Mycobutin.

Opaque, red-brown, hard gelatin capsules Size N°. 0 containing 150 mg rifabutin in transparent PVC/Al blisters or in amber glass bottles.

The capsules are for oral administration.

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.

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 Section 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.

Children

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.

Mycobutin is contra-indicated in patients with a history of hypersensitivity to rifabutin or other rifamycins (eg rifampicin).

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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including rifabutin, and may range in severity from mild diarrhea 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 diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

Rifabutin has been shown to induce the enzymes of the cytochrome P450 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, sulphonamides, 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.

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).

There have been no reports of adverse effects on 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 possible to define with certainty a drug-event relationship. Treatment discontinuation was necessary only in a very few cases. The most commonly reported adverse events, were primarily related to:

- the gastro-intestinal system, such as nausea, vomiting, increase of liver enzymes, jaundice;

- the blood and lymphatic system, such as leucopenia, neutropenia, thrombocytopenia and anemia, where the frequency and severity of haematologic reactions could be increased by combined administration of isoniazid;

- the musculo-skeletal system: arthralgia and myalgia.

Also, fever, rash and rarely other hypersensitivity reactions such as eosinophilia, bronchospasm and shock might occur as has been seen with other antibiotics.

In addition, mild to severe, reversible uveitis has been reported. The risk appears to be low, when Mycobutin is used at 300 mg as monotherapy in MAC prophylaxis, but increases when Mycobutin is administered at higher doses in combination with clarithromycin (or other macrolides) for MAC treatment (see Section 4.4). The possible role of fluconazole (and related compounds) has not been established yet.

Asymptomatic corneal opacities have been reported after long term therapy.

Pseudojaundice (yellow skin discolouration with normal plasma bilirubin) has been reported with high doses of rifabutin. Flu-like syndrome, chest pressure or pain with dyspnoea and rarely hepatitis and haemolysis. Clostridium difficile diarrhoea has been reported rarely.

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

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.

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 µg/ml. Plasma concentrations are maintained above the MIC values for M. tuberculosis up to about 30 hours from administration.

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.

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 lauryl sulphate

Magnesium stearate

Silica gel

None known.

24 months at room temperature.

None.

Transparent PVC/Al blisters in cardboard cartons containing 30 capsules or amber glass bottles containing 30 or 100 capsules.

There are no special instructions for handling.

Pfizer Ltd

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

PL 00057/1017

15th January 2003.

February 2010

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