DAPSONE drug uses, mechanism and review dermatology

Dapsone introduction, mechanism of action, indications, adverse effects and contraindications

1. DAPSONE REVIEW PRESENTER : Dr. Niharikaa J, 3 rd yr PG MODERATOR : Dr. Manobalan.K , Associate Professor- DVL

2. 4,4’-diaminodi- phenyl sulfone

3. ABSORBTION AND BIOAVAILABILITY Lipid soluble, well absorbed(70-80%) orally. Peak conc - 2hrs to 8hrs, 70% plasma protein bound. Crosses placenta (no harmful effects demonstrated yet) & excreted into breast milk. Long elimination half-life has shown to be average between 24 and 36 hrs - Remains in circulation for 30 days even after single oral dose.

4. MECHANISM OF ACTION

5. Pteridine phosphate + PABA Dihydropteroate Tetrahydrofolate Thymidylate, nucleic acid, amino acids Dihydropteroate synthase Glutamate Dihydrofolate Dihydrofolate reductase D a p s o n e

6. METABOLISM AND EXCRETION

7. INDICATIONS FDA approved indications : - Acne vulgaris - Dermatitis herpetiformis - Leprosy Off-label dermatologic indications (consistent efficacy) : - Linear IgA dermatosis - Bullous eruption of SLE - Leprosy - Erythema elevatum diutinum

8. Other (Variable efficacy) Autoimmune bullous dermatoses – B P , P V / PF , Cicatricial pemphigoid, Subcorneal pustular dermatosis(IgA pemphigus). Vasculitis – Cutaneous vasculitis, Urticarial vasculitis. Neutrophilic dermatoses – Acute febrile neutrophilic dermatosis, Pyoderma gangrenosum, Behcet syn./Aphthous stomatitis. Other – Subacute cutaneous LE , relapsing polychondritis , Granuloma annulare, Brown recluse spider bites, Granuloma faciale , Rosacea, panniculitis, Pustular psoriasis, Amyopathic dermatomyositis, Nodulocystic acne.

9. DAPSONE AND LEPROSY Used in multidrug regimens of fixed duration. Competes with para-aminobenzoic acid and inhibits folic acid synthesis Dosage: Adult Bw upto 35kg- 50mg daily and above 35kg- 100mg daily G6PD deficiency- start at 25mg twice weekly, increase every 3-4 weeks to 50-100 mg daily.

10. For MB leprosy , dapsone is given for 12 months. For PB leprosy , dapsone is given for 6 months . Children under ten years of age should receive appropriately reduced doses of dapsone at 2 mg/kg body weight per day. Used in pregnancy and Lactation Dapsone should be avoided in infants at risk for G6PD deficiency Dapsone monotherapy – apparent clinical response and complete killing 3- 6 months, Rate of killing 0.6- 1 log unit/year

11. DERMATITIS HERPETIFORMIS Only FDA- approved drug for treating DH during the 6 to 24 month s period until the gluten free diet is effective Effective in 24 to 36 hrs from initiation. Starting dose - 50 mg/day to minimize potential side effects. Gradually increased up to 200 mg/day until disease is controlled Maintenance dose - 0.5–1 mg/kg/day to control itching and prevent development of new skin lesions Dapsone is not indicated in the paediatric patient for this condition

12. ACNE VULGARIS FDA approval in 2008 - Topical dapsone 5% gel FDA approved IN 2017 - Topical dapsone 7.5% gel Highly effective in treatment of adult female acne S/E: G6PD methemoglobinemia- FDA changed label in July 2015 to “caution of use” Systemic dapsone - effective and safe alternative to isotretinoin in severe acne vulgaris recalcitrant to other topical or systemic drugs

13. ROSACEA Combining topical treatments with oral antibiotics (minocycline/ doxycycline/erythromycin etc.)  Treat papulopustular variants of rosacea 7.5% gel once/day daily X 12 weeks Systemic administration of dapsone - shown success in treating granulomatous rosacea and rosacea fulminans

14. NEUTROPHILIC DISEASES MOA - Inhibiting beta- 2 integrin- mediated adherence of neutrophils downregulation of IL- 8 Neutrophilic dermatoses: Sweet’s syndrome, recurrent neutrophilic dermatosis of the dorsal hands, Pyoderma gangrenosum Partial- to- complete remission in patients with pyoderma gangrenosum (PG) treated with systemic corticosteroids + other therapies, including dapsone and systemic immunosuppressants (cyclosporin, cyclophosphamide etc.) Used as a 2 nd line drug

15. EOSINOPHILIC DISEASES Inhibitory effect of dapsone on eosinophil peroxidase Chronic idiopathic urticaria or delayed pressure urticaria (IgE), Eosinophilic fasciitis, and Eosinophilic folliculitis (Ofuji’s disease) - dapsone sensitive entities Dapsone 100 mg/day until remission of lesions usually within 2 weeks of therapy initiation  The dose is reduced by half (50 mg daily) X 6 weeks  50 mg thrice/week.

16. PUSTULAR DISEASES Acropustulosis of infancy Subcorneal pustular dermatosis (Sneddon- Wilkinson) Infantile generalized pustular psoriasis Can give topical or systemic dapsone therapy Erosive pustular dermatosis (EPD)- rare noninfectious disease of the scalp and/or legs of unknown etiology Clinically- mixture of nonspecific superficial erosions with crusts and pustules on atrophic skin Tremendous efficacy of dapsone- orally or topically Oral dapsone 100 mg daily with remarkable clinical improvement after 6 months and a maintenance duration of 3 years with oral dapsone 50 mg

17. VASCULITIS Therapeutic regimen for erythema elevatum diutinum (EED), leukocytoclastic vasculitis, and urticarial vasculitis EED - dapsone 100 mg/day treatment of choice Several studies - Giant cell arteritis (GCA) Dapsone, along with adalimumab - only useful corticoid- sparing agents in treating GCA.

18. BULLOUS DISEASES 50–200 mg/day- remission induction phase and maintenance phase of Pemphigus vulgaris Other bullous disorders - IgA pemphigus, Linear IgA dermatosis, Bullous pemphigoid, Mucous membrane pemphigoid, LPP, Dermatitis herpetiformis, P.Foleaceus and vegetans Dapsone - adjuvant therapeutic regimen for the treatment of pemphigoid gestationis Used postpartum, pregnancy category C in the United States 50–150 mg daily administered orally is recommended with azathioprine and plasmapheresis when systemic corticosteroids are not sufficient

19. MISCELLANEOUS: Brown recluse spider bite( Loxoscelism ) Spider bite causes damage by activating membrane phospholipids Attributed to its antineutrophilic action

20. FORMULATIONS Dapsone is commercially available as: Topical (5% and 7.5% gel) Oral tablets (50,100 mg) Inhaled formulation

21. CONTRAINDICATIONS Contraindications : Hypersensitivity to dapsone or components of formulation Warnings & Precautions : Hematologic : Blood dyscrasias (agranulocytosis, pancytopenia), Hemolytic anemia (G6PD deficiency, ↓ hemoglobin M), Methemoglobin reductase deficiency Neurologic : Peripheral motor neuropathy Hypersensitivity Reactions : Drug hypersensitivity syndrome (DRESS),Serious dermatologic reactions—EM, SJS/TEN, urticarial, etc.,Sulfonamide cross-reaction. Hepatic : Isolated drug-induced liver injury

22. ADVERSE EFFECTS Pharmacologic : Hemolytic anemia, Methemoglobinemia Idiosyncratic : Hematologic, Leukopenia, Agranulocytosis Hepatic : Hepatitis ( transaminase elevations), I M -like syndrome (dapsone hypersensitivity syndrome/DRESS), Cholestatic jaundice, Hypoalbuminemia

23. Cutaneous Hypersensitivity Reactions : Morbilliform eruption ( exanthematous , maculopapular) Exfoliative erythroderma, Toxic epidermal necrolysis. Gastrointestinal : Gastric irritation with nausea Anorexia. Neurologic and Psychiatric : Psychosis, Peripheral neuropathy (predominantly motor effect), woolly head

24. DDS SYNDROME ( SULPHONE SYNDROME) DDS syndrome usually takes the form of DRESS ( drug reaction[ or rash] with eosinophilia and systemic symptoms. HLA-B*1301 and involves a cytotoxic T-cell response. The onset 4–6 weeks of starting therapy but may be delayed up to 6 months.

25. F ever, a morbilliform rash that progresses to exfoliative dermatitis, lymphadenopathy, hepatitis with elevated liver enzymes, peripheral eosinophilia and atypical lymphocytes. If not recognized, the condition deteriorates and there is a significant risk of death. The drug should be withdrawn immediately and cortico- steroids may be of benefit in controlling it.

26. HEMOLYSIS Mild hemolysis with a drop in hemoglobin of 1–2 g/dL occurs in most patients at a standard therapeutic dose. DDS-NHOH - main metabolite responsible for the hematologic toxicity of dapsone. G6PD-antioxidant enzyme – hydroxylamine metabolites which are strong oxidant G6PD deficiency causes hydroxylamine – damages RBC membrane -hemolysis

27. DDS-NHOH can make changes in the erythrocyte membrane proteins causing hemolysis and, when it reacts to hemoglobin in the presence of oxygen, methemoglobin and nitroso-dapsone are produced The oxidized hemoglobin polymerizes to form HEINZ BODIES. Main risk factors for hemolysis are G6PD deficiency, dosage of dapsone and age. Patient presents with fatigue, dyspnoea and weakness , should suspect anemia and confirms with lab diagnosis.

28. AGRANULOCYTOSIS Direct toxic effect of hydroxylated metabolites Occurs within 3-12 weeks of starting therapy Fever, pharyngitis and mouth ulcers Recovers 7-14 days on stopping dapsone (G-CSF) used to speed the recovery of normal granulocyte number

29. METHEMOGLOBINEMIA Formation of it is also related to the N-hydroxy ( hydroxylamine) metabolites of dapsone C/ F:Headache , shortness of breath, lethargy and bluish discolouration of lips and fingertips Treatment : - Cimetidine 400mg three times daily - Vitamin C 500mg oral or IV - Severe cases : IV methylene blue 1% or plasma exchange

30. Methaemoglobin concentration (g/dl) % of total Hb Symptoms <1.5 10% None 1.5- 3.0 10- 20% Cyanotic skin discolouration 3- 4.5 20- 30% Anxiety, light- headedness, headache, tachycardia 4.5- 7.5 30- 50% Fatigue, confusion, dizziness, tachypnoea, tachycardia 7.5- 10.5 50- 70% Coma, seizures, arrythmias, acidosis >10.5 >70% Death

31. PERIPHERAL NEUROPATHY: Primarily a distal motor neuropathy Distal motor weakness of hands and/or legs with wasting of hand muscles Study shows axonal degeneration

32. PREGNANCY AND LACTATION: Category C drug Crosses placenta Excreted in breast milk It can cause hemolytic anaemia in infants breastfeeding from mothers on dapsone.

33. DRUG INTERACTIONS Probenecid- reduces renal excretion of dapsone Rifampicin- decrease the functional half life of dapsone Folate anatagonists-Sulfamethazole (DHPS) cause myelosuppression Potentially significant interactions - when patients on dapsone take other drugs that are also oxidants

34. DRUG CLASS INTERACTION WITH DAPSONE COMBINATION EFFECTS Didanosine Reverse transcriptase inhibitor Increases dapsone toxicity Increases risk of nerve damage Rifampin Antimycobacterial Decreases Dapsone level Alters metabolism of Dapsone Trimethoprim Methotrexate Pyrimidine inhibitor of DHFR Increase in Dapsone blood level Impairs bone marrow function - haemolysis and methemoglobinemia Griseofulvin A ntifungals Decrease in Dapsone toxicity CYP3A4 inducer

35. MONITORING AND FOLLOW UP

36. Baseline Complete history and physical with emphasis on cardiopulmonary, gastrointestinal, neurologic, and renal systems Lab: CBC, differential count, LFT, RFT, G6PD level, and urinalysis Follow-up CBC with differential every week for four weeks, then every two weeks until week 12, then every 3 to 4 months. Reticulocyte count as needed LFT and RFT every 3 to 4 months Met- hb level as clinically indicated.

37. References Comprehensive Dermatologic Drug Therapy - FOURTH EDITION, Stephen E. Wolverton, MD Ghaoui N, Hanna E, Abbas O, Kibbi AG, Kurban M. Update on the use of dapsone in dermatology. International Journal of Dermatology. 2020

38. THANK YOU