LAMPRENE Soft gelatin capsule Ref.[50443] Active ingredients: Chlofazimine

• Efficacy and safety have not been investigated in children, pregnancy, patients with impaired liver function, and not established in patients co-infected with HIV and treated for HIV infection, hepatitis B and/or C.
• QTc interval prolongation may occur with LAMPRENE 50/100 mg soft gelatin capsules administration, which is likely to be augmented by co-administration of other medicines known to cause QTc prolongation (see section 4.3 Contraindications).

Patient adherence

LAMPRENE 50/100 mg soft gelatin capsules should never be used as monotherapy for the treatment of leprosy or MDR-TB. LAMPRENE 50/100 mg soft gelatin capsules must be used in combination with other medicines (see section 4.2 Posology and method of administration).

Patients should be informed of the importance of adherence with the prescribed treatment regimen in order to prevent medicine resistance. Irregularity in administration of medication and poor adherence can lead to delayed and failed treatment, rendering the patient a source of contamination.

Patients should be trained to recognise the signs and symptoms of reactions and relapses following completion of treatment, and should be made aware of the importance of immediately reporting the earliest manifestations of these signs to the relevant healthcare professional.

Lepra reactions

It is recommended to not interrupt MDT during lepra reactions. See section 4.2 Posology and method of administration, for LAMPRENE 50/100 mg soft gelatin capsules dosing in patients who develop ENL (erythema nodosum leprosum reactions). Some data indicate a trend towards reduction in the frequency and severity of ENL in leprosy patients treated with MDT. This trend may be attributed to the anti-inflammatory properties of LAMPRENE 50/100 mg soft gelatin capsules. Nevertheless, temporary, unexplained increases in the reporting of reversal reactions have also been observed in leprosy patients, usually during the first year of treatment with MDT.

Lepra reactions usually respond satisfactorily to standard anti-inflammatory therapy.

Accumulation of clofazimine

The deposition of large amounts of clofazimine in the intestinal mucosa causes irritation, leading to gastrointestinal disturbances (e.g. abdominal pain (sometimes intermittent), nausea, vomiting and diarrhoea), sometimes with more severe clinical manifestations such as gastrointestinal haemorrhage and intestinal obstruction. Clofazimine has heterogeneous distribution throughout the body and a slow elimination rate, accumulating mainly in fatty tissue, the reticuloendothelial system (macrophages, histiocytes and spleen), and the skin. Adverse reactions to clofazimine are mainly linked to its uptake by tissue and organs. Because of this, the use of high doses for long periods should be avoided. After prolonged administration in high doses, clofazimine may accumulate in various organs, body fluids and tissues as crystals. Among the viscera, the jejunum has the highest drug deposition, closely followed by the spleen. If crystals are deposited in the mesenteric lymph nodes and/or histiocytes at the lamina propria of the jejunal mucosa, this may lead to intestinal obstruction. Fatalities have been reported following gastrointestinal side effects. If gastrointestinal symptoms develop during treatment, the dosage should be reduced or the interval between doses prolonged.

Symptoms may slowly regress on withdrawal of LAMPRENE 50/100 mg soft gelatin capsules.

In the event of persistent diarrhea or vomiting, the patient should be hospitalised.

Skin discolouration

Medical practitioners should be aware that skin discolouration due to LAMPRENE 50/100 mg soft gelatin capsules may result in depression (cases of depression with suicide have been reported). Patients should be warned that LAMPRENE 50/100 mg soft gelatin capsules may cause discolouration of the conjunctiva, lacrimal fluid, sweat, sputum, urine, faeces, nasal secretions, semen and breast milk, and reddish to brownish-black discolouration of the skin. Patients should be told that discolouration of the skin may take several months or years to disappear after the end of therapy with LAMPRENE 50/100 mg soft gelatin capsules.

Torsades de Pointes and QT prolongation

Cases of Torsades de Pointes with QT prolongation have been reported in patients receiving LAMPRENE 50/100 mg soft gelatin capsules mostly at doses higher than usually recommended or in combination with other QT-prolonging medicines (such as bedaquiline, fluoroquinolones, delamanid, rilpivirine, lopinavir, atazanavir, nelfinavir, saquinavir). Concomitant administration with other medicines known to prolong QTc interval up to the time intervals known to induce serious dysrhythmias is contraindicated (see section 4.3 Contraindications and section 4.5 Interaction with other medicines and other forms of interaction). LAMPRENE 50/100 mg soft gelatin capsules should be discontinued if the QTc prolongation exceeds 500 milliseconds (ms) and/or the Qtc prolongation exceeds 60 milliseconds (ms) from baseline or if the patient develops dysrhythmias. Patients receiving LAMPRENE 50/100 mg soft gelatin capsules at recommended doses and/or doses higher than usually recommended and/or in combination with QT-prolonging medicines, should have regular clinical monitoring at baseline and regular ECGs performed to monitor for QT prolongation and cardiac dysrhythmias.

Interactions

As clofazimine is predicted to be a moderate to strong inhibitor of CYP3A (CYP3A4 and CYP3A5) substrates, caution should be exercised while co-administering LAMPRENE 50/100 mg soft gelatin capsules with other medicines which are CYP3A substrates (see section 4.5 Interaction with other medicines and other forms of interaction).

Dapsone

LAMPRENE appears to have no important effects on the pharmacokinetics of dapsone, although a transient increase in the urinary excretion of dapsone occurred in a few patients. Limited data suggesting that dapsone inhibits the anti-inflammatory activity of LAMPRENE 50/100 mg soft gelatin capsules have not been confirmed. If leprosy-associated inflammatory reactions develop in patients being treated with dapsone and LAMPRENE 50/100 mg soft gelatin capsules, it is still advisable to continue treatment with both medicines.

Rifampicin

LAMPRENE reduces rifampicin absorption in leprosy patients, increasing the time it takes for the peak serum concentration to be reached and prolonging the elimination half-life. Total exposure (AUC) of rifampicin was not affected, so this interaction is unlikely to be clinically significant.

Isoniazid

In volunteers receiving clofazimine (150 mg daily) and standard doses of isoniazid (300 mg daily), elevated concentrations of LAMPRENE 50/100 mg soft gelatin capsules were detected in plasma and urine, compared to clofazimine alone.

Interaction with QT prolonging medicines

Cases of Torsades de Pointes with QT prolongation have been reported in patients receiving LAMPRENE 50/100 mg soft gelatin capsules in combination with QT prolonging medicines. Caution is recommended when clofazimine is administered with other medicines (e.g: bedaquiline, fluoroquinolones, delamanid, azithromycin, rilpivirine, lopinavir, atazanavir, nelfinavir, saquinavir) with known QT interval prolonging potential (see section 4.3 Contraindications, section 4.4 Special warnings and precautions for use).

Effects of LAMPRENE 50/100 mg soft gelatin capsules on CYP3A (CYP3A4 and CYP3A5) substrates

As LAMPRENE 50/100 mg soft gelatin capsules is predicted to be a moderate to strong inhibitor of CYP3A (CYP3A4 and CYP3A5) substrates, caution should be exercised while co-administering LAMPRENE 50/100 mg soft gelatin capsules with other medicines which are CYP3A substrates. No clinical interaction studies have been performed with other CYP3A substrates. Clofazimine inhibits the CYP3A enzyme in vitro. Based on Physiologically Based Pharmacokinetic Modelling (PBPK) modeling results, clofazimine is predicted to be a moderate to strong CYP3A inhibitor.

Hence, caution should be exercised with the concomitant administration of LAMPRENE 50/100 mg soft gelatin capsules and CYP3A substrates (e.g.: anti-mycobacterial medicines (bedaquiline, delamanid, clarithromycin), selected unboosted anti-retrovirals (amprenavir, delaviridine, efavirenz, etravirine, indinavir, nelfinavir, raltegravir, rilpivirine, simeprevir, maraviroc), anti-hyperlipidaemic medicines and anti-hypertension medicines (simvastatin, lovastatin, losartan, verapamil, diltiazem, nitrendipine, amlodipine, nislodipine, nifedipine, eplerenone, felodipine, lercanidipine), anti-diabetics (pioglitazone, repaglinide, saxagliptin)).

Effects of other medicines on LAMPRENE 50/100 mg soft gelatin capsules

In a healthy volunteer study of a combination regimen including clofazimine, cycloserine, ethionamide, para-aminosalicyclic acid, and pyridoxine, the C_max and Tmax values of clofazimine were similar to those reported in other studies where clofazimine was administered alone, suggesting no major effects of these medicines on the pharmacokinetics of clofazimine. In patients with pulmonary TB, where clofazimine was dosed alone and in combination with bedaquiline, pyrazinamide and pretomanid, the C_max and AUC values of clofazimine were similar between the groups suggesting no major effects of these medicines on the pharmacokinetics of clofazimine.

Pregnancy

Safety of clofazimine in pregnancy has not been established and experience with LAMPRENE 50/100 mg soft gelatin capsules in pregnancy is limited. Clofazimine crosses the placenta and harm to the foetus cannot be excluded. Skin discolouration has been observed in newborn babies exposed to clofazimine in utero. Use of LAMPRENE 50/100 mg soft gelatin capsules in pregnancy can be considered in patients with limited treatment options. Appropriate counselling of pregnant woman and her partner should be done.

Animal studies revealed no evidence of teratogenicity but adverse effects in the foetus were observed at high doses. In the mouse, there were signs of foetotoxicity (e.g. retardation of foetal skull ossification at high doses).

Breastfeeding

Safety of clofazimine in lactation has not been established.

Clofazimine passes into the breast milk, and skin discolouration may occur in the infant. Women using LAMPRENE 50/100 mg soft gelatin capsules should not breastfeed their infants.

Fertility

There was evidence of impaired fertility in one study in female rats receiving clofazimine 50 mg/kg/day. The effect of clofazimine on fertility in humans is unknown.

Dizziness, reduced visual acuity, nausea, fatigue and headache have been reported on LAMPRENE 50/100 mg soft gelatin capsules therapy. Patients experiencing such adverse reactions should not drive a vehicle or operate machines.

Summary of the safety profile

The safety profile of LAMPRENE 50/100 mg soft gelatin capsules is similar when used in leprosy and DR-TB.

Tabulated summary of side effects

Side effects are listed in Table 2. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first.

Table 2. Summary of side effects:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s publications: https://www.sahpra.org.za/Publications/Index/8.

Not applicable.