4.1. Therapeutic indications

Rifabutin is indicated for:

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

- the treatment of Nontuberculous mycobacteria (NTM) infections (such as that caused by MAC and M. xenopi).

- pulmonary tuberculosis.

4.2. Posology and method of administration

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

Posology

Adults

- prophylaxis of 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 rifabutin is given in association with clarithromycin (or other macrolides) and/or fluconazole (or related compounds) the rifabutin 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, rifabutin 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 this medicine in children at the present time. Currently available data are described in section 5.2 but no recommendation on a posology can be made.

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.

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, rifabutin should not be used in these patients.

4.4. Special warnings and precautions for use

Before starting rifabutin 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.

Rifabutin 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. Rifabutin 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, rifabutin treatment should be suspended.

Uveitis associated with rifabutin 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.

Clostridioides 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:

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

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

Clinical studies have shown that rifabutin 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 rifabutin 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

Coadministered Drugs

Effect on Rifabutin

Effect on Coadministered Drug

Comments

ANTIRETROVIRALS

Amprenavir

2.9-fold ↑ AUC,

2.2-fold ↑ Cmax

No significant change in kinetics.

A 50% reduction in the rifabutin dose is recommended when combined with amprenavir. Increased monitoring for adverse reactions is warranted.

Atazanavir/Ritonavir

48% ↑ in AUC,

149% ↑ Cmax of rifabutin.

990% ↑ in AUC,

677% ↑ Cmax of 25‑O-desacetyl‑rifabutin

No significant change in kinetics.

A 75% reduction in the dose of rifabutin (to 150 mg daily) is recommended. Increased monitoring for adverse reactions is warranted.

Bictegravir

ND

AUC ↓38%

Cmin ↓56%

Cmax ↓20%

Although not studied, co-administration of rifabutin with Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) is not recommended due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in bictegravir.

Darunavir/Ritonavir

No significant change in rifabutin kinetics.

881% ↑ in AUC,

377% ↑ Cmax of 25‑O-desacetyl‑rifabutin

57% ↑ in AUC,

42% ↑ Cmax of darunavir.

66% ↑ in AUC,

68% ↑ Cmax of ritonavir.

A 75% reduction in the dose of rifabutin (to 150 mg daily) is recommended. Increased monitoring for adverse reactions is warranted.

Dolutegravir

ND

No significant change in dolutegravir kinetics at steady state.

Doravirine

ND

50% ↓ in AUC

68% ↓ in C24

↔ in Cmax

If concomitant use is necessary, increase the doravirine dosage as instructed in doravirine-containing product prescribing information.

Elvitegravir/ Cobicistat

No significant change in rifabutin kinetics.

6.3-fold ↑ in AUC,

4.8-fold ↑ Cmax of 25‑O-desacetyl‑rifabutin

No change in elvitegravir except 67% ↓ Ctrough of elvitegravir.

No change in cobicistat exposure.

Co-administration of rifabutin with elvitegravir/cobicistat is not recommended due to an expected decrease in elvitegravir exposure (see section 4.4).

Etravirine

No significant change in rifabutin kinetics.

37% ↓ in AUC, 37% ↓ in Cmax and 35% ↓ in Cmin.

No dose adjustment of rifabutin is required when etravirine is not co-administered with ritonavir.

Fosamprenavir/ritonavir

64% ↑ AUC.**

35% ↑ AUC and 36% ↑ Cmax, no effect Ctrough (amprenavir).

Dosage reduction of rifabutin by at least 75% (to 150 mg every other day or three times per week) is recommended when combined with Fosamprenavir.

Indinavir

173% ↑ in AUC,

134% ↑ Cmax.

34%↓ in AUC, 25%↓ in Cmax.

Dose reduction of rifabutin to half the standard dose and increase of indinavir to 1000 mg every 8 hours are recommended when rifabutin and indinavir are co-administered.

Lopinavir/ritonavir

5.7-fold ↑ AUC,

3.4 fold ↑ Cmax.**

No significant change in lopinavir Kinetics.

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week).

Increased monitoring for adverse reactions is warranted. Further dosage reduction of rifabutin may be necessary.

Saquinavir

No data.

40% decrease in AUC.

Rilpivirine

ND

42% ↓ in AUC

48% ↓ in Cmin

31% ↓ in Cmax

Although not studied, co-administration of rifabutin rilpivirine/tenofovir alafenamide/emtricitabine is not recommended due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in rilpivirine (see section 4.4).

Co-administration of rifabutin with cabotegravir/rilpivirine prolonged‑release injectable suspension is contraindicated (see section 4.3).

Ritonavir

4-fold increase in AUC, 2.5-fold increase in Cmax.

No data.

Due to this multifold increase in rifabutin concentrations and the subsequent risk of side effects, patients requiring both rifabutin and a protease inhibitor, other protease inhibitors should be considered.

Tipranavir/ritonavir

2.9-fold ↑ AUC, 1.7-fold ↑ Cmax.

No significant change in tipranavir Kinetics.

Therapeutic drug monitoring of rifabutin is recommended.

Co-administration of tipranavir with rifabutin may increase concentrations of rifabutin and its metabolite. Reduce rifabutin dose 75% (e.g., 150 mg every other day) 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 clinical relevance.

ANTI-HCV DRUGS

Sofosbuvir

ND

36% ↓ in Cmax and 24% ↓ AUC

Co-administration of rifabutin with sofosbuvir (alone or in combination) is not recommended (see section 4.4).

ANTIFUNGALS

Fluconazole

82% increase in AUC.

No significant change in steady-state plasma concentrations.

Patients receiving rifabutin and fluconazole concomitantly should be carefully monitored (see section 4.4).

Itraconazole

No data.

70-75% decrease in Cmax and AUC.

A case report indicates an increase in rifabutin serum levels in the presence of itraconazole.

Posaconazole

31%↑ Cmax, 72%↑ AUC.

43%↓ Cmax, 49%↓ AUC.

Co-administration of posaconazole with rifabutin increases rifabutin plasma concentrations and decreases posaconazole plasma concentrations. Concomitant use of rifabutin and posaconazole should be avoided unless the benefit to the patient outweighs the risk. However, if concomitant administration is required, close monitoring of breakthrough fungal infections as well as frequent monitoring for adverse reactions due to 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 co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours or from 200 mg to 350 mg orally, every 12 hours (100 mg to 200 mg orally, every 12 hours in patients less than 40 kg). Careful monitoring of full blood counts and adverse events to rifabutin (e.g. uveitis) is recommended when rifabutin is co-administered with voriconazole.

Ketoconazole/miconazole

No data.

No data.

Co-administered medications, such as ketoconazole, that competitively inhibit the CYP3A activity may increase circulating drug levels of rifabutin.

Coadministered Drugs

Effect on Rifabutin

Effect on Coadministered 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 (not sulfamethoxazole had 14% decrease in AUC and 6% in Cmax but were not considered clinically significant.

ANTI-MAC (Mycobacterium avium 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.

ANTI-TB (Tuberculosis)

Bedaquiline

ND

No change in bedaquiline kinetics.

1.4-fold ↑ in M2 and approximately 3.0-fold ↑ in M3 metabolites of bedaquiline.

If the drugs are co-administered, patients should be monitored for adverse events associated with bedaquiline administration.

Pyrazinamide

No significant change in AUC or Cmax

No significant change in AUC or Cmax

No dose adjustment needed.

ORAL CONTRACEPTIVES

Ethinylestradiol/ Norethindrone

ND

Ethinylestradiol: 20% ↓ in Cmax, 35% ↓ in AUC.

Norethindrone: 32% ↓ in Cmax, 46% ↓ in AUC.

Patients should be advised to use other additional non-hormonal methods of contraception.

OTHER

Methadone

No data.

No significant effect.

No apparent effect of rifabutin on either peak levels of methadone or systemic exposure based upon AUC. Rifabutin kinetics not evaluated.

Tacrolimus

No data.

No data.

Rifabutin decreases tacrolimus trough blood levels.

*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

4.6. Fertility, pregnancy and lactation

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

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

The tolerability of rifabutin 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 rifabutin 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

Gastrointestinal 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

Clostridioides 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 rifabutin is used at 300 mg as monotherapy in MAC prophylaxis, versus rifabutin 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 have been reported.

Anti-tuberculosis drug SCARs.

Anti-tuberculosis drug use may lead to the occurrence of drug reactions 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.

4.9. Overdose

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