Clofazimine macleods 100

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLOFAMINE MACLEODS 100 CLOFAMINE MACLEODS 100

Composition:

Active substance: clofazimine;

One film-coated tablet contains clofazimine 100 mg;

Excipients: polyoxylated castor oil, hydrogenated, povidone, polysorbate 80, betadex, microcrystalline cellulose, colloidal anhydrous silicon dioxide, crospovidone, sodium stearyl fumarate;

Coating Instacoat Universal Brown (A05G11412): hypromellose, triacetin, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: light brown, biconvex, oval-shaped film-coated tablets with a division line on one side and smooth on the other. Tablets can be divided into two equal parts.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Antimycobacterial agents. Medicinal products for the treatment of leprosy. ATC code J04BA01.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Clofazimine is a highly lipophilic compound exerting slow bactericidal activity against Mycobacterium leprae (Hansen's bacillus). Clofazimine inhibits the growth of mycobacteria and binds predominantly to mycobacterial DNA. Clofazimine also exerts anti-inflammatory effects in the treatment of leprosy reactions, particularly erythema nodosum leprosum. However, the precise mechanism of action has not been fully elucidated.

The mechanism underlying the antimycobacterial activity of clofazimine may involve effects on membranes, including the bacterial respiratory chain and ion transporters. Intracellular redox reactions, including the oxidation of clofazimine, lead to the accumulation of reactive oxygen species (ROS), particularly superoxide and hydrogen peroxide (H₂O₂). Additionally, interaction of clofazimine with phospholipids in the membrane results in the accumulation of antimicrobial lysophospholipids, causing membrane dysfunction and subsequent K⁺ efflux. Both mechanisms lead to disruption of cellular energy metabolism by interfering with ATP production. The anti-inflammatory properties of clofazimine are primarily explained by inhibition of activation and proliferation of T-lymphocytes. Clofazimine may indirectly affect T-cell proliferation by stimulating the release of ROS and prostaglandins (PG), particularly PGE₂, from neutrophils and monocytes.

Mechanisms of resistance

There is no cross-resistance with rifampicin or dapsone.

Pharmacokinetics.

The absorption characteristics of clofazimine were determined after administration of a single dose of Clofazimine Macleods 100 tablets to healthy volunteers under fed conditions.

Pharmacokinetic parameter	Mean value * (± standard deviation)
Maximum concentration (Cmax)	137 ± 62 ng/mL
Area under the curve (AUC0-72h), measure of extent of absorption	3216 ± 1036 ng·h/mL
Time to reach maximum concentration (tmax)	5.80 ± 1.47 hours

* Arithmetic mean.

The pharmacokinetics of Clofazimine Macleods 100 have not been studied in patients with tuberculosis. The data presented below are based on findings obtained from administration of clofazimine to patients with leprosy. The pharmacokinetic parameters of clofazimine in tuberculosis patients may differ from those in leprosy patients.

Absorption

The absorption of clofazimine in leprosy patients ranges between 45% and 62%. The mean serum concentration of clofazimine in leprosy patients receiving 100 mg and 300 mg daily was 0.7 µg/mL and 1 µg/mL, respectively. Peak serum concentration of clofazimine (mean Tmax) occurs 8–12 hours after administration of the drug following a meal.

Distribution

Clofazimine is a highly lipophilic compound and therefore primarily accumulates in adipose tissue and cells of the reticuloendothelial system. It is distributed throughout the body by macrophages. Autopsy findings in leprosy patients treated with clofazimine showed that clofazimine crystals predominantly accumulated in mesenteric lymph nodes, adrenal glands, subcutaneous adipose tissue, liver, bile, gallbladder, spleen, small intestine, muscles, bones, and skin.

Clofazimine binds to alpha- and beta-lipoproteins in serum, and this binding becomes saturated at plasma concentrations of approximately 10 µg/mL. Binding to gamma-globulins and albumin is negligible.

Metabolism

Information is limited. Three metabolites of clofazimine have been identified in urine following repeated oral doses of clofazimine.

Elimination

After a single 300 mg dose of clofazimine, excretion of unchanged clofazimine and its metabolites in urine over a 24-hour period was minimal. The portion of the ingested drug recovered in feces may represent biliary excretion. A small amount is also excreted in saliva, sebum, and sweat.

The elimination half-life of clofazimine after multiple oral doses of 50 or 100 mg in leprosy patients varied widely, ranging from 6.5 to 160 days. The overall mean elimination half-life of clofazimine in these leprosy patients was 25 days.

Preclinical safety data

Genotoxicity. Results from mutagenicity studies (Ames test) were negative. There is some evidence of clastogenic potential in mice.

Carcinogenicity. Long-term carcinogenicity studies of clofazimine in animals have not been conducted.

Toxic effect on reproductive function. In one study in rats receiving clofazimine (from 9 weeks of age through mating until weaning of offspring) at a dose of 50 mg/kg/day, equivalent to approximately 2.4 times the maximum recommended clinical dose, impaired fertility in females was observed (reduced number of offspring and lower pregnancy rate). Preclinical data on male fertility are lacking.

Clinical characteristics.

Indications.

Treatment of lepromatous leprosy, including dapsone-resistant lepromatous leprocy and lepromatous leprosy complicated by erythema nodosum leprosum.

To prevent the development of resistance, Clofazimine Macleods 100 should be used only as part of combination therapy for initial treatment of lepromatous leprosy.

Contraindications.

Clofazimine is contraindicated in patients with known hypersensitivity to clofazimine or to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Effect on CYP3A substrates

Concomitant administration with clofazimine may increase concentrations of drugs that are CYP3A4/5 substrates, resulting in an increased risk of their toxicity. Monitor for toxicity of these drugs when used concomitantly with Clofazimine Macleods 100.

Drugs that prolong the QT interval

Use of clofazimine with drugs that increase the QT interval (e.g., bedaquiline, delamanid, fluoroquinolones, efavirenz, and certain other antiretroviral drugs for HIV treatment or azole antifungal agents) may cause additive QT prolongation. Monitor ECG for QT prolongation when clofazimine is administered together with other drugs known to prolong the QT interval (see section "Special precautions for use").

No clinically significant differences in the pharmacokinetics of clofazimine were observed when administered concomitantly with bedaquiline, cycloserine, dapsone, ethionamide, para-aminosalicylic acid, pyrazinamide, and pyridoxine.

In patients who received high doses of clofazimine (300 mg daily) and isoniazid (300 mg daily), increased plasma and urinary concentrations of clofazimine were observed, although skin concentrations were lower; however, the clinical significance is unknown.

No clinically significant differences in the pharmacokinetics of dapsone or rifampicin were observed when administered concomitantly with clofazimine.

Special precautions for use.

Gastrointestinal obstruction and other gastrointestinal adverse reactions

Clofazimine may accumulate in various organs as crystals, including in mesenteric lymph nodes and histiocytes in the lamina propria of the intestinal mucosa, spleen, and liver. Deposition in the intestinal mucosa may lead to intestinal obstruction, which may require diagnostic laparotomy. Cases of splenic infarction, gastrointestinal bleeding, and death have been reported. If a patient complains of abdominal pain, nausea, vomiting, or diarrhea, appropriate medical investigations should be carried out and the daily dose of Clofazimine Macleods 100 should be reduced, the dosing interval increased, or treatment discontinued. The dose of Clofazimine Macleods 100 exceeding 100 mg per day should be administered for the shortest possible duration (less than 3 months) and only under strict medical supervision.

QT interval prolongation

Cases of torsades de pointes with QT prolongation have been reported in patients receiving clofazimine at doses exceeding 100 mg per day or in combination with QT-prolonging agents such as bedaquiline, delamanid, fluoroquinolones, efavirenz, and certain other antiretroviral drugs for HIV treatment or azole antifungal agents. ECG monitoring is necessary in patients taking Clofazimine Macleods 100 concomitantly with such medications. Discontinuation of Clofazimine Macleods 100 should be considered if clinically significant ventricular arrhythmia occurs or if the QTcF interval is 500 ms or greater. In case of patient syncope, an ECG should be performed to assess QT interval prolongation.

The combination of moxifloxacin with bedaquiline and clofazimine (three agents that significantly prolong the QT interval) should be avoided in tuberculosis treatment regimens.

Skin discoloration, body fluid discoloration, and other skin reactions

Clofazimine causes discoloration of the skin from orange-pink to brown-black and may also change the color of conjunctiva, tears, sweat, saliva, urine, and feces in 75–100% of patients. Patients should be informed about the likelihood of skin discoloration, which may take several months or years to resolve after completion of therapy. Patients should avoid sunlight exposure and use strong sun protection creams.

Other skin reactions associated with clofazimine therapy include ichthyosis, dry skin, and pruritus.

Psychological effects of skin discoloration

Skin discoloration due to clofazimine therapy has been reported to lead to depression and suicide. Patients should be counseled about skin discoloration, and depression or suicidal thoughts should be monitored during clofazimine therapy.

Fertile women and men

Pregnancy test. Women of childbearing potential who are sexually active should undergo a pregnancy test before starting treatment with Clofazimine Macleods 100.

Contraception. Animal studies have demonstrated that clofazimine is harmful to the developing fetus. Women of childbearing potential who are sexually active should be advised to use effective contraception (methods with less than 1% probability of pregnancy) during treatment with Clofazimine Macleods 100 and for at least 4 months after discontinuation of treatment.

Men receiving Clofazimine Macleods 100 are advised to use condoms during sexual intercourse throughout the treatment period and for at least 4 months after discontinuation of Clofazimine Macleods 100.

Infertility. In one study, female rats treated with clofazimine showed impaired fertility (reduced offspring number and lower pregnancy rate) (see section "Pharmacokinetics"). There are no preclinical data on fertility in males.

Liver function

Clofazimine is partially metabolized by the liver. Clofazimine Macleods 100 should be used with caution in patients with hepatic impairment (Child-Pugh classes A, B, and C). Serum liver enzymes (ALT, ALP, AST, GGT) should be monitored periodically throughout treatment.

Resistance

According to official tuberculosis treatment guidelines, such as those from WHO and local health authorities, clofazimine should be used in combination with appropriate doses of other antituberculosis drugs. Monotherapy with clofazimine may rapidly lead to the development of resistant strains.

Excipients

Clofazimine Macleods 100 contains polyoxyl 40 hydrogenated castor oil, which may cause gastrointestinal disturbances and diarrhea.

Clofazimine Macleods 100 also contains betadex (cyclodextrin). At high doses, cyclodextrins may cause reversible diarrhea and cecal enlargement in animals.

The impact of all excipients contained in the medications taken by the patient should be carefully considered.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate and well-controlled studies of Clofazimine Macleods 100 use in pregnant women. Animal studies have shown reproductive toxicity (see section "Pharmacokinetics").

Skin of infants born to mothers who received clofazimine during pregnancy is pigmented at birth. Limited data are available on reversibility of skin discoloration. Based on previous observations, it can be concluded that newborns' skin gradually returns to its natural color within the first year of life.

Clofazimine Macleods 100 should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus.

The hidden risks associated with major congenital malformations and preterm birth in the population indicated for this drug remain unknown. However, in the general US population, the background risk of major congenital malformations is 2–4%, and the risk of preterm birth is 15–20% for clinically confirmed pregnancies.

Breastfeeding period

Clofazimine is excreted in human breast milk, imparting a pink color. Clofazimine may enhance skin pigmentation in breastfed infants. Therefore, the risk to the newborn/infant cannot be excluded.

A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from clofazimine therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of Clofazimine Macleods 100 on fertility in men or women. Animal studies indicate an effect of clofazimine on fertility (see section "Pharmacokinetics").

Ability to affect reaction speed when driving or operating machinery.

During clofazimine treatment, visual disturbances during both day and night, as well as somnolence, have been reported. Patients should be informed that if such symptoms occur, they should avoid potentially hazardous tasks such as driving vehicles or operating machinery.

Method of Administration and Dosage

Dosage

Clofazimine Macleods 100 is never used as monotherapy in the treatment of Hansen’s disease (leprosy), but only in combination with dapsone and rifampicin.

Dosage depends on the patient's age and body weight.

The usual dosage recommended by the World Health Organization (WHO) is as follows:

Adult patients (aged 15 years and older):

• Clofazimine: 300 mg once monthly (Day 1) under medical supervision + 50 mg daily (from Day 2 to Day 28);
• Rifampicin: 600 mg once monthly (Day 1) under medical supervision;
• Dapsone: 100 mg daily (from Day 1 to Day 28).

Pediatric patients

• Children aged 10 to 14 years:
  • Clofazimine: 150 mg once monthly (Day 1) under medical supervision + 50 mg every other day (from Day 2 to Day 28);
  • Rifampicin: 450 mg once monthly (Day 1) under medical supervision;
  • Dapsone: 50 mg daily (from Day 1 to Day 28).
• Children under 10 years of age:
  • Clofazimine: 100 mg once monthly (Day 1) under medical supervision + 50 mg twice weekly;
  • Rifampicin: 300 mg once monthly (Day 1) under medical supervision;
  • Dapsone: 25 mg daily.

Administration to children under 10 years of age is possible only if 25 mg dapsone tablets are available on the market.

However, other regimens different from those recommended by WHO may be used.

Patients must strictly follow the physician's instructions.

In the treatment of leprosy nodular erythema, the dose of clofazimine may be increased under medical supervision to 200–300 mg daily. Such increased daily doses should not be used for longer than 3 months. The clofazimine dose should then be gradually reduced: first to 100 mg twice daily for 12 weeks, followed by 100 mg once daily for an additional 12–24 weeks.

Method of Administration

Clofazimine Macleods 100 is taken orally. The film-coated tablets should be swallowed whole with milk.

Clofazimine Macleods 100 should be taken with food to avoid gastrointestinal upset and to enhance absorption.

Duration of Treatment

Clofazimine Macleods 100 must be taken concomitantly with two other medicinal agents (dapsone and rifampicin) for at least 12 months.

To achieve the desired therapeutic effect, Clofazimine Macleods 100 should be used regularly at the prescribed doses and for the duration recommended by the physician.

The disappearance of fever or any other symptom does not mean that the patient has fully recovered.

Special Populations

Patients with renal impairment. Dose adjustment is not required in patients with renal impairment.

Patients with hepatic impairment. Clofazimine is partially metabolized by the liver. It should be used with caution in patients with hepatic impairment (Child–Pugh classes A, B, and C) (see section "Special Warnings and Precautions for Use").

Women of childbearing potential

Women of childbearing potential who are sexually active should undergo a pregnancy test before starting treatment with Clofazimine Macleods 100 (see section "Special Warnings and Precautions for Use").

Elderly patients

Clofazimine Macleods 100 should be prescribed with caution to elderly patients. Therapy is generally recommended to start at the lowest doses specified in the treatment regimen, as elderly patients more frequently have impaired liver, kidney, or cardiac function, and other concomitant diseases requiring concomitant medication.

HIV-infected patients

The response to treatment, including treatment of leprosy nodular erythema, in HIV-positive patients with leprosy and impaired immunity is similar to that in other patients. Dose adjustment of the drug is not required for this patient group.

Missed dose and vomiting after administration

It is important that the patient takes the medication regularly as prescribed. Missed doses may increase the risk of resistance to clofazimine and reduce its effectiveness.

If vomiting occurs within 1 hour after taking Clofazimine Macleods 100, the patient should take an additional dose. If vomiting occurs more than 1 hour after administration, the patient does not need to take an additional dose and may take the next scheduled dose as usual.

Children

Use in children under 10 years of age is possible only if 25 mg dapsone tablets are available on the market (see section "Method of Administration and Dosage").

Overdose

There are no specific data on the treatment of clofazimine overdose. However, in case of overdose, the stomach should be emptied by inducing vomiting or performing gastric lavage. Supportive symptomatic treatment should then be initiated.

Adverse Reactions

The undesirable effects listed below were mainly observed during the use of clofazimine for the treatment of leprosy. Common reactions include:

Skin and mucous membranes: Pigmentation ranging from orange-pink to brown-black in 75–100% of patients within several weeks of treatment; ichthyosis and dry skin (8–28%); rash and pruritus (1–5%).

Gastrointestinal tract: Abdominal pain, particularly in the epigastric region, diarrhea, nausea, vomiting, gastrointestinal disturbances (40–50%).

Eyes: Visual impairment, pigmentation of the conjunctiva and cornea due to deposition of clofazimine crystals; dryness; burning; itching; irritation.

Other: Discoloration of urine, feces, saliva, and sweat; elevated blood glucose levels; increased erythrocyte sedimentation rate (ESR).

Adverse reactions observed in less than 1% of patients:

Skin and mucous membranes: Photosensitivity, erythroderma, acneiform eruptions, monilial cheilitis.

Gastrointestinal tract: Intestinal obstruction, gastrointestinal hemorrhage, anorexia, constipation, weight loss, hepatitis, jaundice, eosinophilic enteritis, hepatomegaly.

Eyes: Maculopathy (bull's eye retinopathy).

Nervous system: Dizziness, somnolence, fatigue, headache, malaise, neuralgia, taste disturbances.

Psychiatric: Depression and suicidal ideation associated with skin discoloration.

Laboratory findings: Increased levels of albumin, serum bilirubin, and aspartate aminotransferase (AST); eosinophilia; hypokalemia.

Other: Splenic infarction, thromboembolism, anemia, cystitis, bone pain, edema, fever, lymphadenopathy, vascular pain.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after the medicine has been authorized. This enables ongoing monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions to the marketing authorization holder or, where applicable, through the national reporting system.

Shelf life: 2 years.

Storage conditions:

Store at a temperature not exceeding 30°C. Keep in a light-protected place. Avoid exposure to temperatures above 30°C.

Keep out of reach of children.

Packaging:

10 tablets per strip; 10 strips per cardboard box.

Prescription status: Prescription only.

Manufacturer:

OXALIS LABS.

Manufacturer's address and place of business:

Village Theda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.