V.
`Galderma Laboratories, lnc.
`IPR2015-__
`Exhibit 1011
`Exh. 1011
`
`

`
`therapelJtics for the clinician
`
`Treatment of Rosacea With
`Doxycycline Monohydrate
`
`Joseph B. Bikowski, MD, Pittsburgh, Pennsylvania
`
`Rosacea is one of the most common/y occurring
`inflammatory dermatoses treated by dermatolo-
`gists today. Estimates suggest that at least 13 mil-
`lion Americans have recognized rosacea, and the
`clinical experience of most practitioners would
`add considerably more to that number. Rosacea is
`an inflammatory condition of the skin, c/assica/ly
`presenting with a history of flushing and/or blush-
`ing along with the c/inical findings of erythema,
`edema,
`telangiectasia , papules, pustules, and
`nodules of the face. Severity and distribution vary
`considerably. A patient may have only a few scat-
`tered papules and pustules of the central third of
`the face or there may be numerous inflammatory,
`painful, tender, /arge nodu/es. in some cases, only
`the face may be affected. in other cases, there
`may be lesions of the scalp, neck, and/or torso.
`Although the exact etiology is unknown, rosacea is
`thought by most experts to be an inflammatory
`process incited by vascular instability with subse-
`quent leakage of fluid and inflammatory mediators
`into the dermis.
`
`Treatment frequently consists of a topical med-
`
`ication in combination with a systemic antibi-
`otic. The choice of an appropriate therapeutic
`regimen that fits the Iifesty le and desires of the pa-
`tient is key to patient compliance, which is necessary
`to obtain and maintain suppression of the disease.
`T wo cases of inflammatory rosacea of rhe face in pa-
`tients who desired rapid clearing wirbout the use of
`topical medication are presented. Oral antibiotics are
`a well-established treatment for rosacea, however,
`these patients improved dramatically wirhin 1 to 2
`months of beginning treatment, exclusively with
`doxycycline monohydrate.
`
`Dr. Bikowski is a Clinical Assistant Professor, University of
`Pittsburgh , Oepartment of Dermatology, Pittsburgh, Pennsylvania.
`REPRINT REQUESTS to Sewickley Dermatological Associates
`lnc., 701 Broad Street, Sewickley, PA 15143.
`
`FIGURE 1. A 45-year-old man presented with an ery-
`thematous papulo-pustular eruption on the forehead,
`nose, medial cheeks, and ch in. Forehead lesions were
`most impressive.
`
`Case Reports
`Patient 1-A 45-year-old attorney initially presented
`with a 3- to 4-day history of a pruritic, erythematous,
`linear vesicular eruption of the posrerior righr rhigh.
`A diagnosis of allergic contact dermatitis secondary
`to poison ivy was made, and the patient was treared
`wirb prednisone 40 mg/day for 10 days. The parient
`was also noted to have an inflammatory eruption of
`the face and related a 3-year history of intermittent
`"break outs" that had becorne constant over the pre-
`ceding 6 months. In addition, he recalled episodes
`of flushing, which occurred after drinking alcohol or
`hot beverages. An erythemarous papulo-pustular
`eruption was present on the forehead, nose, medial
`cheeks, and chin. The forehead lesions were most
`impressive (Figure 1). There were no lesions of the
`neck, scalp, ehest, or back. Because of the initial con-
`sideration of a primary pyoderma, a bacterial culrure
`was obtained from a pustule of the forehead, and a 5-
`day course of azithromycin was prescribed. The cul-
`
`VOLUIVIE 66, AUGUST 2000 149
`
`Exh. 1011
`
`

`
`TREATMENT OF ROSACEA
`
`I
`
`FIGURE 2. Nine weeks of therapy with doxycycline
`monohydrate 100 mg daily produced near-complete
`clearance.
`
`ture was positive for a heavy growth of normal skin
`flora and a rare growth of StajJhylococcus aureus. These
`were not thought to be causative.
`Eight days later, the dermatitis on the thigh had
`resolved and there was a marked decrease in the ery-
`thema of the inflammatory lesions on the face. A di-
`agnosis of severe inflammatory stage Ill rosacea was
`made. Treatment with doxycycline monohydrate 100
`mg/day was initiated. The patient refused topical
`medications in combination with the systemic an-
`tibiotic because of his full-face beard. He did not feel
`that he wou ld be compliant with daily application of
`medication to his entire face. Nine weeks later, the
`eruption had essentially cleared (Figure 2). The
`cheeks, chin, and nose were also free of erythema,
`papules, and pustules. The patient had tolerated
`doxycycline monohydrate well and denied headache,
`gastrointestinal upset, or photosensitivity. The same
`dose of doxycycline monohydrate (1 00 mg/day) was
`continued as maintenance therapy and the patient
`remained clear of all inflammatory lesions at follow-
`up 6 months after initiation of therapy.
`Patient 2-A 49-year-old female patient presented
`after 18 months without therapy and complained that
`her rosacea was flaring. She had previously been
`treated with a systemic antibiotic and topical metron-
`idazole, but decided to stop treatment when her face
`cleared.
`In the 2 months before this visit, she had
`noted increased total face flushing and renewed
`"break-outs" on the nose and cheek. On examina-
`there was a
`tender, painful, erythematous
`tion,
`
`150 CUTIS"
`
`FIGURE 3. A 49-year-old fema/e with a history of
`rosacea presented with tender, painful, erythematous
`swelling of the left side of the nasal tip and sympto-
`matic inf/ammatory nodules of the left malar area. She
`was diagnosed with moderately severe stage /II plaque
`rosacea.
`
`swelling of the left side of the nasal tip and two sim-
`ilarly symptomatic inflammatory nodules of the left
`malar area measuring 1.1 and 0.6 cm in diameter.
`There were no lesions on the remainder of the face
`scalp, neck, or torso. The patient was diagnosed with
`moderately severe stage IIl plaque rosacea (Figure 3 ).
`Because of the severity of her condition, she elected
`to pursue systemic antibiotic therapy, but declined the
`conccimitant use of a topical agent because she did
`not feel that she would comply with daily applica-
`tions. Therapy with doxycycline monohydrate 50
`mg/day was initiated.
`The patient was seen in follow-up 1 month later.
`At that time, there was a marked decrease in the
`edema and erythema of the nasal and cheek lesions
`(Figure 4) . She had experienced no ill side effects
`from the doxycycline monohydrate. She was in-
`structed to continue the same dose-50 mg/day-and
`return in 1 month. At follow-up she was essentially
`clear. There was minimal postinflammatory erythema
`of the nasal tip and left cheek (Figure 5). She had no
`complaints of headache, gastrointestinal upset, or in-
`creased sun sensitivity. The doxycycline monohydrate
`was decreased to 50 mg every other day for long-term
`maintenance therapy.
`
`Comments
`The efficacy of systemic antibiotics alone or in com-
`bination with a topical agent for the treatment of
`rosacea is weil documented.1 Initial therapy usually
`includes an oral antibiotic ( tetracycline, erythromy-
`
`Exh. 1011
`
`

`
`TR EATMENT OF ROSACEA
`
`FIGURE 4. After 1 month of therapy with doxycycline
`monohydrate, the patient demonstrated a marked
`decrease in the edema and erythema of the nasal and
`cheek Jesions.
`
`FIGURE 5. Two months alter the initiation of therapy,
`the patient was essentially clear with minimal postin-
`flammatory erythema of the nasal tip and left cheek.
`
`ein, doxycycline, minocycline) in combination with
`a ropical preparation (metronidazole, clindamycin,
`sodium sulfacetamide, and/or sulfur). The clinician's
`goal is to achieve rapid remission with the oral agent
`and to maintain remission with the topical medica-
`tion if at all possible. Any of the commonly used sys-
`temic antibiotics will usually clear the inflammatory
`lesions of moderately severe stage li or IIl rosacea in
`2 to 6 weeks. The topical agents will demonstrate
`clinical improvement in 4 to 12 weeks, although
`complete clearing may not be obtainable in that pe-
`riod of time with topical medications alone. Though
`the ultimate goal is to taper down and/or discontinue
`oral therapy, intermittent low-dose systemic antibi-
`otics in addition to daily topical treatment may be
`necessary to maintain campiere remission in the ma-
`jority of patients.
`After early claims in the French and Belgian Iit-
`erature taured the success of chloramphenicol in the
`treatment of rosacea, Sneddon' became one of the
`first to detail the success of tetracycline for rhis in-
`dication. In studies conducted from 1964 to 1965,
`he noted an 80% success rate treating rosacea pa-
`tients with 250 mg
`tetracycline
`twice daily. '
`Maibach's2 review of the second-generation tetracy-
`clines was extremely thorough and is worthy read-
`ing. The highlights of that srudy and another recent
`study; will be detailed later.
`include
`tetracyclines
`The second-generation
`minocycline, doxycycline hyclate
`(hydrochloric
`acid), and doxycycline monohydrate. When com-
`
`/:)
`
`increased
`three have
`tetracycline, all
`pared
`to
`bioavailability,
`improved absorption when
`taken
`with food, and broader antibacterial activity.
`Minocycline is not photosensitizing, nor is it
`commonly associated with pseudotumor cerebri.
`However, many other adverse effects have been asso-
`ciated to some degree with minocycline rherapy. Two
`long-known side effects are vertioo-which is more
`common in women than in men-and blue staining
`of the legs, feet, face, or gums. Bluish staining may
`also present
`in acne scars.
`Frequently renned
`"minocycline hyperpigmentation,"
`this blue-gray
`staining may appear wirhin 3 ro 6 months of rhe starr
`of therapy. Staining of rhe teeth may also occur, usu-
`ally after more than 5 years of continuous minocy-
`cline use. O ther side effects have more recently been
`identified with minocycline rherapy. Some young
`women experience a lupus-like syndrome characrer-
`ized by pain, swelling, and stiffness of the joints as
`weil as by fever, pleuritic ehest pain, malaise, and fa-
`tigue. A hypersensitivity syndrome has also been iden-
`fever,
`lymphadenopathy,
`tified, characterized by
`eosinophilia, lymphocytosis, or rash, occuring about
`24 days after the start of therapy. Fi.nally, a serutTt sick-
`ness-like reaction has also been identified with onset
`about 2 weeks after the start of minocycline therapy.
`Symptoms include fever, lymphadenoparhy, arthral-
`gias/arthritis, or rash. With a pH of 2, doxycycline
`hyclate has been associated with a high rate of
`esophageal irritation and gastrointestinal upset. How-
`ever, with a neutral pH of 7, doxycycli ne monohy-
`
`VOLUtJIE 6 . AUGUST 2000 151
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`Exh. 1011
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`

`
`TREATMENT OF ROSACEA
`
`drate is not associated with esophageal irritation and
`has a lower incidence of gastrointestinal upset. Doxy-
`cycline is not associated with centrat nervous system
`side effects such as vertigo, but, like all the tetracy-
`clines, it may rarely be associated with pseudotumor
`cerebri. The drug can be photosensitizing-typically
`in fewer than 1% of patients. Photosensitivity is most
`common in patients with excessive summer sun ex-
`posure and presents as redness and blistering of the
`nose, dorsum of the h ands, and fingers. Sunscreen use
`may not prevenr phorosensitivity reactions.
`The second-generation
`tetracyclines have con-
`tributed greatly to the dermatologic armamentarium.
`Though minocycline has been associated with poten-
`tially serious side effects, their incidence is rare and
`sh ould not prevent physicians from prescribing it. Doxy-
`cycline monohydrate represenrs an effective therapeu-
`tic option with advanrages over doxycycline hyclate.
`Doxycycline monohydrate was selected for the pa-
`tienrs presented because it is associated with de-
`creased risk of gastrointestinal upset and esophageal
`ulceration as compared to doxycycline hyclate. O nce-
`daily dosing promotes patient compliance. Doxycy-
`cline monohydrate also carries decreased risk of the
`centrat nervous system side effects associated with
`minocycline therapy.
`
`doxycycline
`
`Information-Monodox®,
`Product
`monohydrate, Oclassen Dermatologics.
`REFERENCES
`I. Sneddon IB: A clinical trial of tetracycline in rosacea. Br J
`Dermatal 78: 649-652, 1966.
`2. Maibach H: Second-generation tetracyclines, a dermato-
`logic overview: clinical uses and pharmacology. Cutis 48:
`411-417, 1991.
`3. Green R, Brown JR, Calvert RT: The disposition of four
`tetracyclines in normal subjects. Eur 1 Clin Pharmacol 10:
`245-250, 1976.
`4. Carlborg B, Farmer J: Esophageal corrosion tests with doxy-
`cycline monohydrate tablets. Curr Ther Res 34: 110-116,
`1983.
`5. White GM: Acne therapy. Disease A Month 45: 301 -332,
`1999.
`6. Rebora A, Drago F, Parodi A: May Helicobacrer pylori be im-
`portant for dermatologists? Dermawlogy 191: 6-8, 1995.
`7. Bonnar E, Eustace P, Powell FC: The Demodex mite pop-
`ulation in rosacea. 1 Am Acad De7mawl 28: 443-448, 1993.
`8. Lloyd KM: Surgical correction of rhinophyma. Arch Derma-
`wl126: 721-723, 1990.
`9. Plewig G , Nikolowski J, Wolff HH: Action of isotretinoin
`in acne, rosacea, and gram-negative folliculitis. ] Am Acad
`Dermawl 6: 766-785 , 1982.
`
`152 CUTIS"
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