Interactions : אינטראקציות

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 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
Coadministered Drugs        Effect on                     Effect on                       Comments Rifabutin                  Coadministered
Drug
ANTIRETROVIRALS
Amprenavir                    2.9-fold ↑ AUC,        No significant           A 50% reduction in the rifabutin 2.2-fold ↑ Cmax        change in kinetics.      dose is recommended when combined with amprenavir.
Increased monitoring for adverse reactions is warranted.
Atazanavir/Ritonavir          48% ↑ in AUC,          No significant           A 75% reduction in the dose of 149% ↑ Cmax of         change in kinetics.      rifabutin (to 150 mg daily) is rifabutin.                                      recommended. Increased monitoring for adverse reactions
990% ↑ in AUC,                                  is warranted.
677% ↑ Cmax of
25-O- desacetyl-rifabutin

Bictegravir                   ND                     AUC 38%                  Although not studied, co- Cmin 56%                 administration of rifabutin with
Cmax 20%                 Biktarvy
(bictegravir/emtricitabine/tenofov ir alafenamide) is not recommended due to an expected decrease in tenofovir alafenamide in addition to the reported reduction in bictegravir.
Darunavir/Ritonavir           No significant         57% ↑ in AUC, 42%        A 75% reduction in the dose of change in              ↑ Cmax of                rifabutin (to 150 mg daily) is rifabutin kinetics.    darunavir.               recommended. Increased monitoring for adverse reactions
881% ↑ in AUC,      66% ↑ in AUC, 68%           is warranted.
377% ↑ Cmax of      ↑ Cmax of ritonavir.
25-O- desacetyl-rifabutin

Dolutegravir                  ND                     No significant change in

                                                 dolutegravir kinetics at steady state.
Doravirine                 ND                    50% in AUC              If concomitant use is necessary, 68% in C24              increase the doravirine dosage as in Cmax             instructed in doravirine- containing product prescribing information.
Elvitegravir/ Cobicistat   No significant        No change in            Co-administration of rifabutin change in             elvitegravir except     with elvitegravir/cobicistat is not rifabutin kinetics.   67% Ctrough of          recommended due to an expected elvitegravir.           decrease in elvitegravir exposure
6.3-fold ↑ in                                 (see section 4.4).
AUC, 4.8-fold ↑     No change in
Cmax of 25-O-       cobicistat exposure.
desacetyl-rifabutin

Etravirine                 No significant        37% in AUC, 37%         No dose adjustment of rifabutin is change in               in Cmax and 35%       required when etravirine is not rifabutin kinetics.    in Cmin.               co-administered with ritonavir.

Fosamprenavir/ritonavir    64% ↑ AUC.**          35% ↑ AUC and           Dosage reduction of rifabutin by 36% ↑ Cmax, no          at least 75% (to 150 mg every effect Ctrough          other day or three times per
(amprenavir).           week) is recommended when combined with Fosamprenavir.
Indinavir                  173%  in AUC,        34% in AUC,            Dose reduction of rifabutin to 134% ↑ Cmax.          25% in Cmax.           half the standard dose and increase of indinavir to 1000 mg every 8 hours are recommended when rifabutin and indinavir are coadministered.
Lopinavir/ritonavir        5.7-fold ↑ AUC,       No significant          Dosage reduction of rifabutin by 3.4 fold ↑ Cmax.**    change in lopinavir     at least 75% of the usual dose of Kinetics.               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            Although not studied, co- 48%  in Cmin           administration of rifabutin rilpivirine/tenofovir
31%  in Cmax 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    No data.                Due to this multifold increase in AUC, 2.5-fold                                 rifabutin concentrations and the increase in Cmax.                             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,       No significant          Therapeutic drug monitoring of 1.7-fold ↑ Cmax.      change in tipranavir    rifabutin is recommended.
Kinetics.               Coadministration 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        Approx. 32%             A large clinical study has shown change in kinetics.   decrease in Cmax and    that these changes are of no AUC.                    clinical relevance.
Delavirdine            No data.              Oral clearance  5-     Study conducted in HIV-1 fold resulting in       infected patients Rifabutin is not significantly lower     recommended for patients dosed mean trough plasma      with delavirdine mesylate 400 mg concentrations          q8h.
(18±15 to 1.0±0.7
M)
Didanosine             No significant        No significant change in kinetics    change in kinetics at steady state.
ANTI-HCV DRUGS
Sofosbuvir             ND.                   36% in Cmax and         Co-administration of rifabutin 24% AUC                 with sofosbuvir (alone or in combination) is not recommended (see section 4.4).
ANTIFUNGALS
Fluconazole            82% increase in       No significant          Patients receiving rifabutin and AUC.                  change in steady-       fluconazole concomitantly should state plasma            be carefully monitored (see concentrations.         section 4.4).
Itraconazole           No data.              70-75% decrease in      A case report indicates an increase Cmax and AUC.           in rifabutin serum levels in the presence of itraconazole.
Posaconazole           31%↑ Cmax, 72%↑       43% Cmax, 49%           Co-administration of AUC.                  AUC.                    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,          Rifabutin (300 mg       If the benefit outweighs the risk, 331%↑ AUC.***        once daily)             rifabutin may be coadministered decreased the Cmax      with voriconazole if the and AUC of              maintenance dose of voriconazole voriconazole at 200     is increased to 5 mg/kg mg twice daily by       intravenously every 12 hours or
69% and 78%,            from 200 mg to 350 mg orally,
respectively.           every 12 hours (100 mg to 200
During co-              mg orally, every 12 hours in administration with     patients less than 40 kg). Careful rifabutin, the Cmax     monitoring of full blood counts and AUC of              and adverse events to rifabutin voriconazole at         (e.g. uveitis) is recommended
350 mg twice daily      when rifabutin is coadministered were 96% and 68%        with voriconazole.
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.
Ketoconazole/          No data.             No data.                Co-administered medications, miconazole                                                          such as ketoconazole, that competitively inhibit the Cyt
P450IIIA activity may increase circulating drug levels of rifabutin.

Coadministered Drugs       Effect on              Effect on                       Comments Rifabutin         Coadministered Drug
ANTI-PCP (Pneumocystis carinii pneumonia)


Dapsone                No data.             Approximately 27%-       Study conducted in HIV 40% decrease in AUC.     infected patients (rapid and slow acetylators).
Sulfamethoxazole-      No significant       Approx. 15-20%           In another study, only Trimethoprim           change in Cmax and   decrease in AUC.         trimethoprim (not AUC.                                          sulfamethoxazole had 14% decrease in 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%         Approx. 50% decrease        Study conducted in HIV increase in AUC.    in AUC.                     infected patientsDose of rifabutin should be adjusted in the presence of clarithromycin.(See Section
4.2, Posology and Method of
Administration and also,
Section 4.4, Special Warnings
& Special Precautions for Use)
ANTI-TB (Tuberculosis)
Ethambutol             No data.             No significant change in AUC or Cmax
Isoniazid              No data.             Pharmacokinetics not affected
Bedaquiline            ND                   No change in             If the drugs are co- bedaquiline kinetics.    administered, patients should be monitored for adverse
1.4-fold ↑ in M2 and     events associated with approximately 3.0-fold   bedaquiline administration.
↑ in M3 metabolites of bedaquiline.
Pyrazinamide      No significant            No significant change    No dose adjustment needed.
change in AUC or          in AUC or Cmax
Cmax
ORAL CONTRACEPTIVES
Ethinylestradiol/ ND                        Ethinylestradiol: 20%    Patients should be advised to Norethindrone                                 in Cmax, 35% in        use other additional non- AUC.                     hormonal methods of contraception.
Norethindrone: 32% in Cmax, 46% in
AUC.
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.
Theophylline                 No data.               No significant change in AUC or Cmax compared with baseline.

*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