/j.det.2010.03.014
`0733-8635/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
`
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`generation of dapsone hydroxylamine (DDS-NOH)
`(Fig. 3). Acetylation is genetically determined, re-
`sulting in significant variability in acetylation (rapid
`or slow acetylator). In fact, dapsone can be admin-
`istered to determine the acetylation phenotype.
`In terms of both efficacy and induction of
`adverse effects, the most important factor is the
`generation of DDS-NOH; this occurs in lesional
`inflammatory processes in skin mediated by acti-
`vated PMN.14 Dapsone is distributed to all organs,
`crosses the blood–brain barrier and placenta, and
`is detectable in breast milk.15,16 Approximately
`20% of dapsone is excreted in urine as unchanged
`drug and 70% to 85% as water-soluble metabo-
`lites. Additionally, a small amount may be excreted
`in feces. The complex metabolic pathway of
`dapsone has been reviewed in detail several
`times.10,12,14,17,18
`
`MECHANISM OF ACTION
`
`The therapeutic efficacy most likely is based on
`differing drug activities when considering path-
`ogen-caused diseases and noninfectious derma-
`tologic disorders (Fig. 4). Antimicrobial activity is
`usually bacteriostatic in nature and seems to
`mimic that of sulfonamides (inhibition of folic acid
`synthesis in susceptible organisms), because anti-
`bacterial activity is inhibited by para-aminoben-
`zoic acid.
`When used as therapy for inflammatory disor-
`ders, however, alternate mechanisms are at
`work. Recent investigation shows that dapsone
`alone (and through its metabolites) has similarities
`to
`nonsteroidal
`anti-inflammatory
`drugs
`(NSAIDs).10 However, these data were obtained
`through varying methods and under different
`experimental conditions. These discrepancies
`raise some important questions, such as which
`types of investigations render the most valid data
`for human use: in vitro versus in vivo investigation,
`animal versus human model, or single administra-
`tion versus steady-state administration.
`Additionally, several investigations have evalu-
`ated the capability of dapsone to ameliorate or
`block specific pathways using drug concentra-
`tions that are not achieved in humans. Therefore,
`despite many experimental
`investigations using
`dapsone,
`the relevance of observed effects
`remains unclear. This problem is even more
`obvious because the pathogenesis of dapsone-
`sensitive
`dermatoses
`has
`not
`been
`fully
`elucidated.
`The ability of dapsone to inhibit reactive oxygen
`species (ROS) seems to contribute to the drug’s
`anti-inflammatory effects.19 ROS can be generated
`through two major pathways: the PMN-mediated
`
`Fig. 1. Emil Fromm (1865–1928). (Courtesy of Institut
`fu¨ r Geschichte der Medizin der Universita¨ t Wien;
`with permission.)
`
`results in serum concentration of 3.26 (maximum)
`and 1.95 mg/L (after 24 hours).13 These dapsone
`serum concentrations, attainable in vivo, must
`be strictly considered when interpreting the
`results of in vitro investigations.
`After absorption, dapsone undergoes enterohe-
`patic circulation. It is metabolized both by the liver
`and activated polymorphonuclear
`leucocytes
`(PMN) or mononuclear cells.14
`In the liver,
`dapsone is metabolized primarily through acetyla-
`tion by N-acetyltransferase to monoacetyldap-
`sone (MADDS), and through hydroxylation by
`cytochrome
`P-450
`enzymes,
`resulting
`in
`
`Fig. 2. Structural formula of dapsone (4,40 diaminodi-
`phenylsulfone).
`
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`Dapsone in Dermatology
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`Fig. 3. Main metabolic pathway of dapsone. MADDS, monacetyl dapsone; DDS-NOH, dapsone hydroxylamine.
`
`intracellular system and an extracellular xanthine/
`xanthine–oxidase system. Both are affected by
`dapsone to the same extent.20
`Niwa and colleagues20 showed that dapsone
`has a scavenger-like effect; it quenches all ROS
`. Although
`except the oxygen intermediate, O2
`Stendahl and colleagues21 ascribed the depres-
`sion of cytotoxic and cytopathic functions of
`PMNs to the ability of dapsone to directly inhibit
`the myeloperoxidase (MPO)–H2O2–halide system,
`it may also be caused by the marked decrease in
`hydrogen peroxide (H2O2), hydroxyl radical (OH),
`and oxygen (O2) levels as a result of scavenger-
`like functions of dapsone. The cytotoxic potency
`in the MPO–H2O2–halide system may not be
`highly powerful, because patients with MPO defi-
`ciency are not unduly susceptible to infections.
`
`Being one of the strongest scavengers known,
`dapsone decreases H2O2 as effectively as
`catalase and is as potent as colchicine, super-
`oxide-dismutase,
`catalase,
`benzoate,
`and
`xanthine in lowering OH levels. Severe tissue
`injury observed in patients with disorders such
`as dermatitis herpetiformis,
`linear
`IgA bullous
`dermatosis, prurigo pigmentosa, leukocytoclastic
`vasculitis, Behc¸ et’s disease, and lupus erythema-
`tosus (LE) must be considered partly as a conse-
`quence of excessive PMN-generated oxygen
`intermediates.20,22,23 The beneficial effects of
`dapsone on these dermatologic disorders are
`most
`likely a result of
`its quenching effects.
` and OH concentrations are linked
`Whether O2
`by
`an
`iron-dependent mechanism is
`still
`unknown.
`
`Duality of dapsone
`
`Pathogen-caused diseses
`
`Non-pathogen-caused diseases
`
`(e. g. leprosy, toxoplasmosis)
`
`(e. g. chronic inflammatory diseses)
`
`Chemotherapeutic agent
`
`Non-steroidal
`
`anti-inflammatory drug
`
`Fig. 4. Different dermatologic targets of dapsone.
`
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`602
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`on
`
`a1-protease
`
`Several reports indicate that dapsone may also
`affect additional
`inflammatory effector systems
`through
` Suppression of integrin-mediated neutro-
`philic adherence24
` Inhibition of generation of 5-lipoxygenase
`products (eg, leukotriene B4 [LTB4], 12-hy-
`droxyeicosatetrenoate [HETE])25
` Inhibition of
`spontaneous or
`induced
`26
`synthesis of prostaglandin E2
` Inhibition of cyclooxygenase I– and II–medi-
`27
`ated generation of thromboxane B2
` Interference with activation or function of
`the G-protein, resulting in an inhibition of
`signal transduction28
` A protective
`effect
`inhibitor29
` Inhibition of cysteinyl
`triene C4)30
` Inhibition of LTB4
`human PMN31
` Inhibition of
`interleukin (IL)-8 production/
`releasing of peripheral blood stimulated
`with lipopolysaccharide32
` Inhibition of mitogen-induced lymphocyte
`transformation.33
`
`leukotrienes (leuko-
`
`receptor binding of
`
`Moreover, it has been shown that dapsone has
`neuroprotective effects against quinolate- and kai-
`nate-induced striatal neurotoxicities in rats and
`attenuates kainic-induced seizures in rats.34–36
`Summarizing these diverse mechanisms, growing
`evidence shows that dapsone is considered to be
`a pharmacodynamically active compound. The
`anti-inflammatory capacity of dapsone is generally
`attributed to the parent compound. The authors
`therefore addressed the question as to whether the
`two major dapsone metabolites (MADDS and
`DDS-NOH) possess anti-inflammatory properties
`of their own. High performance liquid chromatog-
`raphy analysis of 5-lipoxygenase products from
`calcium ionophore–stimulated
`isolated PMN
`showed that DDS-NOH is one magnitude more
`effective than dapsone and MADDS in suppressing
`the generation of LTB4 and 5-HETE (eg, IC50 LTB4:
`DDS-NOH, 0.490 mmol; dapsone, 15 mmol; MADDS,
`40 mmol). Moreover, determination of lucigenin- and
`luminal-enhanced chemiluminescence of zymosan-
`stimulated human whole blood and isolated PMN
`showed that DDS-NOH (0.1–100 mmol) causes
`a significant and dose-dependent inhibition of oxida-
`tive burst, leading to almost complete suppression at
`the highest concentration tested.37 Again, DDS-
`NOH was more effective than dapsone or MADDS.
`After topical pretreatment with MADDS and
`DDS-NOH (both 1% dissolved in acetone) for 2
`
`weeks, 10 ng LTB4 were applied on the upper
`arm skin of eight healthy volunteers. Biopsies
`were taken after 24 hours and PMNs were quanti-
`fied fluorometrically using elastase as a marker
`enzyme. MADDS did not show any inhibitory
`activity on PMN trafficking compared with the cor-
`responding
`control
`and
`nontreated
`area
`(untreated: 790  450 PMN per 10 mg
`skin; P>.05, acetone: 840  578 PMN per 10 mg
`skin; MADDS: 1099  556 PMN per 10 mg skin),
`whereas DDS-NOH caused a statistically signifi-
`cant inhibition of PMN accumulation, as did the
`reference clobetasol-17-propionate (CP)
`(DDS-
`NOH: 128  143 PMN per 10 mg skin; CP: 86 
`131 PMN per 10 mg skin; P<.01).38 These results
`again indicate that only DDS-NOH can inhibit
`LTB4-induced accumulation of PMN in healthy
`individuals.
`In line with these in vivo experiments are results
`with dapsone, MADDS, and DDS-NOH to deter-
`mine their effect on ultraviolet
`(UV)-induced
`erythema. Skin areas were irradiated with UVB
`(295 nm, two minimal erythema doses). Twenty-
`four hours later, UVB-induced erythema was
`quantified using the CR-200b handheld Chroma
`Meter (Minolta, Osaka, Japan) and cutaneous
`blood flow was measured using a Moor Laser
`Doppler
`Imager
`(Moor
`Instruments, Devon,
`England). In control skin, tissue blood flow was
`measured to be 227 units and was significantly
`(P<0.05) decreased by dapsone (186 units),
`DDS-NOH (154 units), and MADDS (195 units).
`UVB-induced erythema was also significantly
`reduced in DDS-NOH– or MADDS-treated skin
`when compared with controls. Thus, these explo-
`rations show that dapsone metabolites exert phar-
`macodynamic effects when applied topically to
`the skin and may at least be equal to dapsone in
`their anti-inflammatory properties.39,40
`In general,
`the UVB-suppressing activity of
`dapsone was subsequently confirmed by Schu-
`macher,41 who observed significant
`inhibitory
`capability of both topically applied (0,1%,
`0,5%, 1%, 5%, 10%) and systemically applied
`dapsone (100 mg/d) on UV-induced erythema
`in healthy volunteers having sun-reactive skin
`(Fig. 5, Table 1). A theoretical
`type II and III
`explanation for
`the observed erythema-sup-
`pressing effect of dapsone could be the drug’s
`inhibitory action on prostaglandins. Against this
`background, it is noteworthy that dapsone unex-
`pectedly
`showed no substantial effect on
`anthralin-induced erythema, sodium dodecylsul-
`fate–induced erythema, LTB4-induced chemo-
`taxis of PMN, and in psoriasis plaque test.41,42
`However,
`the
`investigators
`did
`not
`con-
`sider dapsone metabolites like MADDS and
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`UNIQUE CHARACTERISTICS OF DAPSONE
`
`Dapsone has unique pharmacologic properties
`among the spectra of available antiphlogistic
`agents. Currently, no other drug produces such
`a wide variety of beneficial activities:
`
`1. Combination of antimicrobial and antiphlogistic
`effects (eg, treatment of opportunistic infec-
`tions in patients with acquired immunodefi-
`ciency syndrome, use of dapsone in acne)
`2. Safety of long-term treatment (eg, life-long use
`in leprosy, long-term ongoing or chronic inter-
`mittent approach in inflammatory dermatoses)
`3. Disease-specific antiphlogistic activity (eg,
`prompt decrease of pruritus and control of
`skin lesions in dermatitis herpetiformis and
`amelioration of
`loxoscelism associated with
`brown recluse spider bites)
`4. Steroid-sparing effect (eg, long-term treatment
`in autoimmune blistering diseases and as an
`adjuvant treatment in bronchial asthma)
`5. UV protection (eg, suppression of UVB-induced
`erythema by dapsone and DDS-NOH)
`6. Anticonvulsive effect (eg, in animal models)
`7. Pharmacoeconomic benefits (eg, low cost of
`treatment).
`
`CLINICAL USE OF DAPSONE
`
`is used in
`Dapsone, as a sulfone antibiotic,
`rifampin-based multiple-drug regimens for treating
`leprosy.10,13
`multibacillary and paucibacillary
`Additionally, the sulfone alone or as part of drug
`combination with other antibiotic agents is used
`to treat prophylaxis of P jiroveci (P carinii) pneu-
`monia and toxoplasmosis in individuals infected
`with HIV. The sulfone is designated an orphan
`
`Fig. 5. Right forearm: suppression of ultraviolet (UV)-
`induced erythema with topically applied dapsone (1%
`solved in acetone, 48 hours after UV exposition). Left
`forearm: control.
`
`used.
`human models
`the
`DDS-NOH in
`Regarding the effect of dapsone on chemotaxis,
`some controversial disparate results have been
`noted especially when comparing in vitro and
`in vivo studies. Some authors postulate even
`a selective inhibition of dapsone on specific
`chemotactic factors (eg,
`formyl-methionyl-leuc-
`yl-phenylalanine [fMLP]).24,43
`Summarizing the mechanism of action of
`dapsone, a few theories have been postulated in
`an attempt to explain drug efficacy in chronic
`inflammatory disease states. However,
`little is
`known about
`the specific molecular effector
`systems targeted by dapsone or its metabolites,
`which leads to clinical efficacy. Further exploration
`of dapsone’s mechanism of action in sulfone-
`sensitive dermatoses is needed.44
`
`Table 1
`Dapsone and erythema threshold
`
`Application
`
`Erythema Threshold Time (minimum)a
`
`Topical %
`
`10
`5
`1
`0.5
`0.1
`—
`
`Systemic
`
`—
`—
`—
`—
`—
`100 mg/d
`
`Dapsone
`6.75  1.27
`5.79  1.08
`4.78  0.82
`4.97  0.87
`5.11  1.07
`5.37  1.19b
`
`Control
`4.14  0.85
`4.08  0.74
`3.38  0.45
`3.83  0.51
`4.22  0.76
`4.30  1.06b
`
`Difference
`2.62  0.74
`1.72  0.72
`1.40  0.55
`1.14  0.93
`0.88  0.46
`1.07  0.34
`
`a Dependent on the method of exposure in healthy volunteers (topical, n 5 10; systemic, n 5 8) with ultraviolet skin type
`II and III.
`b Comparison between pre and posttreatment.
`Data from Schumacher K. Humane in-vivo-Untersuchungen zur antientzu¨ ndlichen Wirksamkeit von Diaminodiphenyl-
`sulfon (Dapson) [thesis]. Dresden, Germany: Department of Dermatology, University Hospital Carl Gustav Carus; 1996.
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`drug by US Food and Drug Administration for use
`in the latter condition.10,13
`Extensive clinical experience in treating patients
`with dapsone shows that the sulfone can suppress
`disease activity in several chronic inflammatory
`dermatoses. Dapsone is considered the preferred
`drug for treating dermatitis herpetiformis, subcor-
`neale pustulosis, erythema elevatum diutinum,
`acropustulosis infantilis, and prurigo pigmentosa.
`In these entities, dapsone is primarily indicated
`as monotherapy. In a second group of derma-
`toses, dapsone is used as an adjuvant treatment,
`especially in patients who experience insufficient
`therapeutic response to corticosteroids or other
`first-line agents, who have a need to reduce corti-
`costeroid dosage, or in whom other first-line drugs
`are contraindicated or not tolerated. These entities
`are summarized in Box 1.10,17,18,45–47
`In yet a third group of disorders, dapsone was
`reported anecdotally as being useful, but initial
`enthusiasm has been tempered with subsequent
`controversial or contradictory results or a total
`lack of properly controlled trials showing efficacy.
`Thus, use of dapsone in these latter entities is only
`justified in totally recalcitrant or refractory cases,
`such as those listed in Box 2.
`Current perspective precludes using dapsone in
`psoriasis because of the lack of experimental
`evidence for its efficacy or inferential evidence
`derived from mechanism of action (eg, dapsone
`lacks T-cell
`targeting,
`tumor necrosis factor
`a antagonism, or IL-12/23 p40 blocking ability).48
`In line with this statement, topical 5% dapsone in
`a psoriasis plaque test showed no sulfone efficacy
`compared with inactive vehicle.42 In all conditions
`in which dapsone is used, specific disease-related
`
`Box 1
`Dapsone used in dermatologic entities as an
`adjunctive treatment modality (group II)
`
`Linear IgA dermatosis
`
`Bullous pemphigoid
`
`Pemphigus vulgaris
`
`Sweet’s syndrome
`
`Recurrent neutrophilic dermatosis of the dorsal
`hands
`
`Pyoderma gangrenosum
`
`Relapsing polychondritis
`
`Leukocytoclastic vasculitis/urticaria vasculitis
`
`Brown recluse spider bite (loxoscelism)
`
`Eosinophilic folliculitis (Ofuji’s disease)
`
`Cutaneous lupus erythematosus
`
`Box 2
`Miscellaneous dermatoses in which dapsone
`is used with uncertain benefit (group III)
`
`Alopecia areata
`
`Pressure urticaria
`
`Acute febrile neutrophilic dermatosis (Sweet’s
`syndrome)
`
`Mycetoma
`
`Eosinophilic cellulitis (Well’s syndrome)
`
`Behc¸et’s syndrome
`
`Lupus miliaris disseminatus faciei
`
`Granuloma faciale
`
`Granuloma annulare
`
`Hypereosinophilic syndrome
`
`Lymphomatoid papulosis
`
`Nocardiosis
`
`follicularis/reticular erythematous
`Mucinosis
`mucinosis syndrome
`
`Transient acantholytic dermatosis
`disease)
`
`(Grover’s
`
`Herpes gestationis
`
`Lymphocytic infiltrate (Jessner-Kanof syndrome)
`
`Acrodermatitis continua suppurativa (Hallo-
`peau’s disease)
`
`Pityriasis rosea
`
`Pemphigus benignus chronicus familiaris
`
`Kaposi sarcoma (AIDS)
`
`Psoriasis
`
`Erosive lichen planus/lichen planus pemphigoides
`
`Granulomatous rosacea
`
`adjuvant treatment modalities should be considered
`when appropriate (eg, gluten-free diet in dermatitis
`herpetiformis, adequate UV protection in LE).
`Because the potential for adverse hematologic
`effects associated with systemically administered
`dapsone, considerable work had gone into devel-
`oping a safe topical formulation. Only one topical
`gel formulation of 5% dapsone is currently avail-
`able on the market (Aczone, Allergan, Inc, Irvine,
`CA, USA) for treating acne vulgaris. Results of
`two large-scale studies (dapsone: n 5 1506;
`vehicle: n 5 1504) show an 8% reduction of nonin-
`flammatory lesions compared with placebo after
`a 12-week treatment period (mean change: 32%
`dapsone vs 24% vehicle). Inflammatory lesions
`improved nearly in the same low level
`(mean
`change: 48% dapsone vs 42% vehicle).49 The
`authors highlight that a potential mechanism of
`action of dapsone in acne could be the direct
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`inhibition of PMN trafficking. However, early inves-
`tigations clearly indicate that dapsone itself in vivo
`seems to exert only a minimal inhibitory effect in
`this regard,50–55 whereas in healthy human volun-
`teers, the dapsone metabolite DDS-NOH shows
`a strong inhibitory activity on LTB4-induced accu-
`mulation of PMN into skin.38 Therefore, an expla-
`nation for efficacy of topical dapsone in treating
`acne obviously could be the generation of DDS-
`NOH through activated PMN in the skin.
`
`DOSAGE OF DAPSONE IN CHRONIC
`INFLAMMATORY DERMATOSES
`
`The dosage of dapsone for nearly all sulfone-sensi-
`tive disorders must be individually titrated to deter-
`mine the daily dosage that most effectively controls
`lesions. Dosage in adults is usually initiated at 50 to
`100 mg/d. If the treatment goal is not achieved after
`some weeks, a higher dosage may be tried (150–
`300 mg/d); administration of higher doses depends
`on tolerability and laboratory monitoring. When
`a favorable response is attained, the dosage should
`then be reduced to the minimum that maintains
`a satisfactory clinical state.
`Prophylactic administration of ascorbic acid,
`folate, iron, and vitamin E reportedly may prevent,
`to a small degree, the hematologic adverse effects
`associated with dapsone. In this regard, vitamin E
`(800 U/d) administration seems to be useful but
`still not in a substantial proportion of patients.
`Moreover,
`these therapeutic recommendations
`are not based on randomized, placebo-controlled,
`double-blinded trials.10
`For administration to children, commercially
`available tablets of dapsone must be crushed
`and dissolved, for example, in strawberry syrup.
`Studies evaluating bioavailability of dapsone after
`administration of this preparation have not been
`published. For some indications in childhood,
`such as infantile acropustulosis or eosinophilic
`folliculitis, a daily dosage of 2 mg per kilogram of
`body weight is recommended.56 Dosing of chil-
`dren with this dosage, or 4 mg/kg weekly, results
`in concentrations equivalent to these reached in
`adults receiving 100 mg/d.57
`
`MONITORING GUIDELINES AND PITFALLS
`
`often
`on dapsone
`literature
`Unfortunately,
`suggests a high degree of toxicity, although this
`toxicity is comparable to that of NSAIDs.
`If
`dapsone is used strictly according treatment
`recommendations, it is safe. Millions of patients
`tolerate the drug without serious problems.58
`Before initiation of dapsone therapy, patients
`must undergo a careful clinical evaluation that
`
`includes a complete history and physical examina-
`tion. Use must be avoided in patients with prior
`allergy to dapsone or sulfa antibiotics. In patients
`with severe cardiac or lung diseases, dapsone
`doses should be carefully adjusted because of
`the drug’s inherent ability to cause some degree
`of hemolysis. Dapsone is contraindicated in
`patients with glucose-6-phosphate dehydroge-
`nase (G6PD) deficiency and in those with severe
`hepatic abnormality. Dapsone should be avoided
`during pregnancy and nursing.
`Laboratory evaluation before initiation of the
`medication includes complete blood cell
`(CBC)
`count with differential, white blood cell count,
`and reticulocyte count; liver and renal function
`tests and; G6PD determination. Consideration
`should also be given to determining methemo-
`globin (met-Hb) level and urinalysis.18
`Follow-up visits should include a thorough
`history to determine adverse effects and periodic
`screening evaluation of neurologic functions.
`Laboratory tests include CBC with differential
`and reticulocytes count at least every 2 weeks
`for the first 3 to 6 months, and then every 2
`months. Liver and renal function tests and urinal-
`ysis should be performed monthly in the first 3 to
`6 months and then every 2 months. Special
`caution when treating patients with dapsone
`must be considered in those who are receiving or
`have been exposed to other drugs or agents that
`are capable of inducing met-Hb production or
`hemolysis. Unfortunately,
`this issue is not yet
`widely recognized. For example, some patients
`treated with dapsone have been reported who
`received aromatic amine drugs to accomplish
`local anesthesia, which resulted in a serious
`increase of met-Hb concentration.59 After initiation
`of dapsone therapy, evaluation of met-Hb levels
`should be carefully addressed. Different
`time
`points generally are of relevance (Fig. 6):
`
`1. The kinetics of met-Hb generation after a single
`dapsone dose is maximal after approximately 6
`hours (Fig. 7A).
`2. Approximately 14 days after initiation of treat-
`ment, determination of met-Hb will estimate
`the level under steady-state conditions and
`may also allow evaluation of patient’s adher-
`ence to therapy.
`3. Other met-Hb determinations can be consid-
`ered at any time point if the patient’s condition
`has changed (eg, occurrence of clinical
`complaints, comedication with other drugs,
`smoking, use of pump water in agricultural
`regions with potential content of nitrites/
`anilines, increased dapsone dosage).
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`Fig. 6. Schedule for determining methemoglobin level in patients being treated with dapsone.
`
`If clinical conditions of the patient remain stable,
`met-Hb levels should be checked only if clinically
`indicated.
`
`ADVERSE EVENTS
`
`In general, dapsone toxicity may be categorized as
`either dose-dependent or independent of dosage.
`Most adverse reactions are dose-related and
`uncommon at low doses of 50 to 100 mg/d. Clas-
`sifying adverse events according to organ system
`manifestations is uselful10,13,18,60:
` Hematologic effects
` Dermatologic reactions
` Nervous system effects
` Gastrointestinal effects/hepatic effects
` Renal effects
` Hypersensitivity syndrome.
`
`Hematologic Effects
`
`The most frequent effects of dapsone are dose-
`related hemolytic anemia and production of met-
`Hb. Both effects are essentially unavoidable.
`However, some individuals experience only mild
`hematologic effects, whereas in others hemolysis
`and/or met-Hb production occur to a significant
`degree. Met-Hb caused by dapsone is normally
`well tolerated at a dosage of 100 mg/d. A few
`patients develop clinical cyanosis even at very
`low dosage. Met-Hb has a greater likelihood of
`becoming a serious problem at higher dapsone
`dosages (>200 mg/d) or
`in patients who are
`concomitantly exposed to other potentially met-
`
`Hb–producing agents (eg, anesthetics, nitrites,
`nitrates).
`Methemoglobinemia may be poorly tolerated by
`patients with severe cardiopulmonary diseases.
`The dapsone hydroxylamine metabolites that react
`with hemoglobin cause met-Hb formation.61,62 The
`generation of met-Hb undergoes a time-dependent
`process (Fig. 7B). In the early treatment phase,
`therefore, met-Hb should be determined 4 to 6
`hours after ingestion of dapsone, because the
`maximum level of met-Hb in peripheral blood is
`indicative of real cardiopulmonary risk. For this
`reason, dapsone intake should be recommended
`in the evening in some patients.
`Hemolysis is also dose-dependent. Therefore,
`nearly all patients treated with dapsone experi-
`ence some degree of hemolysis. Unless it
`is
`severe, hemolysis does not generally require
`discontinuation of sulfone therapy. The manufac-
`turer states that the hemoglobin level in patients
`treated with dapsone is generally decreased by
`1 to 2 g/dL, the reticulocyte count is increased
`2% to 12%, and erythrocyte life span is shortened.
`Heinz body formation also occurs frequently.
`Methemoglobinemia and hemolytic anemia are
`observed to a greater extent
`in patients with
`G6PD deficiency.
`Agranulocytosis and aplastic anemia in patients
`treated with dapsone have been reported rarely.13,60
`Most cases of agranulocytosis developed within the
`first 8 to 12 weeks of therapy. This hematologic
`effect is usually reversible within 1 to 2 weeks, but
`it can also be fatal. Administration of hematopoietic
`growth factors is recommended for treatment of
`agranulocytosis.63
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`Dapsone in Dermatology
`
`607
`
`Fig. 7. Methemoglobin concentration (%) after single ingestion of dapsone, 200 mg, in dependence of time (A),
`methemoglobin concentration (%) after daily oral application of dapsone, 200 mg (B).
`
`Dermatologic Reactions
`
`from dapsone include
`reactions
`Cutaneous
`various skin eruptions: exfoliative dermatitis,
`erythema multiforme, urticaria, erythema nodo-
`sum, morbilliform and scarlatiniform exanthema,
`and toxic epidermal necrolysis. Dapsone-induced
`photosensitivity is not restricted to leprosy. Cuta-
`neous reactions are rare, are not dose-dependent,
`and might be caused by not only the parent
`compound
`dapsone
`but
`also
`dapsone
`metabolites.64
`
`Nervous System
`
`Peripheral neuropathy with primarily motor loss
`has been reported rarely in patients receiving
`dapsone. If patients observe muscle weakness
`during dapsone treatment, the drug should be dis-
`continued. Recovery may occur; however, this
`may take many months to several years. Tragic
`
`cases of patients ingesting dapsone on purpose
`to commit suicide confirm the ability of the drug
`to damage the peripheral nervous system,
`including
`the
`optic
`nerve
`(resulting
`in
`blindness).65,66
`
`Gastrointestinal/Hepatic Reaction
`
`Three different hepatic reactions must be
`considered:
`
`1. Isolated abnormalities of liver function test (eg,
`increased bilirubin, aspartate aminotrans-
`ferase, alanine aminotransferase, lactate dehy-
`drogenase) without evidence of hepatitis or
`hepatosis. If any abnormality is detected, the
`dosage of dapsone should be decreased or
`the drug should be discontinued until
`the
`source is established.
`2. Prehepatic jaundice induced by hemolytic
`anemia. Hyperbilirubinemia may occur more
`
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`often in patients with G6PD deficiency. All
`patients should be monitored periodically after
`reduction of dapsone dosage or discontinua-
`tion of treatment.
`3. Toxic or cholestatic hepatitis in conjunction
`with a hypersensitivity syndrome. Hepatic
`coma is the most frequent cause of death.
`
`Some other adverse effects of dapsone with
`unknown mechanisms have been recognized.
`Fortunately, most are rare (eg, albuminuria,
`insomnia, psychosis, impairment of electrolytes,
`atrioventricular block).67 Some of these rarely re-
`ported adverse effects may be partially attributed
`to anemia and/or methaemoglobinemia.
`
`Hypersensitivity Syndrome
`
`A rare adverse reaction of dapsone is the hyper-
`sensitivity syndrome to dapsone, which is poten-
`tially life-threatening. The real
`frequency of
`hypersensitivity syndrome has been a continued
`subject of controversial speculation.68 Until the
`end of October, 2009, only 343 patients with
`hypersensitivity syndrome, aged 5 to 83 years,
`were analyzed from the literature worldwide.69 Ac-
`cording to the results of this analysis, the most
`frequent dapsone dosage was 100 mg/d as mono-
`therapy or in combination with additional drugs
`(eg, rifampin, clofazimine). No evidence was seen
`that concomitant
`therapy with corticosteroids
`avoided the risk for hypersensitivity syndrome.
`The median latency between dapsone initiation
`and first clinical complaint was 2 to 6 weeks (6
`hours minimum, 20 weeks maximum).
`In terms of clinical presentation of hypersensi-
`tivity syndrome to dapsone, nearly all patients
`had a various exanthem, fever, or lymphadenop-
`athy. Most patients additionally showed hepatic
`dysfunction, varying in severity from abnormal liver
`function studies to overt hepato(spleno)megaly,
`jaundice, and finally hepatic coma. Hematologic
`changes were unexpectedly rare (leukocytosis,
`23,6%; eosinophilia, 2