DAPSONE
DESCRIPTION:
Dapsone-USP, 4,4'-diaminodiphenylsulfone (DDS) is a primary treatment for
Dermatitis herpetiformis. It is an antibacterial drug for susceptible cases of
leprosy. It is a white, odorless crystalline powder, practically insoluble in
water and insoluble in fixed and vegetable oils.
Dapsone is issued on prescription in tablets of 25 and 100 mg. for oral use.
Inactive Ingredients: Colloidal silicone dioxide, magnesium stearate,
microcrystalline cellulose, and corn starch.
ACTIONS/CLINICAL PHARMACOLOGY:
ACTIONS: The mechanism of action in Dermatitis herpetiformis has not been
established. By the kinetic method in mice, Dapsone is bactericidal as well as
bacteriostatic against Mycobacterium Leprae.
ABSORPTION AND EXCRETION: Dapsone, when given orally, is rapidly and almost
completely absorbed. About 85 percent of the daily intake is recoverable from
the urine mainly in the form of water-soluble metabolites. Excretion of the drug
is slow and a constant blood level can be maintained with the usual dosage.
BLOOD LEVELS: Detected a few minutes after ingestion, the drug reaches peak
concentration in 4-8 hours. Daily administration for at least eight days is
necessary to achieve a plateau level. With doses of 200 mg. daily, this level
averaged 2.3 mcgm/ml with a range of 0.1-7.0 mcgm/ml. The half-life in the
plasma in different individuals varies from ten hours to fifty hours and
averages twenty-eight hours. Repeat tests in the same individual are constant.
Daily administration (50-100 mg.) in leprosy patients will provide blood levels
in excess of the usual minimum inhibitory concentration even for patients with a
short Dapsone half-life.
INDICATIONS AND USAGE:
Dermatitis herpetiformis: (D.H.)
Leprosy: All forms of leprosy except for cases of proven Dapsone resistance.
CONTRAINDICATIONS:
Hypersensitivity to Dapsone and/or its derivatives.
WARNINGS:
The patient should be warned to respond to the presence of clinical signs such
as sore throat, fever, pallor, purpura or jaundice. Deaths associated with the
administration of Dapsone have been reported from agranulocytosis, aplastic
anemia and other blood dyscrasias. Complete blood counts should be done
frequently in patients receiving Dapsone. The FDA Dermatology Advisory Committee
recommended that, when feasible counts should be done weekly for the first
month, monthly for six months and semi-annually thereafter. If a significant
reduction in leucocytes, platelets or hemopoiesis is noted, Dapsone should be
discontinued and the patient followed intensively. Folic acid antagonists have
similar effects and may increase the incidence of hematologic reactions; if co-
administered with Dapsone the patient should be monitored more frequently.
Patients on weekly Pyrimethamine and Dapsone have developed agranulocytosis
during the second and third month of therapy.
Severe anemia should be treated prior to initiation of therapy and hemoglobin
monitored. Hemolysis and methemoglobin may be poorly tolerated by patients with
severe cardio- pulmonary disease.
Cutaneous reactions, especially bullous, include exfoliative dermatitis and are
probably one of the most serious, though rare, complications of sulfone therapy.
They are directly due to drug sensitization. Such reactions include toxic
erythema, erythema multiforme, toxic epidermal necrolysis, morbilliform and
scarlatiniform reactions, urticaria and erythema nodosum. If new or toxic
dermatologic reactions occur, sulfone therapy must be promptly discontinued and
appropriate therapy instituted.
Leprosy reactional states, including cutaneous, are not hypersensitivity
reactions to Dapsone and do not require discontinuation. See special section.
PRECAUTIONS:
GENERAL: Hemolysis and Heinz body formation may be exaggerated in individuals
with a glucose- 6-phosphate dehydrogenase (G6PD) deficiency, or methemoglobin
reductase deficiency, or hemoglobin M. This reaction is frequently dose-related.
Dapsone should be given with caution to these patients or if the patient is
exposed to other agents or conditions such as infection or diabetic ketosis
capable of producing hemolysis. Drugs or chemicals which have produced
significant hemolysis in G6PD or methemoglobin reductase deficient patients
include Dapsone, sulfanilamide, nitrite, aniline, phenylhydrazine, naphthalene,
niridazole, nitrofurantoin and 8-amino-antimalarials such as primaquine.
Toxic hepatitis and cholestatic jaundice have been reported early in therapy.
Hyperbilirubinemia may occur more often in G6PD deficient patients. When
feasible, baseline and subsequent monitoring of liver function is recommended.
If abnormal, Dapsone should be discontinued until the source of the abnormality
is established.
DRUG INTERACTIONS: Rifampin lowers Dapsone levels 7 to 10-fold by accelerating
plasma clearance; in leprosy this reduction has not required a change in dosage.
Folic acid antagonists such as pyrimethamine may increase the likelihood of
hematologic reactions.
A modest interaction has been reported for patients receiving 100 mg Dapsone od
in combination with trimethoprim 5 mg/kg q6h. On Day 7, the serum Dapsone levels
averaged 2.1 +/- 1.0 mcgm/mL in comparison to 1.5 +/- 0.5 mcgm/mL for Dapsone
alone. On Day 7, trimethoprim levels averaged 18.4 +/- 5.2 mcgm/mL in comparison
to 12.4 +/- 4.5 mcgm/mL for patients not receiving Dapsone. Thus, there is a
mutual interaction between Dapsone and trimethoprim in which each raises the
level of the other about 1.5 times.
CARCINOGENESIS, MUTAGENESIS: Dapsone has been found carcinogenic (sarcomagenic)
for male rats and female mice causing mesenchymal tumors in the spleen and
peritoneum, and thyroid carcinoma in female rats. Dapsone is not mutagenic with
or without microsomal activation in S. Typhimurium tester strains 1535, 1537,
1538, 98, or 100.
PREGNANCY CATEGORY C: Animal reproduction studies have not been conducted with
Dapsone. Extensive, but uncontrolled experience and two published surveys on the
use of Dapsone in pregnant women have not shown that Dapsone increases the risk
of fetal abnormalities if administered during all trimesters of pregnancy or can
affect reproduction capacity. Because of the lack of animal studies or
controlled human experience, Dapsone should be given to a pregnant woman only if
clearly needed. In general, for leprosy, USPHS at Carville recommends
maintenance of Dapsone. Dapsone has been important for the management of some
pregnant D.H. patients.
NURSING MOTHERS: Dapsone is excreted in breast milk in substantial amounts.
Hemolytic reactions can occur in neonates. See section on hemolysis. Because of
the potential for tumorigenicity shown for Dapsone in animal studies a decision
should be made whether to discontinue nursing or discontinue the drug taking
into account the importance of the drug to the mother.
PEDIATRIC USE: Children are treated on the same schedule as adults but with
correspondingly smaller doses. Dapsone is generally not considered to have an
effect on the later growth, development and functional development of the child.
DRUG INTERACTIONS:
Rifampin lowers Dapsone levels 7 to 10-fold by accelerating plasma clearance; in
leprosy this reduction has not required a change in dosage.
Folic acid antagonists such as pyrimethamine may increase the likelihood of
hematologic reactions.
A modest interaction has been reported for patients receiving 100 mg Dapsone od
in combination with trimethoprim 5 mg/kg q6h. On Day 7, the serum Dapsone levels
averaged 2.1 +/- 1.0 mcgm/mL in comparison to 1.5 +/- 0.5 mcgm/mL for Dapsone
alone. On Day 7, trimethoprim levels averaged 18.4 +/- 5.2 mcgm/mL in comparison
to 12.4 +/- 4.5 mcgm/mL for patients not receiving Dapsone. Thus, there is a
mutual interaction between Dapsone and trimethoprim in which each raises the
level of the other about 1.5 times.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
In addition to the warnings listed above, the following syndromes and serious
reactions have been reported in patients on Dapsone.
HEMATOLOGIC EFFECTS: Dose-related hemolysis is the most common adverse effect
and is seen in patients with or without G6PD deficiency. Almost all patients
demonstrate the interrelated changes of a loss of 1-2g of HB, an increase in the
reticulocytes (2-12%), a shortened red cell life span and a rise in
methemoglobin. G6PD deficient patients have greater responses.
NERVOUS SYSTEM EFFECTS: Peripheral neuropathy is a definite but unusual
complication of Dapsone therapy in non-leprosy patients. Motor loss is
predominant. If muscle weakness appears, Dapsone should be withdrawn. Recovery
on withdrawal is usually substantially complete. The mechanism of recovery is
reportedly by axonal regeneration. Some recovered patients have tolerated
retreatment at reduced dosage. In leprosy this complication may be difficult to
distinguish from a leprosy reactional state.
BODY AS A WHOLE: In addition to the warnings and adverse effects reported above,
additional adverse reactions include: nausea, vomiting, abdominal pains,
pancreatitis, vertigo, blurred vision, tinnitus, insomnia, fever, headache,
psychosis, phototoxicity, pulmonary eosinophilia, tachycardia, albuminuria, the
nephrotic syndrome, hypoalbuminemia without proteinuria, renal papillary
necrosis, male infertility, drug- induced Lupus erythematosus and an infectious
mononucleosis-like syndrome. In general, with the exception of the complications
of severe anoxia from overdosage (retinal and optic nerve damage, etc.) these
adverse reactions have regressed off drug.
OVERDOSAGE:
Nausea, vomiting, hyperexcitability can appear a few minutes up to 24 hours
after ingestion of an overdose. Methemoglobin induced depression, convulsions
and severe cyanosis requires prompt treatment. In normal and methemoglobin
reductase deficient patients, methylene blue, 1-2 mg/kg of body weight, given
slowly intravenously is the treatment of choice. The effect is complete in 30
minutes, but may have to be repeated if methemoglobin reaccumulates. For non-
emergencies, if treatment is needed, methylene blue may be given orally in doses
of 3-5 mg/kg every 4-6 hours.
Methylene blue reduction depends on G6PD and should not be given to fully
expressed G6PD deficient patients.
DOSAGE AND ADMINISTRATION:
DERMATITIS HERPETIFORMIS: The dosage should be individually titrated starting in
adults with 50 mg. daily and correspondingly smaller doses in children. If full
control is not achieved within the range of 50-300 mg. daily, higher doses may
be tried. Dosage should be reduced to a minimum maintenance level as soon as
possible. In responsive patients there is a prompt reduction in pruritus
followed by clearance of skin lesions. There is no effect on the gastro-
intestinal component of the disease.
Dapsone levels are influenced by acetylation rates. Patients with high
acetylation rates, or who are receiving treatment affecting acetylation may
require an adjustment in dosage.
A strict gluten free diet is an option for the patient to elect, permitting many
to reduce or eliminate the need for Dapsone; the average time for dosage
reduction is 8 months with a range of 4 months to 2 1/2 years and for dosage
elimination 29 months with a range of 6 months to 9 years.
LEPROSY: In order to reduce secondary Dapsone resistance, the WHO Expert
Committee on Leprosy and the USPHS at Carville, LA, recommend that Dapsone
should be commenced in combination with one or more anti-leprosy drugs. In the
multi-drug program Dapsone should be maintained at the full dosage of 100 mg.
daily without interruption (with correspondingly smaller doses for children) and
provided to all patients who have sensitive organisms with new or recrudescent
disease or who have not yet completed a two year course of Dapsone monotherapy.
For advice and other drugs, the USPHS at Carville, LA, (1 800-642-2477) should
be contacted. Before using other drugs consult appropriate product labeling.
In bacteriologically negative tuberculoid and indeterminate disease, the
recommendation is the coadministration of Dapsone 100 mg. daily with six months
of Rifampin 600 mg. daily. Under WHO, daily Rifampin may be replaced by 600 mg.
Rifampin monthly, if supervised. The Dapsone is continued until all signs of
clinical activity are controlled--usually after an additional six months. Then
Dapsone should be continued for an additional three years for tuberculoid and
indeterminate patients and for five years for borderline tuberculoid patients.
In lepromatous and borderline lepromatous patients, the recommendation is the
coadministration of Dapsone 100 mg. daily with two years of Rifampin 600 mg.
daily. Under WHO, daily Rifampin may be replaced by 600 mg. Rifampin monthly, if
supervised. One may elect the concurrent administration of a third anti- leprosy
drug, usually either Clofazamine 50-100 mg. daily or Ethionamide 250-500 mg.
daily. Dapsone 100 mg. daily is continued 3-10 years until all signs of clinical
activity are controlled with skin scrapings and biopsies negative for one year.
Dapsone should then be continued for an additional 10 years for borderline
patients and for life for lepromatous patients.
Secondary Dapsone resistance should be suspected whenever a lepromatous or
borderline lepromatous patient receiving Dapsone treatment relapses clinically
and bacteriologically, solid staining bacilli being found in the smears taken
from the new active lesions. If such cases show no response to regular and
supervised Dapsone therapy within three to six months or good compliance for the
past 3-6 months can be assured, Dapsone resistance should be considered
confirmed clinically. Determination of drug sensitivity using the mouse footpad
method is recommended and, after prior arrangement, is available without charge
from the USPHS, Carville, LA. Patients with proven Dapsone resistance should be
treated with other drugs.
LEPROSY REACTIONAL STATES
Abrupt changes in clinical activity occur in leprosy with any effective
treatment and are known as reactional states. The majority can be classified
into two groups.
The "Reversal" reaction (Type 1) may occur in borderline or tuberculoid leprosy
patients often soon after chemotherapy is started. The mechanism is presumed to
result from a reduction in the antigenic load: the patient is able to mount an
enhanced delayed hypersensitivity response to residual infection leading to
swelling ("Reversal") of existing skin and nerve lesions. If severe, or if
neuritis is present, large doses of steroids should ALWAYS be used. If severe,
the patient should be hospitalized. In general anti- leprosy treatment is
continued and therapy to suppress the reaction is indicated such as analgesics,
steroids, or surgical decompression of swollen nerve trunks. USPHS at Carville,
LA should be contacted for advice in management.
Erythema nodosum leprosum (ENL) (lepromatous reaction) (Type 2 reaction) occurs
mainly in lepromatous patients and small numbers of borderline patients.
Approximately 50% of treated patients show this reaction in the first year. The
principal clinical features are fever and tender erythematous skin nodules
sometimes associated with malaise, neuritis, orchitis, albuminuria, joint
swelling, iritis, epistaxis or depression. Skin lesions can become pustular
and/or ulcerate. Histologically there is a vasculitis with an intense
polymorphonuclear infiltrate. Elevated circulating immune complexes are
considered to be the mechanism of reaction. If severe, patients should be
hospitalized. In general, anti-leprosy treatment is continued. Analgesics,
steroids, and other agents available from USPHS, Carville, LA, are used to
suppress the reaction.
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