This information is intended for use by health professionals

1. Name of the medicinal product

Dapsone 100 mg tablets

2. Qualitative and quantitative composition

Each tablet contains 100 mg dapsone.

Excipient with known effect:

27.50 mg of lactose per tablet of Dapsone 100 mg tablets.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablets

White or slightly yellowish, round, biconvex tablets, debossed with “D” on one side and with a score line on the other side.

The tablet can be divided into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

1) As part of a multi-drug regimen in the treatment of all forms of leprosy.

2) Treatment of dermatitis herpetiformis and other dermatoses.

3) Prophylaxis of malaria in combination with pyrimethamine.

4) Prophylaxis of Pneumocystis carinii pneumonia in immunodeficient subjects, especially AIDS patients.

4.2 Posology and method of administration

Posology

Adults and children over 12 years:

Multibacillary leprosy (3-drug regimen): 100mg daily for at least two years.

Paucibacillary leprosy (2-drug regimen): 100mg daily for at least six months.

Malaria prophylaxis: 100mg weekly with 12.5mg pyrimethamine.

Dermatitis herpetiformis: Initially 50mg daily, gradually increased to 300mg daily if required. Once lesions have begun to subside, the dose should be reduced to a minimum as soon as possible, usually 25-50mg daily, which may be continued for a number of years. Maintenance dosage can often be reduced in patients receiving a gluten-free diet.

Pneumocystis carinii pneumonia: In combination with trimethoprim, 50-100mg daily; 100mg twice weekly or 200mg once weekly.

Children 6-12 years:

Multibacillary leprosy (3-drug regimen): 50mg daily for at least two years.

Paucibacillary leprosy (2-drug regimen): 50mg daily for at least six months.

Children under the age of 6 years: The safety and efficacy of Dapsone in children aged less than six years has not been established. No data are available.

Elderly:

Dosage should be reduced in the elderly where there is an impairment of hepatic function.

Method of Administration

For oral administration. Tablets should be swallowed whole with a glass of water.

4.3 Contraindications

• Hypersensitivity to dapsone or any of the excipients listed in section 6.1

• severe anaemia

• porphyria

• severe glucose-6-phosphate dehydrogenase deficiency.

Dapsone contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.4 Special warnings and precautions for use

Dapsone should be used with caution in patients with cardiac or pulmonary disease. It is recommended that regular blood counts be performed during treatment with dapsone.

Patients deficient in glucose-6-phosphate dehydrogenase, or methaemoglobin reductase, or with haemoglobin M are more susceptible to the haemolytic effects of dapsone.

Dapsone should be used with caution in anaemia. Severe anaemia should be treated before starting Dapsone.

4.5 Interaction with other medicinal products and other forms of interaction

Oral typhoid vaccine: should not be taken until at least three days after finishing a course of dapsone, because the dapsone could make this vaccine less effective.

Probenecid: Excretion of dapsone is reduced and plasma concentrations are increased by concurrent administration of probenecid.

Rifampicin/ Rifabutin: has been reported to increase the plasma clearance of dapsone.

Saquinavir: should not be used in combination, as this could increase the risk of irregular heartbeat.

Trimethoprim: Increased dapsone and trimethoprim concentrations have been reported following concurrent administration in AIDs patients.

4.6 Fertility, pregnancy and lactation

Pregnancy

It is now generally considered that the benefits of dapsone in the treatment of leprosy outweigh any potential risk to the pregnant patient. Some leprologists recommend 5mg folic acid daily for leprosy patients receiving dapsone during pregnancy.

Breast-feeding

Dapsone diffuses into breast milk and there has been a report of haemolytic anaemia in a breast fed infant. While some feel that dapsone should not be used in lactating mothers, in general treatment for leprosy is continued in such patients.

Fertility

There is limited information available on the effect of dapsone on fertility; it may reduce the numbers and / or motility of sperm, thereby rendering impregnation less likely.

4.7 Effects on ability to drive and use machines

Dapsone has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Dapsone should be discontinued, or reduced in dosage, if severe lepra reactions affecting the eyes or nerve trunks occur.

The frequencies of undesirable effects are reported according to the following convention:

Very common

≥ 1/10 users

Rare

≥1/10,000users;

<1/1000 users

Common

≥1/100users; <1/10 users

Very rare

<1/10,000 users

Uncommon

≥1/1000users;

<1/100 users

Unknown

Cannot be estimated

System Organ Class(SOC)

Frequency

Undesirable effect

Blood Disorders:

Common

Haemolysis1

Methaemoglobinaemia1

Uncommon

Haemolytic anaemia

Rare

Agranulocytosis2

Cardiac Disorders:

Uncommon

Tachycardia

Gastrointestinal Disorders:

Uncommon

Anorexia

Nausea

Vomiting

General Disorders:

Rare

Dapsone Syndrome3

Hepatic Disorders:

Uncommon

Hepatitis

Jaundice

Changes in liver function tests

Metabolic Disorders:

Uncommon

Hypoalbuminaemia

Nervous System Disorders:

Uncommon

Headache

Neuropathy peripheral4

Peripheral motor neuropathy4

Psychiatric Disorders:

Uncommon

Insomnia

Psychoses

Skin Disorders:

Uncommon

Photosensitivity

Pruritis

Rash

Rare

Exfoliative dermatitis

Maculopapular rash

Toxic epidermal necrolysis

Stevens – Johnson syndrome

Very rare

Fixed drug eruptions

1) – these are the most frequently reported adverse effects of dapsone and are dose related; occurring in most subjects administered more than 200 mg daily; doses of up to 100 mg daily do not cause significant haemolysis, but subjects deficient in glucose-6-phosphate dehydrogenase are affected by doses above about 50 mg daily.

2) – this is rare when dapsone is used alone; reports are more common when dapsone has been used with other medicines for malarial prophylaxis.

3) – this may occur following 3 – 6 weeks of therapy; symptoms include rash (always present), fever and eosinophilia. Id dapsone is not stopped immediately; the syndrome may progress to exfoliative dermatitis, hepatitis, albuminuria, and psychosis. Deaths have been recorded. The majority of patients require steroid therapy for several weeks; this is possibly due to prolonged elimination time of dapsone.

4) – peripheral neuropathy may occur as part of leprosy reaction states and it is not an indication to discontinue dapsone.

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms:hypoxia, methaemoglobinaemia and haemolytic anaemia.

Treatment: In severe over-dosage the stomach should be emptied by gastric lavage. Administration of activated charcoal by mouth has been shown to enhance the elimination of dapsone and its monoacetyl metabolite. Methaemoglobinaemia has been treated with slow IV injections of methylene blue 1-2mg/kg bodyweight, repeated after one hour if necessary. Methylene blue should not be administered to patients with glucose-6-phosphate dehydrogenase deficiency since it will not be effective. Haemolysis has been treated by infusion of concentrated human red blood cells to replace the damaged cells.

Supportive therapy includes oxygen to alleviate hypoxia, and administration of fluids to maintain renal flow and promote the elimination of dapsone.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anti-infectives for systemic use; anti-mycobacterials; drugs for treatment of lepra.

ATC code: J04BA02

Dapsone is a sulfone with activity against a wide range of bacteria. The mechanism of action is believed to be similar to that of the sulfonamides; inhibition of folic acid synthesis in susceptible organisms. Dapsone is usually considered bacteriostatic against M. leprae, although it may also possess weak bactericidal activity. Dapsone is also active against Plasmodium and Pneumocystis carinii (Pneumocystis jirovecii). In common with sulfonamides, antibacterial activity is inhibited by p-aminobenzoic acid.

As an antimicrobial agent, dapsone is bacteriostatic in action. It inhibits the synthesis of dihydrofolic acid through by competing with para-aminobenzoic acid for the active site of dihydropteroate synthetase, thus resembling the action of sulfonamides. Sulfones were found to suppress the growth of various pathogenic bacteria such as streptococci, staphylococci, pneumococci, mycobacteria, and other strains. The mechanism of action of topical dapsone in the treatment of acne vulgaris may result from a combination of both anti-inflammatory and antimicrobial effects. In vitro, dapsone has some antibacterial activity against Propionibacterium acnes. Owing to its antimicrobial activities, dapsone is clearly playing a role in the treatment of certain infectious diseases.

5.2 Pharmacokinetic properties

Absorption

Following oral administration, dapsone is almost completely absorbed from the gastrointestinal tract, with reported bioavailability exceeding 86 %. Peak serum concentrations are reached within 2 h – 8 h. Post ingestion of a single 50 mg – 300 mg dose of dapsone, maximum serum concentrations range from 0.63 mg/L to 4.82 mg/L. Under steady state conditions, the most frequently used dose of 100 mg/day, results in serum concentrations of maximum 3.26 mg/L, and a minimum, at 24 h, of 1.95 mg/L. Steady state concentrations are not achieved until after at least 8 days daily administration.

Distribution

Dapsone is 50% – 80% bound to plasma proteins, whereas the principal metabolite, monoacetyldapsone is almost completely bound to plasma proteins. Dapsone is distributed to almost all organs, and is retained in the skin, muscle, kidneys, and liver, with trace concentrations present in these tissues up to 3 weeks post discontinuation. Dapsone is distributed into sweat, saliva, sputum, tears, and bile. It crosses the blood – brain barrier, and the placenta, and is excreted in breast milk. The half-life ranges from 10 h – 80 h.

Biotransformation

Post absorption, dapsone undergoes enterohepatic recirculation. It is metabolised by the liver, and additionally by activated polymorphonuclear leukocytes and mononuclear cells. In the liver dapsone is primarily metabolised via acetylation by Nacetyltransferase to monoacetyldapsone, and through hydroxylation by cytochrome P450 enzymes, resulting in the generation of dapsone hydroxylamine. Dapsone hydroxylamine may be responsible for dapsone associated methaemoglobinaemia and haemolysis. Acetylation exhibits genetic polymorphism, with both rapid and slow acetylators.

Elimination

Around 20 % of dapsone is excreted, unchanged, via urine, with 70 % – 80 % of the dose being eliminated as water soluble metabolites following conjugation with glucuronic acid. A small amount of the dose may be excreted in faeces, including some unidentified metabolites.

Linearity/non-linearity

The drug shows linear pharmacokinetics within the therapeutic range.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate;

Maize starch;

Sodium laurilsulfate (E 487);

Colloidal anhydrous silica (E 551);

Magnesium stearate (E 470b).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Dapsone 100 mg Tablets are packed in white Alu-PVC blister.

Pack containing 28 tablets is available.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Rivopharm UK Ltd.,

30th Floor, 40 Bank Street, Canary Wharf

London E14 5NR

United Kingdom

8. Marketing authorisation number(s)

PL 33155/0084

9. Date of first authorisation/renewal of the authorisation

02/07/2020

10. Date of revision of the text

02/07/2020