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1. Mycobutin
2. Mycobutin

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Mycobutin.

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 150.0 mg of rifabutin.

Excipient(s) with known effect:

For the full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Hard capsule

Opaque, red-brown, Size N°. 0 hard gelatin capsules.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

4.2. Posology and method of administration

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

Posology

Adults

-    prophylaxis ofM. 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 antimycobacterial 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.

4.3 Contraindications

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.

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

4.4 Special warnings and precautions for use

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 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.

4.5. Interaction with other medicinal products and other forms of interaction

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.

Coadministered drugs	Effect on rifabutin	Effect on co-administered Comments drug
ANTIVIRALS
Amprenavir	2.9-fold AUC, 2.2- fold | Cmax	No significant change in kinetics.	A 50% reduction in the rifabuti dose is recommended when combined with amprenavir. Increased monitori for adverse reactions is warranted.
Fosamprenavir/ritonavir	64% t AUC **	35% t AUC and 36% | Cmax, no effect Ctrough (amprenavir)	Dosage reduction of rifabutin b least 75% (to 150 mg every oth day or three times per week) is recommended when combined with fosamprenavir
Indinavir	173% T in	34%^ in AUC, 25%^ in Cmax	Dose reduction of rifabutin to h

	AUC, 134% t Cmax		the standard dose and increase indinavir to 1000 mg every 8 h are recommended when rifabut and indinavir are coadministere
Lopinavir/ritonavir	5.7-fold t AUC, 3.4 fold | Cmax**	No significant change in lopinavir kinetics	Dosage reduction of rifabutin b least 75% of the usual dose of 3 mg/day is recommended (i.e., a maximum dose of 150 mg ever other day or three times per we Increased monitoring for adver reactions is warranted. Further dosage reduction of rifabutin may be necessary.
Saquinavir	No data.	40% decrease in AUC.
Ritonavir	4-fold increase in AUC, 2.5-fold increase in Cmax	No data	Due to this multifold increase ir rifabutin concentrations and the subsequent risk of side effects, patients requiring both rifabutin a protease inhibitor, other prote; inhibitors should be considered.
Tipranavir/ritonavir	2.9-fold T AUC, 1.7-fold | Cmax	No significant change in tipranavir kinetics	Therapeutic drug monitoring of rifabutin is recommended. Coadministration of tipranavir rifabutin may increase concentrations of rifabutin and metabolite. Reduce rifabutin dc 75% (e.g., 150 mg every other and increase monitoring
Zidovudine	No significant change in kinetics	Approx. 32% decrease in Cmax and AUC.	A large clinical study has shown that these changes are of no clin relevance.

ANTIFUNGALS

Fluconazole	82% increase in AUC.	No significant change in steady-state plasma concentrations
Itraconazole	No data.	70-75% decrease in Cmax and AUC.	A case report indicates an increase i rifabutin serum levels in the presenc itraconazole.
Posaconazole	31% Cmax, 72% AUC	43% Cmax, 49% AUC	Co-administration of posaconazole with rifabutin increases rifabutin plasma concentrations and decrease posaconazole plasma concentration Concomitant use of rifabutin and posaconazole should be avoided un the benefit to the patient outweighs risk. However, if concomitant administration is required, close monitoring of breakthrough fungal infections as well as frequent monitoring for adverse reactions dr increased rifabutin plasma

			concentrations (e.g., uveitis, leukopenia) are recommended.
Voriconazole	195% Cmax, 331% AUC ***	Rifabutin (300 mg once daily) decreased the Cmax and AUC of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the Cmax and AUC of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily Cmax and AUC were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily.	If the benefit outweighs the risk, rifabutin may be coadministered w: voriconazole if the maintenance do of voriconazole is increased to 5 m, intravenously every 12 hours or fro 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, ev 12 hours in patients less than 40 kg Careful monitoring of full blood co and adverse events to rifabutin (e.g uveitis) is recommended when rifabutin is coadministered with voriconazole
Ketoconazole/ miconazole	No data.	No data.	Co-administered medications, such ketoconazole, that competitively inf the Cyt P450IIIA activity may incre circulating drug levels of rifabutin.

Coadministered drugs		Effect on rifabutin		Effect on co-administered drug	Comments
ANTI-PCP (Pneumocystis carinii pneumonia)
Dapsone	No data.		Approximately 27%-40% decrease in AUC.		Study conducted in HIV infected patients (rapid and slow acetylators)
Sulfamethoxazole -Trimethoprim	No significant change in Cmax and AUC.		Approx. 15-20% decrease in AUC.		In another study, only trimethoprim sulfamethoxazole had 14% decrease AUC and 6% in Cmax but were not considered clinically significant.
ANTI-MAC (Mycobacterium avium intracellulare complex)
Azithromycin		No PK interaction		No PK interaction
Clarithromycin		Approx. 77% increase in AUC.		Approx. 50% decrease in AUC.	Study conducted in HIV infected patients
OTHER
Methadone		No data.		No significant effect.	No apparent effect of rifabutin on ei peak levels of methadone or system; exposure based upon AUC. Rifabui kinetics not evaluated.
Oral contraceptives		No data.		No data.	Contraceptive cover may not be adequate during concomitant therap with rifabutin, therefore, patients sh be advised to use other methods of

			contraception.
Tacrolimus	No data.	No data.	Rifabutin decreases tacrolimus troug blood levels.

** - Drug plus active metabolite *** - voriconazole dosed at 400 mg twice daily

4.6    Pregnancy and lactation

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).

4.7    Effects on ability to drive and    use machines

There have been no reports of adverse effects on ability to drive and use machines.

4.8    Undesirable effects

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’.

MedDRA System Organ Class	Frequency	Undesirable Effects
Blood and lymphatic system disorders	Very common	Leukopenia

	Common	Anaemia
	Uncommon	Pancytopenia Agranulocytosis Lymphopenia Granulocytopenia Neutropenia White blood cell count decreased Neutrophil count decreased Thrombocytopenia Platelet count decreased
Immune system disorders	Common	Rash
	Uncommon	Hypersensitivity Bronchospasm Eosinophilia
Eye disorders	Uncommon	Uveitis Corneal deposits
Gastrointestin al disorders	Common	Nausea
	Uncommon	Vomiting
Hepatobiliary disorders	Uncommon	Jaundice Hepatic enzyme increased
Skin and subcutaneous tissue disorders	Uncommon	Skin discolouration
Musculoskeletal and connective tissue disorders	Common	Myalgia
	Uncommon	Arthralgia
General disorders and administration site conditions	Common	Pyrexia

Shock and Clostridium difficile colitis are mandated adverse reactions for the pharmacological class; both events were neither observed in the clinical trials nor in the spontaneous reporting for rifabutin.

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.

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

4.9 Overdose

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

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Antibiotics, ATC code: J04AB04

In vitro activity of rifabutin against laboratory strains and clinical isolates ofM. tuberculosis has been shown to be very high. In vitro studies carried out so far have shown that from one-third to half ofM. 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.

5.2 Pharmacokinetic properties

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 pg/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./₂ of rifabutin in man is approximately 35-40 hours.

Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose Sodium lauryl sulphate Magnesium stearate Silica gel

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

6.4    Special precautions for storage

Store below 25°C

6.5 Nature and contents of container

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

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Pfizer Ltd Ramsgate Road Sandwich Kent CT13 9NJ United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00057/1017

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

15 ^th January 2003

10 DATE OF REVISION OF THE TEXT

10/12/2014