Medication Summary
The goals of pharmacotherapy are to reduce morbidity and prevent complications.
Topical metronidazole is commonly used as a first-line agent. Topical azelaic acid, sulfacetamide products, and topical acne medications are also commonly used. Topical and oral antibiotics are also very effective, and for oral rosacea, they are usually considered as a first-line therapy. In many cases, oral and topical antibiotics are used in combination; the oral treatment may be eventually withdrawn and the topical treatment is used alone as maintenance therapy. However, in patients with ocular involvement, oral therapy needs to be maintained. In patients who require a systemic antibiotic, evidence suggests that the newer regimen of 20-50 mg q12h of doxycycline is as effective as the older regimen of 100 mg of doxycycline [20] For many patients, this could represent a significant cost reduction.
Retinoids are advocated by some authorities. [21, 22, 23]
A topical form of the alpha-2 agonist brimonidine was approved by the FDA in August 2013 for treatment of erythema associated with rosacea. Approval was based on data collected from more than 550 patients enrolled in two phase 3 clinical studies of one-month duration. The results from both studies showed that adults who used brimonidine topical gel demonstrated significantly greater improvement in the facial redness of rosacea than those who used vehicle gel alone. [24] In addition, a long-term study in 276 subjects who used brimonidine topical gel for up to 12-months was also conducted.
Another topical alpha agonist, oxymetazoline, was approved in 2017 for persistent facial erythema associated with rosacea in adults. Approval was based on two randomized clinical trials (n=885) that compared the active drug with the cream vehicle. Once-daily topical application of oxymetazoline cream 1% was proven to reduce persistent facial erythema associated with rosacea through 12 hours. The primary efficacy endpoint was at day 29 and defined as the proportion of patients with at least a 2-grade reduction in erythema (improvement) from baseline on both the clinician erythema assessment (CEA) and subject self-assessment (SSA) (composite success). [25]
Topical ivermectin (Soolantra) has been approved by the FDA for treatment of the inflammatory lesions of rosacea. Stein et al reported in 2014 that ivermectin 1% cream was safe and effective for the treatment of inflammatory lesions from papulopustular rosacea, based on 2 randomized, controlled, double-blind, identically designed studies of ivermectin 1% cream versus vehicle applied once daily for 12 weeks. [26] Several case reports have described successful rosacea treatment with topical acaricidal agents, [27, 28, 29] most recently in a 12-year-old girl with D folliculorum –associated rosacea who had complete resolution of her symptoms following a single dose of oral ivermectin. [30] Phase 3 randomized clinical trials to study effects of topical ivermectin 1% cream on rosacea have been completed; these trials compared the safety and efficacy of 1% ivermectin with 0.75% metronidazole cream and 15% azelaic acid gel. [31, 32, 33]
In addition to the agents listed below, anecdotal evidence indicates effective treatment of rosacea with medications that reduce flushing, including beta-blockers, clonidine, naloxone, ondansetron, and selective serotonin reuptake inhibitors.
Topical and opthalmic fusidic acid is available in Canada, but not in the U.S. It is used for the treatment of ocular rosacea. Fusidic acid is a topical antibacterial that inhibits bacterial protein synthesis, causing bacterial death. Rosacea may respond to topical fusidic acid for at least 3 months.
Oral contraceptive therapy has been helpful in patients who provide historical information of worsening rosacea with their hormonal cycle.
Dapsone has been used in severe, refractory rosacea, and dapsone has been particularly beneficial for patients who cannot take isotretinoin. [34]
Immunosuppressants
Class Summary
These agents inhibit immune reactions resulting from diverse stimuli.
Tacrolimus ointment (Protopic)
Tacrolimus ointment reduces itching and inflammation by suppressing the release of cytokines from T cells. It also inhibits transcription of genes encoding IL-3, IL-4, IL-5, GM-CSF, and TNF-alpha, all of which are involved in the early stages of T-cell activation. Additionally, it may inhibit the release of preformed mediators from skin mast cells and basophils, and may down-regulate the expression of FCeRI on Langerhans cells. Tacrolimus ointment can be used in patients as young as 2 years. Drugs of this class are more expensive than topical corticosteroids. It is available as ointment in concentrations of 0.03% and 0.1% and is indicated only after other treatment options have failed.
Antibiotics
Class Summary
Since the 1950s, oral antibiotics have been prescribed off label for treatment because microorganisms were thought to be the underlying cause of disease. In current practice, experts do not believe bacterial infection plays a part in the pathogenesis of rosacea; however, the antibiotics, particularly the tetracyclines, continue to be used for their anti-inflammatory properties. Since 2006, nonantibiotic dosing of doxycycline has become first-line treatment for many clinicians. In many cases, oral and topical antibiotics are used in combination; the oral treatment may be eventually withdrawn and the topical treatment is used alone as maintenance therapy. However, in patients with ocular involvement, oral therapy needs to be maintained.
In patients who require a systemic antibiotic, evidence suggests that the newer regimen of 20-50 mg q12h of doxycycline is as effective as the older regimen of 100 mg of doxycycline. For many patients, this could represent a significant cost reduction.
Metronidazole gel 0.75% or 1% (MetroGel, Noritate, MetroLotion)
Metronidazole is an imidazole ring–based antibiotic active against various anaerobic bacteria and protozoa.
Oral metronidazole has been shown to be beneficial against papules and pustules of acne rosacea.
Topical applications are helpful for mild disease and as an adjuvant to systemic therapy.
Erythromycin (E.E.S., Erythrocin, Ery-Tab) tab or 2% topical solution
Erythromycin inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. It is used for the treatment of staphylococcal and streptococcal infections.
In children, age, weight, and severity of infection determine the proper dosage. When twice-daily dosing is desired, half the total daily dose may be taken every 12 hours. For more severe infections, double the dose.
Erythromycin can be used when tetracyclines are not tolerated or are contraindicated.
It is used for the treatment of ocular rosacea.
Clindamycin topical (Cleocin T, Clindagel, Evoclin)
Clindamycin is a semisynthetic antibiotic produced by 7(S)-chloro substitution of 7(R)-hydroxyl group of its parent compound lincomycin. It inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Clindamycin widely distributes in the body without penetration of the CNS. It is protein bound and excreted by the liver and kidneys.
Upon application to skin, drug is converted to active component, which inhibits the microorganism.
Available as topical solution, lotion, or gel for external use. Solution contains equivalent of 10 mg/mL clindamycin.
Effective against mild-to-moderate papulopustular rosacea.
Tetracycline
Tetracycline inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunit(s). It has anti-inflammatory activity. Improvement is evident within 2-4 months after commencement of therapy.
Minocycline (Dynacin, Minocin, Solodyn)
Minocycline treats infections caused by susceptible gram-negative and gram-positive organisms, in addition to infections caused by susceptible P acnes. The extended-release tablet (Solodyn) has a variety of doses ranging from 45 mg up to 135 mg and can be administered once daily.
Minocycline topical (Zilxi)
The precise mechanism of action by which topical minocycline exerts its affects for acne is unknown, but it is thought to elicit anti-inflammatory effects. The 1.5% topical foam is indicated to treat inflammatory lesions of rosacea in adults.
Doxycycline (Oracea, Doryx, Periostat, Vibramycin)
Doxycycline is a broad-spectrum, synthetically derived, bacteriostatic antibiotic in the tetracycline class. It is almost completely absorbed, concentrates in bile, and is excreted in urine and feces as a biologically active metabolite in high concentrations.
Doxycycline inhibits protein synthesis and, thus, bacterial growth, by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. It may block dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.
Clarithromycin (Biaxin, Biaxin XL)
Clarithromycin is a semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating dissociation of peptidyl tRNA from ribosomes, causing bacterial growth inhibition.
Retinoid-Like Agents
Class Summary
These agents decrease the cohesiveness of abnormal hyperproliferative keratinocytes and may reduce the potential for malignant degeneration. They modulate keratinocyte differentiation, and they have been shown to reduce the risk of skin cancer formation in patients who have undergone renal transplantation.
Tretinoin topical (Avita, Retin-A, Retin-A Micro)
Tretinoin is structurally related to vitamin A. It may be helpful for recalcitrant disease, but recurrence is common. Long-term, low-dose therapy may be suitable for selected patients.
Tretinoin may cause skin irritation in some patients. It has been linked to the promotion of angiogenesis; however, it has not demonstrated increased telangiectasias.
Tretinoin inhibits microcomedo formation and eliminates lesions. It makes keratinocytes in sebaceous follicles less adherent and easier to remove. It is available as 0.025%, 0.05%, and 0.1% creams. It is also available as 0.01% and 0.025% gels.
Isotretinoin (Amnesteem, Claravis, Sotret)
Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of naturally occurring tretinoin (trans -retinoic acid). Isotretinoin may be helpful for recalcitrant disease, but recurrence is common. Long-term, low-dose therapy may be suitable for selected patients.
A US Food and Drug Administration–mandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.
Corticosteroids
Class Summary
These agents are relatively contraindicated, except as a short course in rosacea fulminans.
Prednisolone (Millipred, Orapred, Veripred, Flo-Pred)
Moderately high doses may be helpful in rosacea fulminans. Prednisolone decreases inflammation by suppressing the migration of PMN leukocytes and reducing capillary permeability. Use it in combination with isotretinoin. Rosacea fulminans is treated with moderately high doses of prednisolone (30-60 mg/d) followed by oral isotretinoin.
Antihypertensive Agents
Class Summary
Potassium-sparing diuretics can be used to reduce morbidity.
Spironolactone (Aldactone)
Spironolactone competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions. Aldosterone inhibitors help block the renin-angiotensin system and help prevent potassium loss in distal tubules. The body conserves potassium, and less oral potassium supplementation is needed.
Amiloride
Amiloride is an antikaliuretic drug with weak natriuretic, diuretic, and antihypertensive activity. It decreases the enhanced urinary excretion of magnesium that occurs when a thiazide or loop diuretic is used alone. It exerts a potassium-conserving effect in patients receiving kaliuretic diuretic agents.
Triamterene (Dyrenium)
Triamterene inhibits reabsorption of sodium ions in exchange for potassium and hydrogen ions at the segment of the distal tubule that is under the control of adrenal mineralocorticoids (especially aldosterone). This activity is not directly related to aldosterone secretion or antagonism, and it is a result of a direct effect on the renal tubule.
The fraction of filtered sodium reaching this distal tubular exchange site is relatively small, and the amount that is exchanged depends on the level of mineralocorticoid activity; thus, the degree of natriuresis and diuresis produced by inhibition of the exchange mechanism is necessarily limited.
Increasing the amount of available sodium and the level of mineralocorticoid activity by using more proximally acting diuretics increases the degree of diuresis and potassium conservation. Triamterene may occasionally cause increases in serum potassium, which can result in hyperkalemia. It does not produce alkalosis, because it does not cause excessive excretion of titratable acid and ammonium.
Acne Agents, Topical
Class Summary
Some products in this category can be effective in patients with papules, pustules, and the phymatous and glandular types of rosacea.
Benzoyl peroxide (Benzig, PanOxyl, Zapzyt, Acne Clear Maximum Strength)
Free-radical oxygen is released upon administration and oxidizes bacterial proteins in sebaceous follicles, decreasing the quantity of irritating free fatty acids and of anaerobic bacteria. It is converted on skin into benzoic acid, which has keratolytic and comedolytic effects. However, it can be quite irritating in patients with barrier dysfunction and can cause further erythema. Benzoyl peroxide is available over the counter and by prescription. It is available in 2.5%, 5%, and 10% gels, lotions, creams, or washes.
Azelaic acid (Azelex, Finacea)
Azelaic acid is available in 2 strengths, as a 15% gel or foam (Finacea), or azelaic acid 20% cream (Azelex). It is effective against mild-to-moderate papulopustular rosacea. Azelaic acid can be used twice daily as initial treatment. It may reduce the production of ROS by neutrophils. Some patients report transient burning or stinging.
Sodium sulfacetamide and sulfur (Klaron, Ovace)
Sodium sulfacetamide and sulfur contains 5% sulfur and 10% sodium sulfacetamide. It is used topically for acne rosacea. Sodium sulfacetamide has antibacterial properties, whereas sulfur is considered an antiseptic with keratolytic action.
Ivermectin topical (Soolantra)
The mechanism by which ivermectin topical treats rosacea lesions is unknown. It is indicated for inflammatory lesions caused by rosacea.
Topical Alpha Agonists
Class Summary
Topical alpha1 and alpha 2 agonists have been approved by the FDA to treat rosacea.
Oxymetazoline topical (Rhofade)
Oxymetazoline topical is an alpha1 agonist that elicits vasoconstriction of the cutaneous microvasculature. It is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults.
Brimonidine topical (Mirvaso)
Brimonidine is an alpha-2 adrenergic agonist. It is indicated for persistent facial erythema of rosacea in adults.
-
Histopathology of rosacea. Perifollicular chronic inflammation and vascular ectasia. Courtesy of Dirk Elston, MD.
-
Mild papules and erythema. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/imagedetail/2367).
-
Moderate papules and early pustules. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/imagedetail/2369).
-
Severe erythema, papules, and pustules. Courtesy of DermNet New Zealand (https://www.dermnetnz.org/imagedetail/2371).
