Rifabutin bioavailability is increased by amprenavir,atazanavir,fosamprenavir/ritonavir, indinavir, lopinavir/ritonavir, nelfinavir, tipranavir/ritonavir, and especially ritonavir, with an increased risk of toxicity. Rifabutin modestly decreases bioavailability of indinavir, nelfinavir, and particularly saquinavir(with an increased risk of therapeutic failure), but has no effect onamprenavir, atazanavir, and ritonavir-boosted fosamprenavir.The combination of rifabutin with protease inhibitors may beused,but dosage adjustments of rifabutin or both drugs are often necessary.Rifampicin (rifampin) bioavailability is increased by indinavir,but amprenavir has no effect. Rifampicin markedly reduces thebioavailability of amprenavir,atazanavir/ritonavir, indinavir,indinavir with ritonavir, lopinavir/ritonavir, nelfinavir and saquinavir, but only modestly reduces that of ritonavir. The effects of rifampicin on lopinavir/ritonavir and saquinavir/ritonavir can be overcome by increasing protease inhibitor dose, butthis appears to increase adverse effects (hepatotoxicity).
Rifabutin. When amprenavir 1.2 g twice daily was given with rifabutin 300mg daily to 11 healthy subjects for 10 days there was an almost threefold increase in AUC of rifabutin, but pharmacokinetics of amprenavir were not significantly altered. The combination was poorly tolerated,with 5 of 11 subjects stopping treatment between days 1 and 9 due to adverse events (See reference number 1). When reduced doses of rifabutin (150 mg every other day) were given with fosamprenavir/ritonavir 700/100 mg twice daily rifabutin AUC was unchanged and maximum level was decreased by 14%, when compared with rifabutin 300mg once daily given alone. However, 25-O-desacetylrifabutin AUC and maximum level were increased 11-fold and sixfold, respectively, which could potentially lead to an increase of rifabutin-related adverse events such as uveitis. Based on historical comparison,rifabutin did not appear to reduce amprenavir exposure from fosamprenavir/ritonavir (See reference number 2,3).
1.2 g twice daily with rifampicin 600mg daily to for 4 days pharmacokinetics of rifampicin were not affected, but AUC of amprenavir was reduced by 82%. The maximum plasma level of amprenavir was also reduced by 70%,from 9.2 to 2.78 micrograms/mL (See reference number 1). It is expected that concurrent use of fosamprenavir or fosamprenavir/ritonavir with rifampicin will also result in large decreases in plasma concentrations of amprenavir (See reference number 2,3).
Rifabutin. The manufacturer notes that atazanavir 400mg daily given with rifabutin 150mg once daily for 14 days did not have any important effect on AUC of atazanavir. However, AUC of rifabutin 150mg was 2.3-fold higher than historical data for a standard 300mg dose (See reference number 4).
Rifampicin (Rifampin). When rifampicin 600mg daily was given with atazanavir/ritonavir 300/100 mg once daily, AUC and minimum levels of atazanavir were markedly reduced, by 72 % and 98%, respectively (See reference number 5).
Although there are no data, manufacturer predicts that rifabutin will decrease ritonavir-boosted darunavir levels, and that darunavir/ritonavir will increase rifabutin levels. They also predict that rifampicin will markedly reduce ritonavir-boosted darunavir levels (See reference number 6,7).
1. Rifabutin. When 10 healthy subjects were given rifabutin 300mg once daily with indinavir 800mg every 8 hrs to for 10 days, indinavir maximum serum levels and AUC were reduced by about one-third, whereas rifabutin maximum serum levels and AUC were increased two- to threefold (See reference number 8). When same dose of indinavir (800 mg every 8 hours) was given with half dose of rifabutin (150 mg once daily), AUC of indinavir was similarly reduced (by 32%), but increase in AUC of rifabutin was less (54% increase) (See reference number 8). In a further study, pharmacokinetics of indinavir 1 g every 8 hrs (increased dose) and rifabutin 150mg daily (reduced dose) were investigated in healthy and HIV-positive subjects. The indinavir AUC was same with this increased dose as with indinavir 800mg every 8 hrs alone. However, despite halving rifabutin dose, AUC was still up to 70 % higher than with 300mg dose alone (See reference number 9). When combination was used in practice, there were no treatment failures in 25 patients being treated with rifabutin while receiving HAART (containing indinavir and/or nelfinavir). The rifabutin was given as 300mg twice weekly and indinavir dose was increased from 800mg to 1.2 g every 8 hrs to achieve satisfactory levels (See reference number 10).
2. Rifampicin (Rifampin). A study in 11 AIDS patients given indinavir 800mg every 8 hrs and rifampicin 600mg daily for 14 days found that AUC of rifampicin was increased by 73 % (See reference number 11). In a similar study looking at effects of rifampicin on indinavir, indinavir AUC and maximum serum levels were decreased by 92 % and 86%, respectively (See reference number 12). In another study, giving rifampicin 300mg daily for 4 days to 6 HIV-positive patients already receiving ritonavir-boosted indinavir (indinavir/ritonavir 800/100 mg twice daily) decreased median indinavir plasma levels (measured 12 hrs after last dose) by 87 % and median ritonavir levels by 94 % (See reference number 13).
When healthy subjects were given lopinavir/ritonavir 400/100 mg twice daily with rifabutin 150 or 300mg daily for 10 days AUC of rifabutin was increased threefold and AUC of lopinavir was increased by 17 % (See reference number 14)
Rifampicin (Rifampin). Rifampicin 600mg daily for 10 days decreased AUC of lopinavir (given as lopinavir/ritonavir 400/100 mg twice daily) by 75 % in a study in healthy subjects (See reference number 14). A dose titration of lopinavir/ritonavir was carried out in healthy subjects to try and overcome interaction with rifampicin (See reference number 15). In 10 evaluable subjects, use of rifampicin 600mg daily with lopinavir/ritonavir 800/200 mg twice daily decreased minimum lopinavir level by 57 % without affecting maximum level, when compared with lopinavir/ritonavir 400/100 mg twice daily without rifampicin. In another 9 evaluable subjects, rifampicin 600mg daily with lopinavir/ritonavir 400/400 mg twice daily did not alter maximum or minimum level of lopinavir, but markedly increased ritonavir levels, when compared with lopinavir/ritonavir 400/100 mg twice daily without rifampicin. Of 29 subjects who received adjusted doses of lopinavir/ritonavir with rifampicin, 9 subjects had grade 2 to 3 elevations in liver enzymes, and this was more common in lopinavir/ritonavir 400/400 mg group than lopinavir/ritonavir 800/200 mg group (See reference number 15).
Rifabutin. When rifabutin 300mg daily for 8 days was given with nelfinavir 750mg every 8 hrs for 7 to 8 days, nelfinavir AUC was reduced by 32 % and rifabutin AUC was increased by 207 % (See reference number 16). When nelfinavir 750mg every 8 hrs was given with half dose of rifabutin (150 mg daily), nelfinavir AUC was reduced by a similar amount (23%), whereas rifabutin AUC was increased by a lower amount (83%) (See reference number 17,18).
Rifampicin (Rifampin). Rifampicin 600mg daily for 7 days decreased AUC of nelfinavir 750mg every 8 hrs for 6 days by 82 % (See reference number 16). A 7-monthold infant with HIV and tuberculosis was given a rifampicin-based antimycobacterial regimen with nelfinavir-based HAART. Nelfinavir plasma levels were found to be very low,so ritonavir was added. This improved nelfinavir levels, and also greatly increased those of principal active metabolite of nelfinavir. The regimen was well tolerated and had a good clinical response (See reference number 19).
1. Rifabutin. In a study in 5 healthy subjects when ritonavir 500mg twice daily was given with rifabutin 150mg daily for 8 days, maximum serum level of rifabutin was increased threefold and AUC was increased fourfold (and AUC of its active metabolite, 25-O-desacetylrifabutin, 35-fold). Seven subjects had to be withdrawn due to adverse events,primarily leucopenia (See reference number 20). Retrospective analysis of regimens containing ritonavir found that concurrent use of rifabutin was associated with a higher incidence of rifabutin-related adverse effects including arthralgia, joint stiffness, uveitis and leucopenia (See reference number 21).
2. Rifampicin (Rifampin). When ritonavir 500mg every 12 hrs was given with rifampicin 300 or 600mg daily for 10 days, AUC of ritonavir was 35 % lower and maximum level 25 % lower than in subjects receiving ritonavir alone (See reference number 22).
Rifabutin. The AUC of saquinavir 600mg three times daily was reduced by about 40 % by rifabutin 300mg daily,in 12 HIV-positive subjects (See reference number 23). Similarly, AUC of saquinavir (soft capsules) 1.2 g three times daily was decreased by 47 % by rifabutin 300mg once daily in 14 HIV-positive patients. In addition, rifabutin AUC was increased by 44 % by saquinavir (See reference number 24). However,combined use of ritonavir and saquinavir (hard capsules), both 400mg twice daily, with intermittent rifabutin dosing (300 mg weekly or 150mg every 3 days) for 8 weeks was reported to be safe and manageable. Rifabutin did not significantly alter protease inhibitor levels, and rifabutin pharmacokinetics were similar to those usually seen with rifabutin 300mg daily alone (See reference number 25).
Rifampicin (Rifampin). Rifampicin 600mg once daily decreased AUC of saquinavir (soft capsules) 1.2 g three times daily by 70 % (See reference number 26). It was suggested that combination of ritonavir and saquinavir (both 400mg twice daily) could cancel out effects of rifampicin on saquinavir, so therapeutic levels of all three drugs could be achieved. This assumption has been confirmed in HIV-positive patients (See reference number 27,28). Five of 20 patients originally given combination developed hepatotoxicity, 2 of whom had comorbidities (See reference number 28). However, in a further study in healthy subjects, severe hepatotoxicity with transaminase elevations of about 20 times upper limit of normal occurred in 11 of 17 subjects after they took saquinavir/ritonavir 1000/100 mg twice daily with rifampicin 600mg once daily for 1 to 5 days (See reference number 29,30).
The manufacturer notes that tipranavir/ritonavir 500/200 mg twice daily increased plasma rifabutin levels by up to threefold,and its active metabolite by up to 20-fold after a single 150mg dose of rifabutin (See reference number 31,32).
Although there are no data, manufacturer predicts that rifampicin will markedly reduce ritonavir-boosted tipranavir levels (See reference number 31,32).
Rifampicin is a potent inducer of cytochrome P450 isoenzyme CYP3A4, by which protease inhibitors are at least partially metabolised, and therefore it markedly reduces protease inhibitor levels. Rifabutin is a weak inducer of CYP3A4. The protease inhibitors are inhibitors of CYP3A4, with ritonavir being most potent, and can therefore increase levels of rifamycins.
Established interactions of clinical importance. The protease inhibitors increase levels of rifabutin, with a consequent increase in adverse effects unless rifabutin dose is reduced. Ritonavir is most potent pro-tease inhibitor in this regard, and combination has been considered contraindicated. However, CDC in US say that combination may be used if dose of rifabutin is markedly reduced (See reference number 33). In addition, rifabutin decreases levels of some protease inhibitors, particularly saquinavir, increasing risk of treatment failure. Rifabutin should not be used when saquinavir is sole protease inhibitor (no longer recommended). However,there is some evidence that rifabutin can be used with ritonavir-boosted saquinavir. table 1 below, summarises clinical recommendations for concurrent use of protease inhibitors and rifabutin. Therapy should be well monitored. Note that, in one analysis, use of rifabutin 150mg twice weekly with low-dose ritonavir and a second protease inhibitor was associated with low rifabutin levels (See reference number 34). Recommended doses of rifabutin in patients taking ritonavir-boosted protease inhibitors are 150mg every other day or three times per week (See reference number 33).
Rifampicin markedly reduces levels of many of protease inhibitors, and its use with unboosted protease inhibitors should be avoided, because of risk of reduced antiviral efficacy and emergence of resistant viral strains. There are limited data to suggest that ritonavir as sole pro-tease inhibitor, or ritonavir used as a pharmacokinetic enhancer with other protease inhibitors such as saquinavir, can be used with rifampicin (See reference number 33). However, further study has shown a high incidence of hepatotoxicity with saquinavir/ritonavir 1000/100 mg twice daily and rifampicin, and manufacturers of ritonavir and saquinavir advise that these drugs should not be given together with rifampicin (See reference number 22,29,30,35). Current UK guidelines state that,until more data are available, ritonavir-boosted protease inhibi
5 Summary of manufacturers’ dosage recommendations (unless stated other
Rifabutin dose at least halved (150 mg daily or every other day,or 300mg three times per week). Amprenavir dose unchanged.
Not recommended (indinavir levels markedly reduced,rifampicin levels raised).
3,6-8
3,9, 10
May be used at usual doses,although limited data (ritonavir levels reduced). May lead to loss of virologic response.
3,11
3,12, 13
14,15
3,16
Not recommended (lopinavir levels markedly reduced). However, adjusted doses of lopinavir/ritonavir (800/200 mg or 400/400 mg twice daily) may overcome pharmacokinetic interaction, but have a high incidence of elevated liver enzymes, and so if used, close monitoring is needed.
3,17-19
Rifampicin dose unchanged. Saquinavir/ritonavir 400/400 mg twice daily. Note that a regimen of 1000/100 mg twice daily with rifampicin was associated with severe hepatotoxicity, and combination is contraindicated.
3,20, 21
22,23
Agenerase (Amprenavir). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.
Agenerase (Amprenavir). GlaxoSmithKline. US Prescribing information,May 2005.
Centers for Disease Control and Prevention. Updated guidelines for use of rifamycins for treatment of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. January 20,2004. Available at http://www.cdc.gov/tb/TB_HIV_Drugs/default.htm (accessed 22/08/07).
Telzir (Fosamprenavir). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.
Lexiva (Fosamprenavir). GlaxoSmithKline. US Prescribing information,February 2007.
Jaruratanasirikul S,Sriwiriyajan S. Pharmacokinetics of rifampicin administered alone and with indinavir. J Antimicrob Chemother (1999) 44 (Suppl A),58.
Crixivan (Indinavir sulfate). Merck Sharp & Dohme Ltd. UK Summary of product characteristics,May 2007.
Crixivan (Indinavir sulfate). Merck & Co.,Inc. US Prescribing information,November 2006.
Viracept (Nelfinavir mesilate). Roche Products Ltd. UK Summary of product characteristics,January 2007.
Viracept (Nelfinavir mesilate). Agouron Pharmaceuticals,Inc. US Prescribing information,January 2007.
Norvir Soft Capsules (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.
Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of product characteristics,April 2007.
5 Summary of manufacturers’ dosage recommendations (unless stated otherwise) for combined use of protease inhibitors and rifamycins (continued)
Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Company. US Prescribing information,March 2007.
Prezista (Darunavir). Janssen-Cilag Ltd. UK Summary of product characteristics,February 2007.
Prezista (Darunavir). Tibotec,Inc. US prescribing information,June 2006.
Justesen US,Andersen ÅB, Klitgaard NA, Brøsen K, Gerstoft J, Pedersen C. Pharmacokinetic interaction between rifampin and combination of indinavir and low-dose ritonavir in HIV-infected patients. Clin Infect Dis (2004) 38,426-9.
Kaletra (Lopinavir/ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,March 2007.
Kaletra Tablets (Lopinavir/ritonavir). Abbott Laboratories. US Prescribing information,January 2007.
la Porte CJL,Colbers EPH, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP, Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother (2004) 48,1553–60.
Invirase (Saquinavir mesilate). Roche Products Ltd. UK Summary of product characteristics,May 2007.
Invirase (Saquinavir mesilate). Roche Pharmaceuticals. US Prescribing information,September 2005.
Aptivus (Tipranavir). Boehringer Ingelheim Ltd. UK Summary of product characteristics,March 2007.
Aptivus (Tipranavir). Boehringer Ingelheim. US Prescribing information,February 2007.
tors should not be used with rifampicin. They say that rifampicin should be switched to rifabutin for use with protease inhibitors, or protease inhibitor should be changed to an alternative antiretroviral if this is possible (See reference number 36). Similarly,US guidelines say that rifampicin may only be used with full-dose ritonavir, and cannot be used safely with ritonavir-boosted regimens. They recommend use of rifabutin (See reference number 37).
Polk RE,Brophy DF, Israel DS, Patron R, Sadler BM, Chittick GE, Symonds WT, Lou Y,Kristoff D, Stein DS. Pharmacokinetic interaction between amprenavir and rifabutin or rifampin in healthy males. Antimicrob Agents Chemother (2001) 45, 502–508.
Telzir (Fosamprenavir calcium). GlaxoSmithKline UK. UK Summary of product characteristics,February 2007.
Lexiva (Fosamprenavir calcium). GlaxoSmithKline. US Prescribing information,June 2007.
Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary ofproduct characteristics,April 2007.
Reyataz (Atazanavir sulfate). Bristol-Myers Squibb Company. US Prescribing information,March 2007.
Prezista (Darunavir ethanolate). Janssen-Cilag Ltd. UK Summary of product characteristics,July 2007.
Prezista (Darunavir). Tibotec,Inc. US Prescribing information, June 2006.
Kraft WK,McCrea JB, Winchell GA, Carides A, Lowry R, Woolf EJ, Kusma SE, DeutschPJ, Greenberg HE, Waldman SA. Indinavir and rifabutin drug interactions in healthy volunteers. J Clin Pharmacol (2004) 44, 305–13.
Hamzeh FM,Benson C, Gerber J, Currier J, McCrea J, Deutsch P, Ruan P, Wu H, Lee J, Flexner C, for the AIDS Clinical Trials Group 365 Study Team. Steady-state pharmacokinetic interaction of modified-dose indinavir and rifabutin. Clin Pharmacol Ther (2003) 73, 159–
69.
Narita M,Stambaugh JJ, Hollender ES, Jones D, Pitchenik AE, Ashkin D. Use of rifabutinwith protease inhibitors for human immunodeficiency virus-infected patients with tuberculosis. Clin Infect Dis (2000) 30, 779–83. Correction. ibid. 992.
Jaruratanasirikul S,Sriwiriyajan S. Pharmacokinetics of rifampicin administered alone andwith indinavir. J Antimicrob Chemother (1999) 44 (Suppl A), 58.
McCrea J,Wyss D, Stone J, Carides A, Kusma S, Kleinbloesem C, Al-Hamdan Y, Yeh K,Deutsch P. Pharmacokinetic interaction between indinavir and rifampin. Clin Pharmacol Ther (1997) 61, 152.
Justesen US,Åndersen AB, Klitgaard NA, Brøsen K, Gerstoft J, Pedersen C. Pharmacokinetic interaction between rifampin and the combination of indinavir and low-dose ritonavir inHIV-infected patients. Clin Infect Dis (2004) 38, 426–9.
Bertz R,Hsu A, Lam W, Williams L, Renz C, Karol M, Dutta S, Carr R, Zhang Y, Wang Q,Schweitzer S, Foit C, Andre A, Bernstein B, Granneman GR, Sun E. Pharmacokinetic interactions between lopinavir/ritonavir (ABT-378r) and other non-HIV drugs (abstract P291).AIDS (2000) 14 (Suppl 4), S100.
la Porte CJL,Colbers EPH, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, Koopmans PP,Hekster YA, Burger DM. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combinedwith rifampin in healthy volunteers. Antimicrob Agents Chemother (2004) 48, 1553–60.
Kerr B,Yuep G, Daniels R, Quart B, Kravcik S, Sahai J, Anderson R. Strategic approach tonelfinavir mesylate (NFV) drug interactions involving CYP3A metabolism. 6(See reference number th) EuropeanConference on Clinical Aspects and Treatment of HIV-infection, Hamburg, 1997. 256.
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Bergshoeff AS,Wolfs TFW, Geelen SPM, Burger DM. Ritonavir-enhanced pharmacokinetics of nelfinavir/M8 during rifampin use. Ann Pharmacother (2003) 37, 521–5.
Cato A,Cavanaugh J, Shi H, Hsu A, Leonard J, Granneman R. The effect of multiple dosesof ritonavir on the pharmacokinetics of rifabutin. Clin Pharmacol Ther (1998) 63, 414–21.
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Aptivus (Tipranavir). Boehringer Ingelheim. US Prescribing information,February 2007.
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| Table 1 Summary of the manufacturers’ dosage recommendations (unless stated other | wise) for combined use of protease inhibitors and rifamycins | ||
|---|---|---|---|
| Protease inhibitor | Rifabutin | Rifampicin | Refs |
| Protease inhibitors | |||
| Amprenavir | Rifabutin dose at least halved (150 mg daily or every other day, or 300mg three times per week). Amprenavir dose unchanged. | Not recommended (amprenavir levels markedly reduced). | 1-3 |
| Fosamprenavir | Rifabutin dose at least halved (150 mg daily or 300mg three times per week). Fosamprenavir dose unchanged. | Not recommended (amprenavir levels expected to be markedly reduced). | 3-5 |
| Indinavir | Rifabutin dose halved (150 mg daily or 300mg three times per week). Indinavir dose increased (1 to 1.2 g every 8 hours). | Not recommended (indinavir levels markedly reduced, rifampicin levels raised). | 3, 6-8 |
| Nelfinavir | Rifabutin dose at least halved (150 mg once daily or 300mg three times per week). Nelfinavir dose unchanged (1.25 g twice daily preferred) or increase to 1 g every 8 hours. | Not recommended (nelfinavir levels markedly reduced). | 3, 9, 10 |
| Ritonavir alone | Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Further dose reductions may be necessary.* Ritonavir dose unchanged. | May be used at usual doses, although limited data (ritonavir levels reduced). May lead to loss of virologic response. | 3, 11 |
| Saquinavir alone | Not recommended (saquinavir levels reduced). | Not recommended (saquinavir levels markedly reduced). | 3 |
| Ritonavir boosted protease inhibitors | |||
| Atazanavir/ritonavir | Rifabutin dose reduced by up to 75 % (150 mg every other day or three times per week). Atazanavir/ritonavir dose unchanged. | Not recommended (atazanavir levels markedly reduced). | 3, 12, 13 |
| Darunavir/ritonavir | Rifabutin dose reduced to 150mg every other day. | Not recommended (darunavir levels predicted to be markedly reduced). | 14, 15 |
| Fosamprenavir/ritonavir | Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Fosamprenavir/ritonavir dose unchanged. | Not recommended (amprenavir levels predicted to be markedly reduced). | 3-5 |
| Indinavir/ritonavir | Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Indinavir/ritonavir dose unchanged. | Not recommended (indinavir levels markedly reduced). | 3, 16 |
| Lopinavir/ritonavir | Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Lopinavir/ritonavir dose unchanged. | Not recommended (lopinavir levels markedly reduced). However, adjusted doses of lopinavir/ritonavir (800/200 mg or 400/400 mg twice daily) may overcome the pharmacokinetic interaction, but have a high incidence of elevated liver enzymes, and so if used, close monitoring is needed. | 3, 17-19 |
| Saquinavir/ritonavir | Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Appropriate saquinavir/ritonavir dose not established. Consider usual dose (1000/100 mg twice daily). | Rifampicin dose unchanged. Saquinavir/ritonavir 400/400 mg twice daily. Note that a regimen of 1000/100 mg twice daily with rifampicin was associated with severe hepatotoxicity, and the combination is contraindicated. | 3, 20, 21 |
| Tipranavir/ritonavir | Rifabutin dose reduced by at least 75 % (150 mg every other day or three times per week). Further dose reductions may be necessary. Tipranavir/ritonavir dose unchanged. | Not recommended (tipranavir levels predicted to be markedly reduced). | 22, 23 |