The pipeline for drugs for control and elimination of neglected tropical diseases: 2. Oral anti-infective drugs and drug combinations for off-label use.

In its 'Road map for neglected tropical diseases 2021-2030', the World Health Organization outlined its targets for control and elimination of neglected tropical diseases (NTDs) and research needed to achieve them. For many NTDs, this includes research for new treatment options for case management and/or preventive chemotherapy. Our review of small-molecule anti-infective drugs recently approved by a stringent regulatory authority (SRA) or in at least Phase 2 clinical development for regulatory approval showed that this pipeline cannot deliver all new treatments needed. WHO guidelines and country policies show that drugs may be recommended for control and elimination for NTDs for which they are not SRA approved (i.e. for 'off-label' use) if efficacy and safety data for the relevant NTD are considered sufficient by WHO and country authorities. Here, we are providing an overview of clinical research in the past 10 years evaluating the anti-infective efficacy of oral small-molecule drugs for NTD(s) for which they are neither SRA approved, nor included in current WHO strategies nor, considering the research sponsors, likely to be registered with a SRA for that NTD, if found to be effective and safe. No such research has been done for yaws, guinea worm, Trypanosoma brucei gambiense human African trypanosomiasis (HAT), rabies, trachoma, visceral leishmaniasis, mycetoma, T. b. rhodesiense HAT, echinococcosis, taeniasis/cysticercosis or scabies. Oral drugs evaluated include sparfloxacin and acedapsone for leprosy; rifampicin, rifapentin and moxifloxacin for onchocerciasis; imatinib and levamisole for loiasis; itraconazole, fluconazole, ketoconazole, posaconazole, ravuconazole and disulfiram for Chagas disease, doxycycline and rifampicin for lymphatic filariasis; arterolane, piperaquine, artesunate, artemether, lumefantrine and mefloquine for schistosomiasis; ivermectin, tribendimidine, pyrantel, oxantel and nitazoxanide for soil-transmitted helminths including strongyloidiasis; chloroquine, ivermectin, balapiravir, ribavirin, celgosivir, UV-4B, ivermectin and doxycycline for dengue; streptomycin, amoxicillin, clavulanate for Buruli ulcer; fluconazole and isavuconazonium for mycoses; clarithromycin and dapsone for cutaneous leishmaniasis; and tribendimidine, albendazole, mebendazole and nitazoxanide for foodborne trematodiasis. Additional paths to identification of new treatment options are needed. One promising path is exploitation of the worldwide experience with 'off-label' treatment of diseases with insufficient treatment options as pursued by the 'CURE ID' initiative.

Indications for Rituximab Use in an Integrated Health Care Delivery System.

BACKGROUND: Rituximab is a top-selling biologic that was first approved by the FDA in 1997 for a non-Hodgkin lymphoma orphan indication. It has since been approved for additional orphan indications, with rheumatoid arthritis as the only FDA-approved, nonorphan indication. Evidence suggests that rituximab is frequently used off-label, but information on its use over time and indications for use in the United States is limited. OBJECTIVE: To assess incident rituximab use over time in an integrated health care delivery system. METHODS: This was a cross-sectional, retrospective study. Data were collected from administrative databases and manual chart reviews. Patients who received their first rituximab infusion between October 1, 2009, and December 31, 2017, and who were not a part of a clinical trial were included. Indication for use (FDA-approved orphan/nonorphan, off-label) was determined. Proportions of use were assessed over time. Multivariable logistic regression modeling was performed to assess factors associated with receiving rituximab for an FDA-approved indication. RESULTS: A total of 1,674 patients were included. The majority (66.4%) of patients had an FDA-approved indication, with lymphoma being the most common approved indication (66.4%). The most common indication for off-label use was neurologic conditions (72.7%), predominantly demyelinating diseases. Off-label indication use increased from 1.2% in 2009 to 55.6% in 2017. Factors associated with rituximab use for an FDA-approved indication included increased age (adjusted odds ratio [AOR] = 1.05, 95% CI = 1.04-1.07) and increased burden of chronic disease (chronic disease score: AOR = 1.07, 95% CI = 1.02-1.12; Charlson Comorbidity Index score: AOR = 3.52, 95% CI = 3.03-4.10). CONCLUSIONS: Off-label use of rituximab grew dramatically over the course of the study. With the recent FDA approval of the rituximab biosimilar and its expected lower price, off-label use will likely continue to rise. Opportunities for cost savings and to ensure appropriate use of these medications should be evaluated. DISCLOSURES: This study was funded by Kaiser Permanente. All authors except Hansen are employed by Kaiser Permanente. Hansen has nothing to disclose. Preliminary results were presented at the Mountain States Conference for Residents and Preceptors in May 2019 in Salt Lake City, UT, and at an encore presentation October 2019 at the American College of Clinical Pharmacy Annual Meeting in New York, NY.

Update on the use of dapsone in dermatology.

Dapsone (4,4'-diaminodiphenylsulfone) is the only remaining sulfone used in anthropoid therapeutics and is commercially available as an oral formulation, an inhaled preparation, and a 5% or 7.5% cream. Dapsone has antimicrobial effects stemming from its sulfonamide-like ability to inhibit the synthesis of dihydrofolic acid. It also has anti-inflammatory properties such as inhibiting the production of reactive oxygen species, reducing the effect of eosinophil peroxidase on mast cells and down-regulating neutrophil-mediated inflammatory responses. This allows for its use in the treatment of a wide variety of inflammatory and infectious skin conditions. Currently in dermatology, the US Food and Drug Administration (FDA)-approved indications for dapsone are leprosy, dermatitis herpetiformis, and acne vulgaris. However, it proved itself as an adjunctive therapeutic agent to many other skin disorders. In this review, we discuss existing evidence on the mechanisms of action of dapsone, its FDA-approved indications, off-label uses, and side effects.

Clinical use and control of the dispensing of thalidomide in Brasilia-Federal District, Brazil, from 2001 to 2012.

The use of thalidomide was never discontinued in Brazil where it is prescribed for leprosy type 2 reaction. Babies with birth defects compatible with the thalidomide embryopathy phenotype were born after 1965, an indication that control on drug dispensing and use failed in the country. The article reports data on thalidomide dispensing and clinical uses in the Federal District in 2011/12, when new rules were put into effect, and data on drug dispensing and use obtained ten years earlier. It was found that the number of patients making use of thalidomide declined from 819 in 2001 to 369 in 2011/12. Leprosy accounted for over 70% of prescriptions in both time periods analyzed in this study. In the same time interval, however, use for lupus erythematosus decreased from 13.7 to 4.9%, while that for multiple myeloma increased from 2.9 to 20.3% of all prescriptions. Thalidomide prescription for the remaining approved indications was far less frequent, and so was the use for off label indications that accounted for <1% of prescriptions in 2001 and 2011/12. Registration of prescribing doctors, patients and dispensing units at the state department of health, apparently rendered this control more effective and reliable.

Clinical use and control of the dispensing of thalidomide in Brasilia-Federal District, Brazil, from 2001 to 2012 / Uso clínico e controle sobre a dispensação de talidomida em Brasília-DF, Brasil, de 2001 a 2012

The use of thalidomide was never discontinued in Brazil where it is prescribed for leprosy type 2 reaction. Babies with birth defects compatible with the thalidomide embryopathy phenotype were born after 1965, an indication that control on drug dispensing and use failed in the country. The article reports data on thalidomide dispensing and clinical uses in the Federal District in 2011/12, when new rules were put into effect, and data on drug dispensing and use obtained ten years earlier. It was found that the number of patients making use of thalidomide declined from 819 in 2001 to 369 in 2011/12. Leprosy accounted for over 70% of prescriptions in both time periods analyzed in this study. In the same time interval, however, use for lupus erythematosus decreased from 13.7 to 4.9%, while that for multiple myeloma increased from 2.9 to 20.3% of all prescriptions. Thalidomide prescription for the remaining approved indications was far less frequent, and so was the use for off label indications that accounted for <1% of prescriptions in 2001 and 2011/12. Registration of prescribing doctors, patients and dispensing units at the state department of health, apparently rendered this control more effective and reliable.

O uso da talidomida nunca foi interrompido no Brasil, sendo prescrita para tratar a reação tipo 2 da hanseníase. Crianças com defeitos congênitos compatíveis com o fenótipo da embriopatia causada pela talidomida nasceram após 1965, evidenciando que o controle do uso e da dispensação do medicamento falhou no país. O artigo relata dados sobre a dispensação e usos clínicos da talidomida no Distrito Federal em 2011/12, quando a nova regulamentação passou a vigorar, e dados sobre a dispensação e uso do medicamento 10 anos antes. Os resultados mostraram que o número de pacientes que usaram talidomida decresceu de 819 em 2001 para 369 em 2011/12. A hanseníase foi a indicação clínica para mais de 70% das prescrições nos períodos analisados no estudo. No mesmo período, entretanto, o uso para lupus eritematoso reduziu de 13,7 para 4,9%, enquanto o uso para mieloma múltiplo cresceu de 2.9 para 20,3% de todas as prescrições. A prescrição de talidomida para as outras indicações aprovadas foi muito menor, enquanto para indicações não aprovadas correspondeu a < 1% das prescrições em 2001 e 2011/12. O cadastro dos prescritores, pacientes e unidades dispensadoras na secretaria estadual de saúde, aparentemente tornou esse controle mais eficiente e confiável.

Off-label use of azathioprine in dermatology: a systematic review.

OBJECTIVE: To summarize evidence regarding the effectiveness, efficacy, and safety of off-label azathioprine use in dermatology. DATA SOURCES: We searched the MEDLINE (1950-2009), EMBASE (1980-2009), and CENTRAL (1996-2009) databases on October 9, 2009. The main search terms were azathioprine and its synonyms. No restrictions were imposed regarding publication date. Only articles in English, French, German, or Dutch were included. STUDY SELECTION: Randomized controlled trials, cohorts, and case series concerning the use of azathioprine in an off-label dermatologic setting were independently assessed for eligibility by 2 coauthors. The search retrieved 3870 articles, and 148 articles were selected for detailed review. DATA EXTRACTION: Forty-three articles matching the inclusion and exclusion criteria were reviewed for methodologic quality by 2 reviewers independently, including an evaluation of components associated with biased estimates of treatment effect. DATA SYNTHESIS: High-quality evidence (level A) was found for a moderate therapeutic effect in severe atopic dermatitis. Evidence of moderate quality (level B) was found for efficacy in parthenium dermatitis (an airborne plant allergen contact dermatitis), bullous pemphigoid, chronic actinic dermatitis, and leprosy type 1 reaction. Furthermore, favorable therapeutic effects existed for erythema multiforme, lichen planus, and pityriasis rubra pilaris, although the quality of evidence was low (level C). CONCLUSIONS: A strong clinical recommendation was given for azathioprine in atopic dermatitis. Conclusions regarding safety in an off-label setting could not be reached because of scarce and incomplete data (level C evidence). Long-term registries and prospective studies could add to the existing evidence and provide legal support for off-label drug use in dermatology.

Innovative uses of thalidomide.

Thalidomide is approved for treating erythema nodosum leprosum and multiple myeloma, but it has also emerged as a useful treatment option for many refractory dermatologic disorders. Some of the innovative but off-label uses of thalidomide include aphthous stomatitis, Behçet's disease, lupus erythematosus, prurigo nodularis, sarcoidosis, actinic prurigo, graft-versus-host disease, Langerhans cell histiocytosis, erythema multiforme, lichen planus, Kaposi sarcoma, Jessner lymphocytic infiltrate, uremic pruritus, pyoderma gangrenosum, scleroderma, scleromyxedema, and necrobiosis lipoidica. This article reviews the background, pharmacology, and innovative uses of thalidomide in dermatology.