Clofazimine

The absorption of clofazimine after oral administration in leprosy patients ranges from 45 to 62%. Clofazimine, being highly lipophilic, primarily accumulates in fatty tissues and cells of the reticuloendothelial system. It is taken up by macrophages and distributed throughout the body. Crystalized deposits of clofazimine have been detected in various organs and tissues, including the mesenteric lymph nodes, adrenals, subcutaneous fat, liver, bile, gall bladder, spleen, small intestine, muscles, bones, and skin.After repeated oral doses of clofazimine, three metabolites have been identified in the urine. The pharmacological activity of these metabolites remains unclear. Metabolite I may be formed through the hydrolytic dehalogenation of clofazimine, while metabolite II is believed to be produced through a hydrolytic deamination reaction followed by glucuronidation. Elimination of clofazimine occurs partly through the feces, which may involve excretion in the bile. A small amount of the drug is also eliminated in the sputum, sebum, and sweat. The excretion of unchanged clofazimine and its metabolites in a 24-hour urine collection is minimal.

The precise mechanism(s) of action of clofazimine have not been fully understood, but it is believed to exert its antimicrobial activity by targeting the bacterial membrane. It was previously believed that its lipophilicity contributed to the generation of intracellular reactive oxygen species (ROS), such as H2O2 and superoxide, through redox cycling. These ROS were thought to play a role in the antimicrobial effect of clofazimine. However, a more recent and compelling theory suggests that clofazimine interacts with bacterial membrane phospholipids, leading to the production of antimicrobial lysophospholipids. The combined effects of clofazimine and lysophospholipids destabilize the bacterial membrane, interfering with K+ uptake and ultimately disrupting ATP production, resulting in bactericidal efficacy. Clofazimine also exhibits anti-inflammatory activity by inhibiting the activation and proliferation of T-lymphocytes. The mechanisms underlying this activity are multifaceted. One proposed mechanism is the direct antagonism of T-cell Kv 1.3 potassium channels. Additionally, clofazimine indirectly acts by promoting the release of E-series prostaglandins and reactive oxygen species from neutrophils and monocytes, which are bystander cells involved in the inflammatory response

• Aphthous Ulcers, Severe (off-label use):
• Oral:
• Initial: Begin with a daily dose of 25 mg for 3 days.
• Increase the dose by 25 mg daily every 3 days up to 100 mg daily for 3 days.
• Subsequently, increase the dose by 25 mg daily every 7 days up to 150 mg daily.
• Administer in 2 divided doses (75 mg dose is given in 3 divided doses).
• Maintenance: Use a dosage of 100 to 150 mg daily in 2 divided doses, with or without concomitant colchicine.
• Bullous Systemic Lupus Erythematosus (off-label use):
• Oral: Start with a dose of 50 mg once daily initially, with or without immunosuppressive therapy.
• The dosage range is 25 to 200 mg daily.
• Dermatitis Herpetiformis (adjunctive agent):
• Oral:
• Initial: Begin with a daily dose of 25 to 50 mg.
• Increase the dose as needed to achieve a range of 100 to 200 mg daily for full control.
• Once the rash is under control, gradually taper the dose to a minimum maintenance dosage based on clinical response.
• Immune Thrombocytopenia (alternative agent) (off-label use):
• Oral: Administer a dosage of 50 to 100 mg daily or 1 to 2 mg/kg/day.
• The duration of therapy should be at least 21 days.
• Leprosy:
• Oral: Use a daily dose of 100 mg as part of an appropriate combination regimen.
• The treatment duration is 12 months for tuberculoid (paucibacillary) disease and 24 months for lepromatous (multibacillary) disease.
• Pemphigus Vulgaris (adjunctive agent) (off-label use):
• Oral:
• Begin with a daily dose of 25 mg for 7 days.
• Increase the dose by 25 mg daily every 7 days up to 100 mg daily for 7 days (4 weeks total therapy).
• Administer in 2 divided doses (a 75 mg dose is given in 3 divided doses).
• The usual dose range is 50 to 200 mg daily.
• Taper and discontinue gradually based on lesion response.
• Pneumocystis Pneumonia in Patients with HIV (alternative agent) (off-label use):
• Oral:
• Prophylaxis (primary or secondary): Administer 100 mg once daily or in 2 divided doses as monotherapy.
• Prophylaxis in combination with weekly pyrimethamine and leucovorin: Use a dosage of 50 mg daily or 200 mg weekly.
• Treatment for mild to moderate disease: Administer 100 mg once daily in combination with trimethoprim for 21 days.
• Pyoderma Gangrenosum (alternative agent) (off-label use):
• Oral: Use a dosage of 50 to 200 mg daily.
• Relapsing Polychondritis (off-label use):
• Oral: Administer a daily dosage of 25 to 200 mg.
• T. Gondii Encephalitis in Patients with HIV (alternative to preferred therapy) (off-label use):
• Primary prophylaxis: Administer 50 mg daily or 200 mg weekly in combination with weekly pyrimethamine and leucovorin.
• Continue until CD4 count is >200 cells/mm3 for >3 months in response to antiretroviral therapy (ART).

Acne Vulgaris:

Important Considerations: This treatment is recommended for patients who have not responded adequately to initial treatments (Ref). Avoid using it simultaneously with benzoyl peroxide, as it may cause temporary yellow-orange discoloration of the skin and facial hair.

Topical Treatment:

• Gel 5%: Apply a small amount, equivalent to the size of a pea, in a thin layer to the affected areas twice daily.
• Gel 7.5%: Apply a small amount, equivalent to the size of a pea, in a thin layer to the entire face once daily. It may also be applied to other affected areas of the body once daily.

• Capsules: 50mg

Leprosy, Lepromatous (Multibacillary):

• National Hansen Disease Program Dosing:
• Children and Adolescents: Oral: 1 mg/kg/dose once daily for 24 months; maximum dose: 50 mg/dose. If needed, doses of 2 mg/kg/dose every other day are acceptable based on dosage form constraints.
• World Health Organization Dosing:
• Children <10 years: Oral: 50 mg twice weekly and 100 mg once monthly for 12 months.
• Children ≥10 years and Adolescents <15 years:
• <40 kg: Oral: 50 mg twice weekly and 100 mg once monthly for 12 months.
• ≥40 kg: Oral: 50 mg once every other day and 150 mg once monthly for 12 months.
• Adolescents ≥15 years: Oral: 50 mg once daily and 300 mg once monthly for 12 months.

Mycobacterial Infection:

• Odontogenic Infection, Osteomyelitis:
• Children 3 to 9 years: Oral: 1 mg/kg/dose once daily as part of a combination regimen.
• Pulmonary Infection in Patients without Cystic Fibrosis:
• Children and Adolescents: Oral: 3 to 5 mg/kg/dose once daily as part of a combination regimen; maximum dose: 100 mg/dose.
• Pulmonary Infection in Patients with Cystic Fibrosis:
• Children and Adolescents: Oral: 1 to 2 mg/kg/dose once daily as part of a combination regimen; maximum dose: 100 mg/dose.

Tuberculosis, Active; Treatment:

• Tuberculosis, Active (Drug-Resistant); Treatment:

• Children and Adolescents: Oral: 2 to 5 mg/kg/dose once daily as part of a combination regimen; maximum dose: 100 mg/dose. Higher doses may be administered every other day if needed based on dosage form constraints.

Abdominal Obstruction and Other Gastrointestinal Adverse Reactions:

Clofazimine may lead to the accumulation of crystals in various organs, including the mesenteric lymph nodes, intestinal mucosa, spleen, and liver. This deposition in the intestinal mucosa can result in intestinal obstruction, potentially requiring exploratory laparotomy. Cases of splenic infarction, gastrointestinal bleeding, and even death have been reported. If a patient experiences abdominal pain, nausea, vomiting, or diarrhea, appropriate medical investigations should be initiated, and the daily dose of Clofazimine may need to be reduced, the dosing interval increased, or the drug discontinued. High doses of Clofazimine (>100 mg daily) should be administered for the shortest duration possible (less than 3 months) and under close medical supervision.

QT Prolongation:

There have been reports of Torsade de Pointes and QT prolongation in patients receiving Clofazimine at a daily dose higher than 100 mg or in combination with medications known to prolong the QT interval. Patients with QT prolongation or Torsade de Pointes should be closely monitored under medical supervision, including regular electrocardiograms (ECGs) to assess for QT prolongation and cardiac rhythm disturbances. It is important to monitor ECGs in patients concurrently taking Clofazimine and bedaquiline, discontinuing Clofazimine if clinically significant ventricular arrhythmia is observed or if the QTcF interval exceeds 500 ms. If syncope occurs, an ECG should be obtained to detect QT prolongation.

Skin and Body Fluid Discoloration and Other Skin Reactions:

Clofazimine can cause skin discoloration ranging from orange-pink to brownish-black, affecting not only the skin but also the conjunctivae, tears, sweat, sputum, urine, and feces in 75-100% of patients. Patients should be advised that skin discoloration is likely to occur and that it may take several months or even years to reverse after completing therapy. Other skin reactions associated with Clofazimine treatment include ichthyosis, dry skin, and pruritus (itchiness).

Psychological Effects of Skin Discoloration:

Skin discoloration resulting from Clofazimine therapy has been associated with reports of depression and suicidal ideation. Patients should be informed about the possibility of skin discoloration and closely monitored for signs of depression or suicidal thoughts during Clofazimine therapy.

I. Use in Pregnant Women

● Insufficient data on Clofazimine use in pregnant women to determine associated risk

● Adverse effects observed in mice, including fetal skull ossification retardation, increased abortions and stillbirths, and impaired neonatal survival, after prenatal exposure to Clofazimine at a dose equivalent to 0.6 times the maximum recommended human daily dose

● Pregnant women should be informed about the potential risk to the fetus

II. Background Risk and Clinical Considerations

● Unknown background risk of major birth defects and miscarriage for the indicated population

● Estimated background risk of major birth defects in the general U.S. population is 2-4%, and the risk of miscarriage is 15-20% of clinically recognized pregnancies

● Fetal/neonatal adverse reactions: Pigmentation of infants' skin at birth when born to mothers who received Clofazimine during pregnancy

● Limited data on the reversibility of discoloration, with observations indicating gradual fading over the first year

Use Clofazimine during pregnancy only if the potential benefit justifies the fetal risk

Animal studies conducted according to standards at the time of initial drug approval (1986) and not under current regulatory standards.

Common:

● Skin discoloration (orange-pink to brownish-black)

● Dry and scaly skin

● Rash

● Itching

● Abdominal pain

● Nausea

● Vomiting

● Diarrhea

● Increased sweating

● Changes in color of urine/stool/mucus

Less common:

● Eye irritation or burning

● Eye dryness

● Itchy eyes

● Eye discoloration

● Elevated blood sugar levels

● Food intolerances

Rare:

● QT prolongation (affecting the electrical activity of the heart)

● Torsade de Pointes (a type of irregular heart rhythm)

● Hepatic dysfunction (liver impairment)

● Severe abdominal obstruction

● Impaired neonatal survival (observed in animal studies)

● Retardation of fetal skull ossification (observed in animal studies)

● Increased incidences of abortions and stillbirths (observed in animal studies)

Effect of Clofazimine on Substrates of CYP3A:

Concomitant use of Clofazimine may affect drugs that are metabolized by CYP3A4/5 enzymes. This can result in increased concentrations of these drugs, potentially leading to an increased risk of toxicity. It is important to monitor for any signs of drug toxicity when Clofazimine is used together with these medications.

Drugs that Prolong QT Interval:

There have been reports of QT prolongation and Torsade de Pointes in patients receiving Clofazimine along with other medications known to prolong the QT interval, such as bedaquiline. Regular electrocardiograms (ECGs) should be performed to monitor for any QT prolongation when Clofazimine is administered in combination with these QT prolonging drugs.

● Changes in skin color

● Dry and scaly skin

● Rash

● Itching

● Abdominal pain

● Diarrhea

● Nausea

● Vomiting

● Food intolerances

● Eye irritation or burning

● Eye dryness

● Itchy eyes

● Eye discoloration

● Changes in color of urine/stool/mucus

● Elevated blood sugar

● Sweating

I. Use in Pregnant Women

● Insufficient data on Clofazimine use in pregnant women to determine associated risk

● Adverse effects observed in mice, including fetal skull ossification retardation, increased abortions and stillbirths, and impaired neonatal survival, after prenatal exposure to Clofazimine at a dose equivalent to 0.6 times the maximum recommended human daily dose

● Pregnant women should be informed about the potential risk to the fetus

II. Background Risk and Clinical Considerations

● Unknown background risk of major birth defects and miscarriage for the indicated population

● Estimated background risk of major birth defects in the general U.S. population is 2-4%, and the risk of miscarriage is 15-20% of clinically recognized pregnancies

● Fetal/neonatal adverse reactions: Pigmentation of infants' skin at birth when born to mothers who received Clofazimine during pregnancy

● Limited data on the reversibility of discoloration, with observations indicating gradual fading over the first year

Use Clofazimine during pregnancy only if the potential benefit justifies the fetal risk

There is no specific information regarding the treatment of Clofazimine overdose. However, in the event of an overdose, it is recommended to empty the stomach through methods such as inducing vomiting or gastric lavage. Supportive symptomatic treatment should also be provided.

Clofazimine exerts a slow bactericidal effect on Mycobacterium leprae (Hansen's bacillus) primarily by targeting the bacterial outer membrane. It may also impact the bacterial respiratory chain and ion transporters. Additionally, it possesses anti-inflammatory properties by suppressing T-lymphocyte activity. Due to its extended residence time in the body, clofazimine has a relatively long duration of action, necessitating daily administration.

In approximately 75-100% of patients receiving clofazimine, there may be a noticeable skin color change ranging from orange-pink to brownish-black, affecting the skin, conjunctivae, and bodily fluids. The reversal of skin discoloration may take several months or even years after discontinuation of therapy. Clofazimine has been associated with abdominal obstruction, including potentially fatal cases, caused by the accumulation of the drug and the formation of crystals in the intestinal mucosa. If patients experience abdominal pain and nausea/vomiting, prompt investigation is necessary, and the dosage of clofazimine should be reduced or discontinued if it is determined to be the cause.

Patients with hepatic dysfunction should avoid the use of clofazimine.

Absorption:

● The absorption of clofazimine in leprosy patients ranges from 45% to 62%.

Effect of Food:

● Under fed conditions, the time taken to reach the peak plasma concentration (median Tmax) of clofazimine decreases from 12 hours to 8 hours compared to the fasted state.

Distribution:

● Clofazimine, being lipophilic, predominantly deposits in fatty tissue and cells of the reticuloendothelial system.

● Macrophages throughout the body uptake clofazimine.

● Autopsies of leprosy patients who received Clofazimine revealed that clofazimine crystals were mainly found in the mesenteric lymph nodes, adrenals, subcutaneous fat, liver, bile, gall bladder, spleen, small intestine, muscles, bones, and skin.

● Clofazimine binds to alpha- and primarily beta-lipoproteins in serum, with saturation occurring at plasma concentrations of approximately 10 mcg/mL. Binding to gamma-globulin and albumin is minimal.

Elimination:

● The average elimination half-life of clofazimine is approximately 25 days (ranging from 6.5 to 160 days) in leprosy patients after repeated oral doses of 50 or 100 mg of Clofazimine.

Metabolism:

● Limited information is available regarding the metabolism of clofazimine.

● Three clofazimine metabolites were detected in urine following repeated oral doses of Clofazimine.

Excretion:

● Following a single dose of 300 mg Clofazimine, the elimination of unchanged clofazimine and its metabolites in a 24-hour urine collection is negligible.

● The excretion of the ingested drug via feces may occur, possibly through the bile.

● A small amount of clofazimine is also eliminated in sputum, sebum, and sweat.