Mycobutin is indicated for:

- the prophylaxis of M. avium intracellulare complex (MAC) infections in patients with HIV disease with CD4 counts lower than 75 cells/mcl.

- the treatment of non-tuberculous mycobacterial disease (such as that caused by MAC and M. xenopi).

- pulmonary tuberculosis.

Mycobutin can be administered as a single, daily, oral dose at any time independently of meals.

Posology

Adults

- prophylaxis of M. avium intracellulare complex (MAC) infections in patients with HIV disease with CD4 counts lower than 75 cells/mcl:

300 mg (2 capsules) as a single agent.

- treatment of non-tuberculous mycobaterial disease:

450 - 600 mg (3 - 4 capsules) in combination regimens for up to 6 months after negative cultures are obtained.

When Mycobutin is given in association with clarithromycin (or other macrolides) and/or fluconazole (or related compounds) the Mycobutin dosage may need to be reduced to 300 mg (see sections 4.4 and 4.5).

- treatment of pulmonary tuberculosis:

150 - 450 mg (1 - 3 capsules) in combination regimens for at least 6 months.

In accordance with the commonly accepted criteria for the treatment of mycobacterial infections, Mycobutin should always be given in combination with other anti-mycobacterial drugs not belonging to the family of rifamycins.

Paediatric population

There are inadequate data to support the use of Mycobutin in children at the present time.

Elderly

No specific recommendations for dosage alterations in the elderly are suggested.

Hypersensitivity or history of hypersensitivity to the active substance, other rifamycins (e.g. rifampicin) or to any of the excipients listed in section 6.1.

Concomitant use with rilpivirine containing prolonged-release suspension for injection is contraindicated (see section 4.5).

Due to insufficient clinical experience in pregnant and breast-feeding women and in children, Mycobutin should not be used in these patients.

Before starting Mycobutin prophylaxis, patients should be assessed to ensure that they do not have active disease caused by pulmonary tuberculosis or other mycobacteria.

Prophylaxis against MAC infection may need to be continued throughout the patient's lifetime.

Mycobutin may impart a red-orange colour to the urine and possibly to skin and body secretions. Contact lenses, especially soft, may be permanently stained.

Mild hepatic impairment does not require a dose modification. Mycobutin should be used with caution in cases of severe liver insufficiency. Mild to moderate renal impairment does not require any dosage adjustment.

Severe renal impairment (creatinine clearance below 30 ml/min) requires a dosage reduction of 50%.

It is recommended that white blood cell and platelet counts and liver enzymes be monitored periodically during treatment.

Because of the possibility of occurrence of uveitis, patients should be carefully monitored when rifabutin is given in combination with clarithromycin (or other macrolides) and/or fluconazole (and related compounds). If such an event occurs, the patient should be referred to an ophthalmologist and, if considered necessary, Mycobutin treatment should be suspended.

Uveitis associated with Mycobutin must be distinguished from other ocular complications of HIV.

HIV protease inhibitors act as substrates or inhibitors of CYP450 3A4 mediated metabolism. Therefore, due to significant drug-drug interactions between protease inhibitors and rifabutin, their concomitant use should be based on the overall assessment of the patient and patient specific drug profile (see section 4.5).

Rifabutin is a CYP450 3A inducer. Therefore, co-administration with antiretroviral medicines including but not limited to bictegravir, elvitegravir, oral rilpivirine, or doravirine and anti-HCV medicines including but not limited to sofosbuvir (alone or in combination) is not recommended due to the expected decrease in plasma concentrations of the antiretrovirals and anti-HCV medicines which may lead to loss of virologic response and possible development of resistance (see section 4.5).

For further recommendations, please refer to the most recent prescribing information of the antiretrovirals or contact the specific manufacturer.

Clostridium difficile associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including rifabutin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhoea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

There have been reports of severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) with anti-tuberculosis drugs (see section 4.8). If patients develop a skin rash they should be monitored closely and suspect drug(s) discontinued if lesions progress. Identifying the specific drug is difficult, as multiple anti-tuberculosis drugs are prescribed in association concurrently. Specifically, for DRESS, a multi-system potential life-threatening SCAR, time to onset of the first symptoms may be prolonged. DRESS is a clinical diagnosis, and its clinical presentation remains the basis for decision making. An early withdrawal of the suspect drug is essential because of the syndrome's mortality and visceral involvement (e.g., liver, bone marrow or kidney).

Excipients:

Mycobutin contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

Rifabutin has been shown to induce the enzymes of the cytochrome P450 3A (CYP450 3A) subfamily and therefore may affect the pharmacokinetic behaviour of drugs metabolised by the enzymes belonging to this subfamily. Upward adjustment of the dosage of such drugs may be required when administered with Mycobutin.

Similarly, Mycobutin might reduce the activity of analgesics, anticoagulants, corticosteroids, cyclosporin, digitalis (although not digoxin), oral hypoglycaemics, narcotics, phenytoin and quinidine.

Clinical studies have shown that Mycobutin does not affect the pharmacokinetics of didanosine (DDI), and isoniazid (however, for the latter refer also to undesirable effects). On the basis of the above metabolic considerations no significant interaction may be expected with ethambutol, theophylline, sulfonamides, pyrazinamide and zalcitabine (DDC).

As p-aminosalicylic acid has been shown to impede GI absorption of rifamycins it is recommended that when it and Mycobutin are both to be administered they be given with an interval of 8 - 12 hours.

The following table provides details of the possible effects of co-administration, on rifabutin and the co-administered drug, and risk-benefit statement.

Table 1: Rifabutin Interaction Studies

*ND - No data

AUC - Area under the Concentration vs. Time Curve

Cmax - Maximum serum concentration

Ctrough - Concentration immediately prior to administration of the next dose

** - Drug plus active metabolite

*** - voriconazole dosed at 400 mg twice daily

Due to lack of data in pregnant women, as a precautionary measure, Mycobutin should not be administered to pregnant women or those breast-feeding children even though in experimental animal studies the drug was not teratogenic.

Mycobutin may interact with oral contraceptives (see section 4.5).

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

The tolerability of Mycobutin in multiple drug regimens, was assessed in both immunocompetent and immunocompromised patients, suffering from tuberculosis and non-tuberculous mycobacteriosis in long term studies with daily dosages up to 600 mg.

Bearing in mind that Mycobutin was often given in these studies as part of a multidrug regimen it is not always possible to define with certainty a drug-event relationship. Treatment discontinuation was necessary only in a very few cases. Adverse reactions identified through clinical trials or post-marketing surveillance by system organ class (SOC) are listed below in the following frequencies, very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1,000 to < 1/100, rare ≥ 1/10,000 to < 1/1,000, very rare <1/10,000 and 'not known'.

Clostridium difficile colitis is a mandated adverse reaction for the pharmacological class; this event was neither observed in the clinical trials nor in the spontaneous reporting for rifabutin.

Anaphylactic shock has occurred with other antibiotics of the same class.

Mild to severe, reversible uveitis has been reported less frequently when Mycobutin is used at 300 mg as monotherapy in MAC prophylaxis, versus Mycobutin in combination with clarithromycin (or other macrolides) for MAC treatment (see section 4.4).

Flu-like syndrome, chest pressure or pain with dyspnoea and rarely hepatitis and haemolysis has been reported.

Anti-tuberculosis drug SCARs.

Anti-tuberculosis drug use may lead to the occurrence of drug reaction with eosinophilia and systemic symptoms (DRESS) as well as other SCARs such as SJS, TEN, and AGEP (see section 4.4).

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.

Gastric lavage and diuretic treatment should be carried out. Supportive care and symptomatic treatment should be administered.

Pharmacotherapeutic group: Antibiotics, ATC code: J04AB04

In vitro activity of rifabutin against laboratory strains and clinical isolates of M. tuberculosis has been shown to be very high. In vitro studies carried out so far have shown that from one-third to half of M.tuberculosis strains resistant to rifampicin are susceptible to rifabutin, indicating that cross-resistance between the two antibiotics is incomplete.

The in vivo activity of rifabutin on experimental infections caused by M. tuberculosis was about 10 times greater than that of rifampicin in agreement with the in vitro findings.

Rifabutin was seen to be active against non-tuberculous (atypical) mycobacteria including M. avium-intracellulare (MAC), in vitro as well as in experimental infections caused by these pathogens in mice with induced immuno-deficiency.

Absorption

In man, rifabutin is rapidly absorbed and maximum plasma concentrations are reached around 2-4 hours after oral administration. The pharmacokinetics of rifabutin is linear after single administration of 300, 450, and 600 mg to healthy volunteers. With these doses, C max is in the range of 0.4-0.7 µ g/ml. Plasma concentrations are maintained above the MIC values for M tuberculosis up to about 30 hours from administration.

Distribution

Rifabutin is widely distributed in various animal organs with the exception of the brain. In particular, in human lung tissue the concentrations measured up to 24 hours after dosing were about 5-10 times higher than the plasma levels.

The intracellular penetration of rifabutin is very high as demonstrated by intracellular/extracellular concentration ratios which ranged from 9 in neutrophils to 15 in monocytes, both obtained from human sources.

The high intracellular concentration is likely to play a crucial role in sustaining the efficacy of rifabutin against intracellular pathogens such as mycobacteria.

Elimination

Rifabutin and its metabolites are eliminated mainly by the urinary route. The t_½ of rifabutin in man is approximately 35-40 hours.

Preclinical safety studies of rifabutin indicate a good safety margin in rodents and in monkeys.

In repeated dose studies, target organs were identified at doses producing blood levels higher than those achieved with recommended doses for human therapy. The main target organs are liver and, to a lesser degree, erythrocytes.

Rifabutin did not show any teratogenic, mutagenic or carcinogenic potential.

Microcrystalline cellulose

Sodium laurylsulfate

Magnesium stearate

Silica gel

Not applicable.

2 years.

Store below 25° C

Transparent PVC/Al blisters in cardboard cartons containing 30 capsules.

No special requirements.