Erythroderma (Generalized Exfoliative Dermatitis)

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Practice Essentials

Erythroderma is a general term used to describe severe, intense skin inflammation; exfoliative dermatitis (ED) refers to a scaling erythematous dermatitis involving 90% or more of the cutaneous surface. Exfoliative dermatitis is characterized by erythema and scaling involving the skin's surface and often obscures the primary lesions that are important clues to understanding the evolution of the disease.

Determining specific etiologies in exfoliative dermatitis (ED) often is not possible; however, it is necessary to attempt since etiology may impact disease course and management options. The list of conditions that can cause exfoliative dermatitis is extensive and continues to expand. 

The most common causes of exfoliative dermatitis are best remembered by the mnemonic device ID-SCALP. The causes and their frequencies are as follows[1] :

Clinicians are challenged to find the cause of exfoliative dermatitis by eliciting the history of illness prior to erythema and scaling, by probing with biopsies, and by performing blood studies. See the images below.



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Exfoliative dermatitis diffuse skin involvement.



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Exfoliative dermatitis close-up view showing erythema and scaling.

Idiopathic exfoliative dermatitis is characterized by marked palmoplantar keratoderma, dermatopathic lymphadenopathy, and a raised level of serum immunoglobulin E (IgE) and is more likely to persist than other types.

A non-IgE-mediated anaphylactoid adverse event characterized by pruritus, erythroderma, wheezing, flushing, and hypotension following rapid infusion of vancomycin was originally named Red man syndrome (RMS).  It has since been reported with oral or topical vancomycin.[2]    The use of the term 'red man syndrome' is now discouraged as it leads to underdiagnosis among non-White patients.[3]

In contrast, L'homme rouge historically refers to either idiopathic exfoliative dermatitis or exfoliative dermatitis often secondary to cutaneous T-cell lymphoma (CTCL).  Regarding CTCL, it is important to differentiate between indolent and aggressive subtypes, particularly erythrodermic mycosis fungoides and Sézary syndrome, as treatment options differ.[4]  

Pathophysiology

An increased skin blood perfusion occurs in exfoliative dermatitis (ED) that results in temperature dysregulation (resulting in heat loss and hypothermia) and possible high-output cardiac failure. The basal metabolic rate rises to compensate for the resultant heat loss. Fluid loss by transpiration is increased in proportion to the basal metabolic rate. The situation is similar to that observed in patients following burns (negative nitrogen balance characterized by edema, hypoalbuminemia, loss of muscle mass).

A marked loss of exfoliated scales occurs that may reach 20-30 g/d. This contributes to the hypoalbuminemia commonly observed in exfoliative dermatitis. Hypoalbuminemia results, in part, from decreased synthesis or increased metabolism of albumin. Edema is a frequent finding, probably resulting from fluid shift into the extracellular spaces. Immune responses may be altered, as evidenced by increased gamma-globulins, increased serum IgE in some cases, eosinophil infiltration, and CD4+ T-cell lymphocytopenia in the absence of HIV infection. Oxidative stress is also associated with drug-induced erythroderma.[5]

Chronic erythroderma in elderly men may represent a unique condition distinct from adult atopic dermatitis.[6]

Etiology

Determining specific etiologies in exfoliative dermatitis (ED) often is not possible; however, it is necessary to attempt since etiology may impact disease course and management options. The list of conditions that can cause exfoliative dermatitis is extensive and continues to expand. Cutaneous diseases that cause exfoliative dermatitis and the systemic diseases associated with them include the following[7, 8, 9] :

The most common causes of exfoliative dermatitis are best remembered by the mnemonic device ID-SCALP. The causes and their frequencies are as follows[1] :

More than 135 drugs have been implicated in the causation of exfoliative dermatitis (see Table 1 below). In many cases of protracted exfoliative dermatitis classified as being of undetermined cause, careful follow-up care and reevaluation implicated atopic dermatitis in older patients, intake of drugs overlooked by the patient, and prelymphomatous eruption as causative factors. It should be noted that psoriasiform erythroderma has been induced by the tumor necrosis factor (TNF)-α inhibitor golimumab.[10]

Table 1. Drugs Implicated in the Causation of Exfoliative Dermatitis



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See Table

Sarcoidosis-associated erythroderma may demonstrate lichenoid papules as a clue to the diagnosis.[39]

Epidemiology

Age-, sex-, and race-related demographics

Exfoliative dermatitis onset usually occurs in persons older than 40 years, except when the condition results from atopic dermatitis, seborrheic dermatitis, staphylococcal scalded skin syndrome, or a hereditary ichthyosis. Age of onset primarily is related to etiology.[40, 41]

Male-to-female ratio is 2-4:1.

No racial predilection is reported for exfoliative dermatitis.

Prognosis

The prognosis of exfoliative dermatitis depends largely on underlying etiology. The disease course is rapid if it results from drug allergy, lymphoma, leukemia, contact allergens, or staphylococcal scalded skin syndrome.  In acute erythroderma, skin failure can be life-threatening and can require treatment in the intensive care unit (ICU). Systemic complications are less frequent in chronic presentations.[1]

A study[42] of pediatric patients (aged < 19 y) found that fever is a poor prognostic marker and may indicate a susceptibility to rapid deterioration. In this group, those with the following characteristics have a higher tendency to develop hypotension:

The risk of toxic shock syndrome is increased especially in children with erythroderma and fever who have the following additional features: age of 3 years or younger, ill appearance, elevated creatinine value, and hypotension upon arrival.

The disease course is gradual if it results from generalized spread of a primary skin disease (eg, psoriasis, atopic dermatitis).

The mean duration of illness typically is 5 years, with a median of 10 months.

Mortality varies according to the disease's cause. In a study of 91 of 102 patients with exfoliative dermatitis by Sigurdsson et al,[43] a mortality of 43% was observed. Only 18% of the deaths were directly related to exfoliative dermatitis. In 74% of the deaths, causes unrelated to exfoliative dermatitis were implicated.

Patient Education

Educate patients on the specifics of the underlying cause of their exfoliative dermatitis and the importance of diligent follow-up management as indicated. Patients should be educated on the benefits of a healthy lifestyle and to immediately treat occurrences of erythroderma to better manage their diseases in the long term. Patients should be advised to avoid the use of and/or contact with of irritant soaps, lotions, detergents, and chlorine, and special considerations should be made for allergies, especially for patients with atopic dermatitis.[44]  Excessive sweating should also be avoided.

For patient education resources, see Skin Conditions & Beauty Center and Life-Threatening Skin Rashes

History

History is the most important aid in diagnosing exfoliative dermatitis.[45] Patients may have a history of the primary disease (eg, psoriasis, atopic dermatitis). Elicit a comprehensive drug history, including over-the-counter drugs.

Disease usually evolves rapidly when it results from drug allergens, lymphoma, leukemia, or staphylococcal scalded skin syndrome. Disease evolution is more gradual when it results from psoriasis, atopic dermatitis, or the spread of primary disease.

Pruritus is a prominent and frequent symptom. Malaise, fever, and chills may occur.

Physical Examination

Patients often present with generalized erythema. Scaling appears 2-6 days after the onset of erythema, usually starting from flexural areas. Pruritus commonly results in excoriations. When exfoliative dermatitis persists for weeks, hair may shed; nails may become ridged and thickened and also may shed. Periorbital skin may be inflamed and edematous, resulting in ectropion (with consequent epiphora).

In chronic cases, pigmentary disturbances can occur (especially in darker-skinned races); patchy or widespread loss of pigment (resembling vitiligo) has been reported.

Diligent search for residual signs of underlying disease occasionally yields dividends. Residual signs may include the following:

Dermatopathic lymphadenopathy can occur in exfoliative dermatitis not caused by lymphoma or leukemia. A lymph node biopsy is advised when lymph nodes exhibit lymphomatous characteristics (eg, large size, rubbery consistency) and the cause of exfoliative dermatitis is undetermined.

The general picture is modified according to the nature of the underlying disease and the patient's general physical condition.

Complications

Complications in exfoliative dermatitis depend on underlying disease. Secondary infection, dehydration, electrolyte imbalance, temperature dysregulation, and high-output cardiac failure are potential complications in all cases.

Laboratory Studies

Increased erythrocyte sedimentation rate, anemia, hypoalbuminemia, and hyperglobulinemia are frequent findings.

Byer and Bachur[42]  report that the levels of glucose, calcium, and creatinine and the platelet and polymorphonuclear leukocyte counts are of prognostic significance in children who present with erythroderma and fever.

A clinical diagnosis is made for psoriasis, as there is no consensus on diagnostic criteria and tests.

Increased immunoglobulin E (IgE) may be observed in exfoliative dermatitis when caused by atopic dermatitis.

Peripheral blood smears and bone marrow examination may be useful in a leukemia workup.

Immunophenotyping, flow cytometry, and particularly, B- and T-cell gene rearrangement analysis may be helpful in confirming the diagnosis if lymphoma is strongly suspected. High-scatter T cells are a biomarker for cutaneous T-cell lymphoma (CTCL),[47]  and high throughput T-cell receptor sequencing is helpful for diagnosis.[48]

Skin scrapings may reveal hyphae or scabies mites.

Cultures may show bacterial overgrowth or the herpes simplex virus.

Perform HIV testing in the right setting; use polymerase chain reaction for viral detection, rather than enzyme-linked immunoassay, since exfoliative dermatitis has been reported to predict seroconversion in HIV infection. CD8 T-cell infiltration of the skin has been observed in patients with HIV infection and severe erythroderma.[49]

In a report by Griffiths et al,[50] decreased CD4+ T-cell count was observed in patients with exfoliative dermatitis in the absence of HIV disease.

Imaging Studies

Pursue further tests (eg, positron emission tomography [PET], computed tomography [CT], magnetic resonance imaging [MRI], chest radiography, mammography) if the clinical features so indicate. Fluorescence diagnosis can be helpful in assessing the response to therapy in patients with mycosis fungoides.[51]

Other Tests

If the cause of exfoliative dermatitis is in doubt, survey patients for occult tumors or cancers. Perform chest radiography and routine cancer screenings appropriate for age and sex (eg, mammography, stool occult blood test, sigmoidoscopy, prostate examination, serum prostate specific antigen level, cervical smear).

Patch testing can be performed to unveil contact allergens but should be performed only during periods of remission. In the patch test, include systemic drugs the patient was taking prior to the onset of exfoliative dermatitis.

Direct immunofluorescence studies diagnosed at least two reported cases of pemphigoid erythroderma, according to Scrivener et al.[52]  TP53 mutations have been noted in Sézary syndrome and erythrodermic mycosis fungoides.[53]

Procedures

Skin biopsies reveal nonspecific findings of spongiotic dermatitis; however, primary disease may be evident.

Histologic Findings

The appearance of exfoliative dermatitis usually masks the underlying disease's specific histologic features. The most common histopathologic appearance is of either subacute or chronic dermatitis; however, biopsy is indicated, since diagnostic findings are present in 40-60% of cases.[54]

A search for the underlying cause is necessary because of possible prognostic and therapeutic implications. Detailed histopathologic analysis with clinicopathologic correlation is mandatory in the remaining cases for which a specific cause is not apparent. Often, repeated biopsies and hematologic studies may be necessary to detect specific conditions (eg, CTCL).[55]

Repeated biopsies have been reported to result in a diagnosis in 50% of cases that do not reveal specific findings initially.

Approach Considerations

Patients presenting acutely with exfoliative dermatitis often require admission for inpatient management because their total body functions (including intake and output) can require monitoring. Hospital admission should be seriously considered in pediatric patients who present with erythroderma and fever because this presentation is a predictor of hypotension and even toxic shock syndrome.

The principle of management is to maintain skin moisture, avoid scratching, avoid precipitating factors, apply topical steroids, and treat the underlying cause and complications. Exfoliative dermatitis commonly resists therapy until the underlying disease is treated (eg, phototherapy, systemic medications in psoriasis). Outcome is unpredictable in idiopathic exfoliative dermatitis.[56]  The course is marked by multiple exacerbations, and prolonged glucocorticoid therapy often is needed.

Medical Care

Topical steroids are the primary category of medications used to treat exfoliative dermatitis. A sedative antihistamine may be a useful adjunct for pruritic patients, since it helps patients to sleep at night, thus limiting nocturnal scratching and excoriations. Antimicrobial agents often are used if an infection is suspected to be precipitating or complicating exfoliative dermatitis. Biologics are the most rapidly growing treatment option, with their use most common in psoriasis. Other drugs specifically indicated for management of underlying etiology of exfoliative dermatitis may be necessary.

Discontinue all unnecessary medications. Carefully monitor and control fluid intake, because patients can dehydrate or go into cardiac failure; monitor body temperature, because patients may become hypothermic.

Apply tap water–wet dressings (made from heavy mesh gauze); change every 2-3 hours. Apply intermediate-strength topical steroids (eg, triamcinolone cream 0.025-0.5%) beneath wet dressings. Suggest a tepid bath (as it may be comforting) once or more daily between dressing changes. Reduce frequency of dressings and gradually introduce emollients between dressing applications as exfoliative dermatitis improves.

Institute systemic antibiotics if signs of secondary infection are observed. Antihistamines help reduce pruritus and provide needed sedation.

Systemic steroids may be helpful in some cases but should be avoided in suspected cases of psoriasis and staphylococcal scalded skin syndrome.

Increased capillary permeability occasionally is severe enough to justify plasma infusion.

Preexisting malnutrition may become more marked and require nutritional intervention in older patients.

Traditionally, topical corticosteroids under moist occlusion and phototherapy have been used to manage psoriatic erythroderma.[57] Five biologic agents have been approved for the treatment of psoriasis in the United States: infliximab, adalimumab, etanercept, ustekinumab,[58] and secukinumab[59] ; however, their high costs have been a deterrent to widespread use.

Secukinumab has shown efficacy in treating severe refractory erythrodermic psoriasis.[60] Ustekinumab and secukinumab may be particularly effective in patients with overlapping features of psoriasis and pityriasis rubra pilaris.[61] At least some of these patients have CARD14 mutations.

Small-molecule agents are emerging as a lower-cost therapeutic alternative.[62] According to the Medical Board of the National Psoriasis Foundation, cyclosporine[63] and infliximab appear to be the most effective first-line treatments; other more slowly working, but still effective, therapies are acitretin and methotrexate.[64] For secondary treatment options, the Board recommended etanercept and combination therapy.[65]

The treatment of mycosis fungoides is determined by the staging of the disease. For early refractory mycosis fungoides, skin-directed therapies are the first line of treatment and include topical corticosteroids, topical chemotherapy, topical retinoids, phototherapy, and radiotherapy.[66] In aggressive or advanced-stage disease, systemic therapy is applied, including interferon, oral retinoids,[67, 68] histone deacetylase inhibitors, monoclonal antibodies,[69] extracorporeal photopheresis,[70] and single- and multi-agent chemotherapy. In a select patient population with advanced mycosis fungoides, allogeneic stem cell transplantation has been beneficial.[71]

Although combination therapy for advanced-stage mycosis fungoides has been frequently reported, Humme et al[72] found that no combination therapy was more effective than monotherapy in their systematic review. Chemotherapy has been found to have only modest efficacy,[73] and biologic agents and histone deacetylase inhibitors have shown better survival rates than multiagent chemotherapy (2.5 y vs 9 mo).[62]  Histone deacetylase inhibitors were developed to inhibit the dysregulation of histone deacetylase enzymes that causes epigenetic changes and contributes to cancer development.[74, 75, 76]

Atopic dermatitis, despite being the most common dermatologic condition among the causes of erythroderma, has no specific targeted treatment options.[77]  Therapy is based on avoiding allergens, and emollients and topical and systemic immunosuppressants are used with varying efficacy. There are no approved biologics for atopic dermatitis, mainly owing to their toxicity, contradictory outcomes, and high costs.[44] Oral immunotherapy is an emerging therapy for a select patient population.

Appropriate in/outpatient medications are influenced by the underlying etiology of exfoliative dermatitis. For example, prednisone may be contraindicated in exfoliative dermatitis secondary to psoriasis, whereas retinoids are an excellent choice for this disease. In patients with mycosis fungoides, who receive a differential diagnosis of psoriasis, special attention must be made prior to prescribing tumor necrosis factor (TNF)-α inhibitors, given that they might cause mycosis fungoides to progress.[78]

Diet

Ensure adequate nutrition with an emphasis on protein intake; exfoliative dermatitis patients lose a great deal of protein through excessive desquamation and show a tendency toward hypoalbuminemia. Alter diet as necessary if ingestion of a certain food group is suspected as the etiology of exfoliative dermatitis.

Activity

Patient activity may be engaged in as tolerated.

Prevention

Prevention of exfoliative dermatitis depends on adequate control of underlying etiology. For example, gentle skin care is key to preventing exfoliative dermatitis flareups in atopic dermatitis, and specific treatments for psoriasis should be adhered to when it is the underlying cause.

Consultations

Consult a dermatologist for all cases of exfoliative dermatitis.

Long-Term Monitoring

Follow patients discharged from the hospital on an outpatient basis for continued management of underlying disease.

Closely follow patients with no discernible underlying disease (idiopathic exfoliative dermatitis) using multiple serial biopsies to exclude cutaneous T-cell lymphoma (CTCL). Because low-dose methotrexate has been shown to be efficacious in the management of erythrodermic CTCL (as reported by Zackheim et al[79] ), some have advocated the use of methotrexate between rebiopsy periods in patients with idiopathic exfoliative dermatitis that is unremitting despite the use of topical steroids.

Such an approach, however, should be taken with the understanding that CTCL develops only in a minority of patients with idiopathic exfoliative dermatitis (7%), especially in the subgroup with persistent chronic disease on long-term follow-up care (as reported by Sigurdsson et al[80] ), and that methotrexate is associated with many adverse effects, including toxicities of the liver, lungs, and bone marrow.

The widespread use of biologics has been deterred not only by the high cost of these agents but also by fear of an increased risk of new or recurrent malignancies in patients with psoriasis, though this fear is not supported by the currently available evidence.[81]  However TNF-α inhibitors and monoclonal antibodies can cause the formation of antidrug antibodies (ADAs) that affect the clinical response, with ADAs reported in 0-44.8% of patients.[82]

Triamcinolone topical (Kenalog Orabase, Kenalog topical, Pediaderm TA)

Clinical Context: 

Hydroxyzine (Vistaril)

Clinical Context: 

Cyclosporine (Gengraf, Neoral, Sandimmune)

Clinical Context: 

Bexarotene (Targretin)

Clinical Context: 

Vorinostat (Zolinza)

Clinical Context: 

Romidepsin (Istodax)

Clinical Context: 

Belinostat (Beleodaq)

Clinical Context: 

Etanercept (Enbrel, Erelzi, Etanercept-szzs)

Clinical Context: 

Adalimumab (Abrilada, Adalimumab-aacf, Adalimumab-adaz)

Clinical Context: 

Ustekinumab (Imuldosa, Otulfi, Pyzchiva)

Clinical Context: 

Secukinumab (Cosentyx)

Clinical Context: 

Infliximab (Avsola, Inflectra, Infliximab-abda)

Clinical Context: 

What is exfoliative dermatitis (ED)?What is the pathophysiology of exfoliative dermatitis (ED)?Which cutaneous and associated systemic diseases cause exfoliative dermatitis (ED)?What are the most common causes of exfoliative dermatitis (ED)?Which drugs have been implicated in the etiology of exfoliative dermatitis (ED)?What are the demographics of exfoliative dermatitis (ED)?What is the prognosis of exfoliative dermatitis (ED)?What information should be provided in the patient education on exfoliative dermatitis (ED)?What is the clinical history of exfoliative dermatitis (ED)?What are the physical findings in exfoliative dermatitis (ED)?What are the complications of exfoliative dermatitis (ED)?What are the differential diagnoses for Erythroderma (Generalized Exfoliative Dermatitis)?Which lab studies are indicated in the workup of exfoliative dermatitis (ED)?When are imaging studies indicated in the workup of exfoliative dermatitis (ED)?What other studies are indicated in the workup of exfoliative dermatitis (ED)?What does a skin biopsy contribute to the workup of exfoliative dermatitis (ED)?What are the histologic findings of exfoliative dermatitis (ED)?How is exfoliative dermatitis (ED) treated?What is the medical care for exfoliative dermatitis (ED)?Which biologic agents are available for the treatment for exfoliative dermatitis (ED)?What is the treatment for mycosis fungoides relative to exfoliative dermatitis (ED)?What is the treatment of atopic dermatitis relative to exfoliative dermatitis (ED)?Which medications are used for the treatment of exfoliative dermatitis (ED)?What dietary recommendations are indicated in the treatment of exfoliative dermatitis (ED)?What activity restrictions are indicated in the treatment of exfoliative dermatitis (ED)?How is exfoliative dermatitis (ED) prevented?Which specialist consultations are indicated in the treatment of exfoliative dermatitis (ED)?What is involved in long-term monitoring of patients with exfoliative dermatitis (ED)?Which medications are used to treat exfoliative dermatitis (ED)?Which medications in the drug class Immunosuppressants are used in the treatment of Erythroderma (Generalized Exfoliative Dermatitis)?Which medications in the drug class Antineoplastics, HDAC Inhibitors are used in the treatment of Erythroderma (Generalized Exfoliative Dermatitis)?Which medications in the drug class Antineoplastics, Retinoids are used in the treatment of Erythroderma (Generalized Exfoliative Dermatitis)?Which medications in the drug class Calcineurin Inhibitors are used in the treatment of Erythroderma (Generalized Exfoliative Dermatitis)?Which medications in the drug class Antihistamines, 1st Generation are used in the treatment of Erythroderma (Generalized Exfoliative Dermatitis)?Which medications in the drug class Corticosteroids, Topical are used in the treatment of Erythroderma (Generalized Exfoliative Dermatitis)?

Author

Edward J Zabawski, Jr, DO, MBA, Adjunct Assistant Professor, Clinical Sciences

Disclosure: Nothing to disclose.

Specialty Editors

Rosalie Elenitsas, MD, Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

A Paul Kelly, MD, Chief, Clinical Professor, Department of Internal Medicine, Division of Dermatology, King/Drew Medical Center, Charles Drew University of Medicine and Science

Disclosure: Nothing to disclose.

James W Patterson, MD, Professor of Pathology and Dermatology, Director of Dermatopathology, University of Virginia Medical Center

Disclosure: Nothing to disclose.

Sanusi H Umar, MD, FAAD, Clinical Instructor of Medicine, Department of Medicine, Division of Dermatology, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

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Exfoliative dermatitis diffuse skin involvement.

Exfoliative dermatitis close-up view showing erythema and scaling.

Exfoliative dermatitis diffuse skin involvement.

Exfoliative dermatitis close-up view showing erythema and scaling.

99mTC-sestamibi[11] ACE inhibitorsAllopurinolAminoglutethimideAmiodarone
AmitriptylineAmoxicillinAmpicillinAngiogenetic inhibitors[12] Arsenic
AspirinAtropineAuranofinAurothioglucoseBarbiturates
BenactyzineBeta-blockersBeta caroteneBumetanideBupropion
ButabarbitalButalbitalCaptoprilCarbamazepineCarbidopa
Cephalosporins[13] ChloroquineChlorpromazineChlorpropamideCimetidine
CiprofloxacinCisplatinClofarabine[14] ClofazimineClofibrate
Co-trimoxazoleCromolynCytarabineDapsoneDemeclocycline
DesipramineDiazepamDiclofenacDiflunisalDiltiazem
DoxorubicinDoxycyclineEfavirenz[15] EnalaprilEscitalopram[16]
Esomeprazole[17] Ethambutol[18] EtodolacFenofibrate[19] Fenoprofen
FluconazoleFluindione[20] Fluoxetine[21] FluphenazineFlurbiprofen
FurosemideGemfibrozilGliclazide[22, 1] Glipizide[23] Gold
GriseofulvinHydroxychloroquineImatinib[24, 25] ImipramineIndomethacin
Intravenous immunoglobulin[26] Intravesical mitomycin C[27] Iodixanol[28] IsoniazidIsosorbide
KetoconazoleKetoprofenKetorolacLeflunomide[29] Lithium
MeclofenamateMefenamic AcidMeprobamateMethylphenidate
Midodrine[30] MinocyclineMorphine sulfate[31] Nalidixic AcidNaproxen
Nevirapine[32] Nitrazepam[23] NifedipineNitrofurantoinNitroglycerin
NizatidineNorfloxacinOmeprazolePantoprazole[33] Penicillamine
PenicillinPentobarbitalPerphenazinePhenobarbitalPhenothiazines
PhenylbutazonePhenytoinPiroxicamPrimidoneProchlorperazine
PropranololPyrazinamide[18] PyrazolonesQuinaprilQuinidine
QuinineRetinoidsRifampinSorafenib[34] Streptomycin
Strontium ranelate[35] SulfadoxineSulfamethoxazoleSulfasalazineSulfisoxazole
SulfonamidesSulfonylureasSulindacTerbinafine[36] Tetracycline
TobramycinTocilizumab[37] TrazodoneTrifluoperazineTrimethoprim
VancomycinVerapamilWarfarin[38]