Update on Rifampin and Rifabutin Drug Interactions

Update on Rifampin and Rifabutin Drug Interactions ANNE M. BACIEWICZ, PHARMD, MBA; CARY R. CHRISMAN, PHARMD; CHRISTOPHER K. FINCH, PHARMD, BCPS; TIMOTHY H. SELF, PHARMD

ABSTRACT: Rifampin is a potent inducer of cytochrome P-450 oxidative enzymes as well as the P-glycoprotein transport system. Several examples of well-documented clinically significant interactions include warfarin, oral contraceptives, cyclosporine, itraconazole, digoxin, verapamil, nifedipine, simvastatin, midazolam, and human immunodeficiency virus–related protease inhibitors. Rifabutin reduces serum concentrations of antiretroviral agents, but less so than rifampin. Examples of clinically relevant interactions demonstrated by recent reports in-

clude everolimus, atorvastatin, rosiglitazone/pioglitazone, celecoxib, clarithromycin, caspofungin, and lorazepam. To avoid a decreased therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, clinicians need to be cognizant of these interactions. Studies and cases of rifampin drug interactions continue to increase rapidly. This review is a timely reminder to clinicians to be vigilant. KEY INDEXING TERMS: Rifampin; Rifabutin; Drug interactions. [Am J Med Sci 2008;335(2):126–136.]

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rifampin in hepatocytes is associated with enhanced pregnane X receptor activation. In addition to effects on the CYP enzyme system and P-gp transport system, rifampin has been demonstrated to induce glucuronidation which renders drugs more polar and thereby facilitates excretion.8 Glucuronidation is mediated by uridine 5=-diphosphate-glucuronosyltransferases (UGTs). Increased glucuronidation by rifampin has been reported for lorazepam and propafenone.5,8 With the constant availability of new drugs, clinicians are challenged with a growing number of clinically significant rifampin and rifabutin drug interactions. Since the last review of this topic,5 several new interactions involving rifampin and rifabutin have been reported. Summaries of previously reviewed rifampin and rifabutin interactions1–5 that are well documented and of major clinical significance are given in Table 1 and Table 2, and rifampin interactions that may be clinically relevant but less well documented are listed in Table 3.

ifampin is a potent inducer of both the hepatic and intestinal cytochrome P-450 (CYP) enzyme system and P-glycoprotein (P-gp) transport system, which results in numerous clinically significant drug interactions. 1–5 Recent research has enhanced knowledge of the mechanisms of these interactions. It has been demonstrated that induction of the CYP enzyme system and P-gp by rifampin is mediated by activation of the nuclear pregnane X receptor.6 Tirona et al7 reported that human organic anion transporting polypeptide-C (OATP-C) is a major determinant of rifampin-mediated pregnane X receptor activation. Rifampin hepatocellular uptake is mediated by OATP-C, and increased accumulation of

From the Department of Pharmacy (AMB), Johns HopkinsBayview Medical Center, Baltimore, Maryland; Methodist Medical Center of Oak Ridge (CRC), Oak Ridge, Tennessee, and Department of Clinical Pharmacy, University of Tennessee Health Science Center; Methodist University Hospital (CKF), Memphis, Tennessee, and Department of Clinical Pharmacy, University of Tennessee Health Science Center; and Department of Clinical Pharmacy (THS), University of Tennessee Health Science Center, Methodist University Hospital, Memphis, Tennessee. Submitted March 19, 2007; accepted in revised form June 29, 2007. Anne Baciewicz owns drug company stocks (eg, Bristol Myers Squibb, GlaxoSmithKline, Merck, and Pfizer US Pharmaceutical Group) and via mutual funds. Cary Chrisman has no type of investment of involvement with any pharmaceutical companies via stock or mutual funds. Christopher Finch owns drug company stocks primarily via mutual funds. Timothy Self owns drug company stocks primarily via mutual funds. Correspondence: Dr. Timothy H. Self, University of Tennessee Health Science Center, 910 Madison Avenue, Room 308, Memphis, TN 38163 (E-mail: [email protected]).

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Immunosuppressants Cyclosporine Previous reviews have described the highly significant cyclosporine-rifampin drug interaction.2– 4 However, Zelunka9 published the first reported interaction in a pediatric patient who received a bone marrow transplant (BMT) and developed acute graft versus host disease (GVHD) after concomitant therapy. February 2008 Volume 335 Number 2

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Table 1. Well-Documented Rifampin Drug Interactions* Drug/Drug Class

Comments

HMG-CoA reductase inhibitors Anticoagulants (oral) Contraceptives (oral) Cyclosporine Digitoxin

Monitor lipid panel; increased dose will likely be needed for simvastatin Monitor international normalized ratio; increase anticoagulant dose will likely be needed Use alternative form(s) of birth control; counsel patient and document in chart Monitor serum cyclosporine concentrations; increased dosage will likely be needed Monitor arrhythmia control, signs and symptoms of heart failure, and serum digitoxin concentrations Increase dose of glucocorticoid 2- to 3-fold Prefer to avoid use with rifampin; if must use, increase dose and monitor response Increase methadone dose with concomitant rifampin; monitor and control withdrawal symptoms Prefer to avoid use with rifampin; use another agent if possible Monitor serum phenytoin concentrations and seizure activity; increase dosage if needed Monitor clinical response; increased dose may be needed Or use another agent if possible Monitor serum quinidine concentrations and arrhythmia control; increase dosage if needed Monitor serum tacrolimus concentrations and clinical response; increased dose may be needed Or use another agent if possible Monitor serum theophylline concentrations; increase dosage if needed Use alternative agent to verapamil since large oral verapamil doses may not be adequate; monitor patient for clinical response†

Glucocorticoids Itraconazole/ketoconazole Methadone Midazolam/triazolam Phenytoin Propafenone Quinidine Tacrolimus Theophylline Verapamil

* Adapted from Baciewicz et al1,2, Borcherding et al3, Strayhorn et al4, and Finch et al5. Carefully adjust doses when rifampin use is discontinued. Enzyme induction effect is gradually reduced during a 1- to 2-week period or longer. Antiretroviral interactions are listed in Table 2. † See also diltiazem and nifedipine (Table 3).

The occurrence of the interaction was 5 days after concomitant therapy and dissipated 9 days after discontinuing rifampin. To achieve therapeutic cyclosporine concentrations, the cyclosporine dose was increased 2.5-fold. Cyclosporine concentrations should be monitored frequently with appropriate dosage adjustments made. Everolimus Kovarik and associates10 assessed the effect of rifampin on the immunosuppressant everolimus. In Table 2. Well-Documented Rifampin/Rifabutin Drug Interactions: Antiretroviral Agents: Percentage by Which Rifampin and Rifabutin Lower the AUCs of PIs and NNRTIs

Indinavir Ritonavir Ritonavir/Lopinavir Nelfinavir Atazanavir Fosamprenavir Ritonavir/Darunavir Ritonavir/Tipranavir Saquinavir Delavirdine Nevirapine Efavirenz

Rifampin %

Rifabutin %

89 35 75 82 72 82** NR NR 84 96 20–58 25

32 0 0 0–32* 115 15** ND ND 40 80 16 0

Adapted from Reference 43, Reyataz (Atazanavir) prescribing information; Lexiva (Fosamprenavir) prescribing information. * Thirty-two percent with 750 mg q 8 h and no change if 1250 mg q 12 h. ** Data based on studies with amprenavir; similar results would be expected with fosamprenavir, a prodrug of amprenavir. 1Rifabutin increase atazanavir levels by 15%. NR denotes no data but not recommended; ND, no data.

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an open-label, single-sequence, crossover study, 12 healthy volunteers received a single oral 4-mg everolimus dose alone and after 8 days of rifampin (600 mg orally daily). During coadministration of rifampin and everolimus, the average everolimus clearance increased by 172%. Decrease in average half-life of everolimus, average AUC and average peak plasma concentration (Cmax) was 26%, 63%, and 58%, respectively. Urinary excretion of 6␤-hydroxycortisol was significantly elevated during rifampin therapy. When rifampin is indicated in patients receiving everolimus, the everolimus dose will need to be titrated based on monitoring of everolimus concentrations. Tacrolimus The tacrolimus-rifampin interaction has been previously summarized.4,5 Bhaloo and Prasad11 described the case of a 40year-old woman who received a renal transplant and demonstrated an increase in the metabolism of tacrolimus by rifampin. A 5-fold tacrolimus dose increase was required. Rifampin’s induction effect was able to overcome the inhibitory effect of concomitant diltiazem, fluconazole and clarithromycin therapy in this patient. Monitoring of tacrolimus concentrations and dose adjustments will be necessary if rifampin has to be administered concurrently with tacrolimus even in the presence of P450 inhibitors. Mycophenolate Mofetil A possible drug interaction was observed between mycophenolate mofetil (MMF) and rifampin.12 A 51year-old patient who had a combined heart double lung allograft was receiving tacrolimus 7 mg orally 127

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Table 3. Rifampin Drug Interactions* Drug/Drug Class

Comments

5 HT3 Antiemetics ␤-Adrenergic blocking agents Buspirone Chloramphenicol† Clarithromycin Clozapine Dapsone

Monitor clinical response; increase dose if needed; use another agent if needed Monitor patient for clinical response; increased propranolol or metoprolol dose may be needed Monitor clinical response; increased dose will likely be needed Or use another agent if possible Monitor serum chloramphenicol concentrations; may need to increase dosage Monitor signs and symptoms of infection; more study needed Monitor clinical response; increase dose if needed Or use another agent if possible Monitor clinical response; additional study needed when used for Pneumocystis carinii prophylaxis; monitor for hematologic toxic effects Monitor clinical response; may need to increase diazepam dosage Monitor arrhythmia control and signs and symptoms of heart failure; monitor digoxin serum concentrations Use alternative agent if possible because large oral doses of diltiazem may be ineffective; monitor clinical response Monitor arrhythmia control; increase dosage if needed Monitor clinical response; increase dosage if needed Monitor clinical response; may need to increase fluconazole dosage; less reduction in serum concentrations vs other azoles Monitor clinical response; increase dosage if needed Monitor TSH; increased dose likely needed Monitor patient for clinical response; may need to increase dosage Monitor for decrease clinical response; increase dose if needed Alternative class of agents should be considered; monitor clinical response; dosage increase may be needed† Monitor clinical response and serum nortriptyline concentrations Monitor pain control and clinical response Monitor clinical response; increase dose if needed Monitor blood glucose levels; base any dosage adjustments on blood glucose control Monitor clinical response; increased dose likely needed Monitor arrhythmia control; increase dosage if needed Monitor clinical response; increased dose may be needed Or use another agent if possible

Diazepam† Digoxin (Oral)† Diltiazem† Disopyramide Doxycycline Fluconazole Haloperidol† Levothyroxine Losartan Metronidazole Nifedipine Nortriptyline Opiates (morphine, codeine) Sertraline Sulfonylureas Tamoxifen/toremifene Tocainide Zolpidem

* Adapted from Baciewicz et al,1,2 Borcherding et al,3 Strayhorn et al,4 and Finch et al.5 Additional study needed to clearly establish clinical significance. Carefully adjust doses when rifampin use is discontinued. Enzyme induction effect is gradually reduced during a 1- to 2-week period or longer. † Probably of clinical significance. See also verapamil (Table 1).

twice daily and MMF 2 g orally daily to prevent rejection. Coadministration of rifampin even with a decreasing dose from 600 mg to 450 mg orally daily caused the tacrolimus dose to be increased to 22 mg orally twice daily and MMF to 6 g orally daily. Mycophenolic acid (MPA) drug dosage and clearance decreased by more than 50% and 69%, respectively, when rifampin was discontinued. Additionally, tacrolimus drug dosing and clearance decreased by 59% and 55%, respectively, when rifampin was discontinued. The proposed mechanism of the interaction between MMF and rifampin is induction of uridine diphosphate-glucuronosyltransferase in the kidney, liver, and intestines. When rifampin was simultaneously administered with MMF, there was a marked reduction in dose-corrected MPA exposure. Cardiovascular Drugs Atenolol Although rifampin interactions with other ␤-blockers2,3 have been reported, Goldberg et al13 are the first to describe a possible interaction with atenolol. A 66-year-old man was receiving atenolol (50 mg 128

orally daily) for well controlled exertional angina and required treatment for pulmonary tuberculosis. Rifampin (600 mg orally daily) was prescribed concomitantly with pyrazinamide, ethambutol, and pyridoxine. The patient developed chest pressure while walking short distances, which abated when the antituberculosis agents were stopped. Rifabutin (300 mg orally daily) was prescribed with no change in the patient’s baseline exercise threshold tolerance. Rifabutin has approximately 60% less CYP450 induction than rifampin. This is the first report of a low bioavailable, hydrophilic, renally eliminated ␤-blocker to possibly exhibit this interaction.14 A rat study evaluated the metabolic action of a single oral atenolol dose (6 mg/kg).15 The authors noted that approximately 9% of atenolol is metabolized by the CYP450 system and its P450 dependent functions were not inhibited. A controlled study is needed to determine if there is a rifampin-atenolol interaction. Nilvadipine Five healthy volunteers received nilvadipine (4 mg orally) before and after a 6-day course of rifampin (450 mg orally daily).16 Nilvadipine’s mean February 2008 Volume 335 Number 2

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AUC was approximately 30 times greater before rifampin therapy. Pharmacodynamically, there was a significant decrease in the diastolic blood pressure (– 8 mm Hg) and reflex tachycardia (5 beats/minute) with nilvadipine alone; these changes in vital signs were negated after rifampin. A significant 5-fold increase in urinary 6␤ hydroxycortisol/cortisol ratio was noted post rifampin therapy. Because rifampin may decrease the oral bioavailability of nilvadipine through hepatic CYP3A activity, caution is needed when both drugs are prescribed concurrently in hypertensive patients. Atorvastatin In a randomized, crossover study in 10 healthy volunteers, placebo or rifampin (600 mg orally daily) was administered for 5 days.17 On day 6, a single 40-mg oral atorvastatin dose was given. Rifampin significantly reduced the mean AUC of unchanged atorvastatin (80%) and its active metabolites, 2-hydroxyatorvastatin acid (43%) and 4-hydroxyatorvastatin acid (81%) and the mean AUC of their lactones by 93%, 61%, and 76%, respectively. Rifampin decreased the mean half-lives of atorvastatin (74%), 2-hydroxyatorvastatin acid (70%), and 4-hydroxyatorvastatin acid (79%) as well as their lactones halflives. The atorvastatin-rifampin drug interaction mechanism is postulated to be induction by primarily CYP3A4 along with induction by P-gp, efflux transporter multidrug resistant-associated protein 2 (MDRP2), and uridine diphosphate-glucuronosyltransferase. It is advisable to increase the atorvastatin dose when it is administered with rifampin and other inducers of CYP3A4. Pravastatin Kyrklund et al,18 in a randomized, crossover, 2-phase study evaluated 10 healthy volunteers who received a single oral 40-mg pravastatin dose after a 5-day pretreatment with rifampin (600 mg orally daily) or placebo. During the rifampin phase, pravastatin’s mean AUC was decreased by 31% with considerable inter-individual variation. Rifampin had no significant effect on pravastatin’s Cmax, half-life, or renal clearance. Of the 3-hydroxy-3methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors, pravastatin appears to be the least susceptible to rifampin’s inducing effect. Antidiabetic Agents Sulfonylureas Gliclazide. Kihara and Otsuki19 described a 65year-old male diabetic who required a doubling of his gliclazide dose from 80 mg to 160 mg orally daily after rifampin (450 mg orally daily) was initiated for treatment of Mycobacterium gordonae. Other medications included INH (400 mg), ethambutol (750 mg), and clarithromycin (400 mg) orally daily. The THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

fasting plasma glucose increased approximately 2 times after rifampin administration. Gliclazide’s plasma concentration increased over 3-fold after rifampin was discontinued. Gliclazide, like the oral hypoglycemics tolbutamide and glibenclamide, is metabolized by CYP2C9 and its effective concentration is decreased. Park et al20 studied the pharmacokinetics and pharmacodynamics of gliclazide in a randomized, 2-way crossover study in 9 healthy Korean subjects. The volunteers were given placebo or rifampin (600 mg orally daily) for 6 days. On day 7, a single 80-mg oral dose of gliclazide was administered. Rifampin decreased gliclazide’s mean AUC and mean elimination half-life by 70% and 61%, respectively. Gliclazide’s oral clearance was increased about 4 times after rifampin compared with placebo. Concomitant use of rifampin and gliclazide can reduced the glucose lowering effect of gliclazide through CYP2C9 induction. Glimepiride. The oral hypoglycemic glimepiride was studied by Neimi and colleagues21 after rifampin administration utilizing a 2-phase crossover design in 10 healthy volunteers. Subjects were given placebo or rifampin (600 mg orally daily) for 5 days. A single oral 1-mg glimepiride dose was administered on day 6. Rifampin decreased glimepiride’s mean AUC by 34% and its mean elimination half-life by 25%. No significant changes were observed in blood glucose between the placebo and rifampin groups. Megitinides Repaglinide. Hatorp and colleagues22 assessed the effects of rifampin on repaglinide in a randomized, open-labeled, 2-period crossover study in 8 healthy men. Rifampin (600 mg orally daily) was given for 7 days with concomitant administration on day 7 of 4 mg oral repaglinide. Compared with repaglinide alone, concomitant rifampin decreased repaglinide’s mean AUC by 31%, Cmax by 26% and mean half-life by 56%. Niemi and coworkers23 noted a more significant effect by rifampin with a decrease of repaglinide’s mean AUC by 57%, possibly due to the repaglinide dose or the administration time of rifampin and repaglinide doses. Bidstrup et al24 studied 12 male volunteers in a randomized, 2-period crossover trial that evaluated the effects of rifampin (600 mg orally daily) for 7 days either on a single 4-mg oral repaglinide dose given concurrently with rifampin on day 7 or by itself on day 8, 24 hours after the last rifampin dose. When rifampin and repaglinide were given concurrently, repaglinide’s median AUC was reduced by 50%. However, Cmax, time to reach peak plasma concentration and half-life were not significantly affected. When repaglinide was administered 24 hours after the last rifampin dose, repaglinide’s median AUC was reduced by 80%. Additionally, the median Cmax decreased by 79% but neither time to 129

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reach peak plasma concentration or half-life were significantly affected. Nateglinide. Niemi and coworkers25 investigated the pharmacokinetics and pharmacodynamics of nateglinide in a randomized, 2-phase crossover study. Ten healthy volunteers received placebo or rifampin 600 mg orally daily for 5 days. A single 60-mg oral nateglinide dose was ingested on day 6. Rifampin decreased nateglinide’s mean AUC and mean half-life by 22% and 19%, whereas the M7 metabolite of nateglinide’s mean AUC and mean half-life were decreased by 22% and 24%. Rifampin had no significant effect on the blood glucose lowering effect of nateglinide. Rifampin’s influence on nateglinide appears minimal. Thiazolidinediones Rosiglitazone. Rifampin’s effect on rosiglitazone was investigated in 2 different studies.26,27. Park and colleagues26 studied the pharmacokinetics of rosiglitazone in a randomized, 2-way crossover study in 10 healthy male Korean subjects. The volunteers were given placebo or rifampin (600 mg orally daily) for 6 days. On day 7, a single 8-mg oral dose of rosiglitazone was administered. Rifampin decreased rosiglitazone’s mean AUC, mean elimination half-life and mean Cmax by 66%, 62%, and 31%, respectively. The oral clearance of rosiglitazone increased about 3-fold after rifampin therapy. Niemi et al27 evaluated the effects of rifampin on the pharmacokinetics of rosiglitazone. In a randomized, crossover study in 10 healthy volunteers, placebo or rifampin (600 mg orally daily) was administered for 5 days. On day 6, a single 4-mg oral rosiglitazone dose was administered. Rifampin reduced rosiglitazone’s mean AUC, mean Cmax, and mean half-life by 54%, 28%, and 50%, respectively. Rifampin increased the formation of N-desmethylrosiglitazone. Monitoring of blood glucose is advisable when a diabetic patient receiving rosiglitazone has rifampin therapy initiated or discontinued. Pioglitazone. Jaakkola and colleagues28 studied the effects of rifampin on the pharmacokinetics of pioglitazone and its metabolites, M-IV and M-III. Ten healthy volunteers in a randomized, 2-phase crossover study received either placebo or rifampin (600 mg orally daily) for 6 days. A single 30-mg oral pioglitazone dose was given on day 6. Rifampin decreased pioglitazone’s mean AUC by 54% and its dominant half-life by 47%. Rifampin decreased both M-IV and M-III’s mean AUC by 34% and 39%, decreased their mean half-lives by 50% and 55% and increased the mean AUC ratio of M-IV and M-III to pioglitazone by 44% and 32%, respectively. The mean M-IV/pioglitazone and mean M-III/pioglitazone urinary ratios were increased by 98% and 95% with rifampin. When rifampin therapy is added or discontinued, it is advisable to closely monitor the 130

blood glucose levels in patients receiving pioglitazone. Analgesics Opiates Fentanyl. Takane and colleagues29 described a 61-year-old patient who was using a fentanyl transdermal dose patch of 2.5 mg every 3 days for pain control from lung metastasis. Severe pain developed the day after initiation of rifampin (300 mg), INH (300 mg), and ethambutol (750 mg) orally daily. Fentanyl serum concentrations continued to decrease despite increasing the fentanyl transdermal dose patch to 7.5 mg every 3 days. The ratio of serum fentanyl concentration to dose (C/D) decreased from baseline by 20% to 50%, indicating increased drug clearance. When fentanyl is coadministered with rifampin, pain control and fentanyl dose need to be carefully monitored. Kharasch et al30 studied the influence of rifampin on the acute disposition and effect of oral transmucosal fentanyl citrate (OTF). Using a randomized, crossover design, 12 healthy volunteers took rifampin (600 mg orally daily) for 5 days. On day 6, OTF was administered at a dose of 10 mcg/kg (600 mcg or 800 mcg lozenge). The subject’s rubbed the drug over the buccal mucosa for 15 minutes. Rifampin increased fentanyl’s apparent mean oral clearance (124%) and mean elimination rate (85%) while decreasing fentanyl’s mean AUC (63%) and apparent mean oral bioavailability (62%). Rifampin minimally affected fentanyl’s Cmax and clinical effects but duration of effect was significantly shortened. These effects were medicated though hepatic and intestinal CYP3A activity. As duration of analgesia may be affected, repeat fentanyl doses may be necessary. Cyclooxygenase (Cox) 2 Inhibitors Celecoxib. Jayasagar et al31 studied the affects of rifampin on celecoxib in 12 healthy male volunteers. Celecoxib (200 mg orally) was administered either alone or after rifampin (600 mg orally daily) for 5 days. Rifampin treatment decreased celecoxib’s mean AUC, mean Cmax and mean half-life by 64%, 56%, and 57%, respectively, whereas celecoxib’s mean clearance increased by 185%. Concurrent administration of celecoxib and rifampin may result in diminished analgesic effect and increased celecoxib dose may be warranted in patients. A similar interaction is noted for rofecoxib.32 Acetaminophen hepatotoxicity with rifampin or INH or both was previously discussed.4 Stephenson and colleagues33 described a 32-year-old patient who developed severe acetaminophen hepatotoxicity possibly enhanced by rifampin. February 2008 Volume 335 Number 2

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Antiretroviral Agents It is well documented that persistent subtherapeutic levels of antiretrovirals can result in development of resistance. Rifampin may result in human immunodeficiency virus (HIV) treatment failures in patients on antiretrovirals, if doses are not appropriately adjusted, by increasing the metabolism of some antiretrovirals, particularly protease inhibitors (PIs), although non-nucleoside reverse transcriptase inhibitors (NNRTIs) are affected as well but to a smaller extent. It is crucial to make dosage adjustments of these medications to avoid limiting future treatment options. However, large interpatient and intrapatient variability in metabolism of both antiretroviral and antimycobacterial drugs have been observed in HIV and HIV/tuberculosis (TB) coinfected patients, therefore making adjustments more complicated. The metabolism of nucleoside reverse transcriptase inhibitors are minimally affected by rifamycin and current guidelines suggest no dosage alterations are required with this class of antiretrovirals. In a study of 12 HIV infected patients, the fusion inhibitor T-20, did not demonstrate any drug interactions with rifampin,34 and likewise tenofovir, a nucleotide reverse transcriptase inhibitor and first line option in an initial HIV/AIDS treatment regimen, was not found to significantly interact with rifampin in 23 healthy volunteers.35 Rifabutin, owing to its less potent enzyme induction relative to rifampin, is easier to use in HIV/TB coinfection from the standpoint of dosing changes, albeit significant adjustments are still required, and has the additional benefit of being easier to tolerate then rifampin for some patients.36 However, in many parts of the world, rifampin is the only available/affordable option among the rifamycins. Rifapentine, with its simple administration requirement of once to twice weekly dosing, is not recommended in HIV/TB coinfection, as a study in 61 subjects reported development of resistance.37 Additionally, in a pharmacokinetic substudy of 102 patients with HIV/AIDS, lower serum levels of antituberculosis drugs, in particular rifabutin, have been correlated with acquired rifamycin resistance in the treatment of tuberculosis.38 Rifampin levels were also found to be significantly low in 7 HIV/AIDS patients and 9 HIV/TB coinfected patients suffering from diarrhea infected with cryptosporidia.39 Protease Inhibitors All currently available PIs interact with rifamycins to some extent. A recent pharmacokinetic study in 32 non–HIV-infected volunteers suggests that adjusted dose lopinavir-ritonavir may be feasible when coadministered with rifampin. The authors state that tolerability may be a problem and close THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

hepatic and therapeutic drug monitoring of serum drug levels may be necessary with this combination.40 Due to similar problems encountered in other studies, rifampin is not recommended to be coadministered with ritonavir (RTV) boosted PI regimens. Even when given with full dose RTV as the sole PI, the result is a decrease of RTV levels by approximately 35%. However, a recent study examined a once-daily regimen of RTV (200 mg/SQV scg 1600 mg) plus ddI/3TC in 32 patients receiving standard antituberculosis regimens that included rifampin (600 mg daily).41 Although the treatment outcome was generally favorable, with 62% of the intent to treat population having HIV RNA ⬍50 copies/mL at a 48-week follow-up, the authors noted a 44% reduction in the mean SQV trough. This was worrisome due to potential of resistance developing, and suggested a future study using a higher dosage of SQV. Rifabutin is recommended as the rifamycin of choice in the setting of HIV/TB coinfection, and suggested dosage adjustments are listed in the recent NIH update of HIV treatment guidelines.42 Nonetheless, 2 recent studies, a single case report and a pharmacokinetic analysis of 123/238 HIVinfected inmates treated with rifabutin, document both the difficulty in predicting how rifabutin alters levels of other drugs and how other factors may alter rifabutin levels even when given in adjusted doses, which can negatively impact treatment outcome.43,44 Non-nucleoside Reverse Transcriptase Inhibitors Currently available NNRTIs are variably affected by rifamycins, depending on the particular NNRTI. Gender and race were found to be correlated with efavirenz concentrations in a study of 255 patients, whereas body mass may also affect NNRTI levels and therefore may make dosage adjustments more complicated.40,45 Efavirenz and nevirapine are generally enzyme inducers, whereas delavirdine is an enzyme inhibitor. Both rifabutin and rifampin decrease delavirdine levels to a large extent, so that most would not coadminister with this NNRTI. The 2006 DHHS guidelines regarding efavirenz and nevirapine dosage adjustments are listed in Table 2. Several recent papers explored the pharmacokinetic and clinical impact of varying doses of efavirenz and rifampin, suggesting that different strategies may be required depending on the clinical setting. Manosuthi and colleagues46 reported similar 48-week results in 65 Thai patients with average body mass of 50 kg when either 600 or 800 mg of efavirenz was given with rifampin daily. LopezCortez et al47 did find that similar efavirenz levels were observed when 60 patients taking 800 mg of efavirenz plus rifampin daily were changed to 600 mg after rifampin was discontinued. They state that since no relationship was observed between efavirenz Cmin levels and virologic outcome, this ad131

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justment may not be always required. Sheehan and colleagues48 extended this concept in their abstract involving 16 patients which suggested that both 600 and 800 mg of efavirenz when given with rifampin commonly resulted in potentially toxic levels of efavirenz, and found that the 600-mg dose did not result in subtherapeutic levels. Nevirapine adjustments have been similarly debated. Manosuthi49 also reported that in 70 Thai patients with a mean body mass of 55 kg, a follow-up study showed that although nevirapine levels increased after rifampin was discontinued, the standard 400-mg dose of nevirapine was equally as efficacious when given with rifampin compared with a control group of HIV-infected patients who did not have TB. In contrast, Ramachandran et al50 noted that in Indian patients with a mean body mass of 58 kg, increasing the nevirapine dose to 300 mg twice daily in patients on rifampin caused the nevirapine levels to increase from subtherapeutic to therapeutic levels in this small pilot study of 7 patients. Antibiotics Commonly Used as Treatment or Prophylaxis of Opportunistic Infections in Patients With HIV or AIDS Clarithromycin Clarithromycin, a CYP P450-3A4 substrate, is commonly used in the management of HIV-infected patients for the treatment of Mycobacterium avium complex (MAC). These patients occasionally receive rifabutin in addition to macrolide therapy for MAC. Yamamoto el al51 evaluated the effects of rifampin on clarithromycin serum concentrations in 9 patients with lung disease due to MAC. The serum concentration of clarithromycin’s active metabolite, 14-R-hydroxy-clarithromycin (M-5), was also measured. Each patient received clarithromycin (400 to 600 mg/day) (weight-based) 1 week before the addition of rifampin (300 to 450 mg/day) (physician preference) for 1 week. When clarithromycin and rifampin were given concomitantly, clarithromycin serum concentrations significantly decreased in all 9 patients, with a mean decline from 3.57 mcg/mL to 0.74 mcg/mL. M-5 serum concentrations were unchanged. Although previous reports describe increases in the AUC of rifabutin during clarithromycin co-administration, rifampin serum concentrations were not measured in this study. Considering the 80% reduction in clarithromycin serum concentrations, the authors concluded that doses of clarithromycin should be increased when treating patients with lung disease due to MAC. Trimethoprim/Sulfamethoxazole Trimethoprim/sulfamethoxazole (TMP/SMX) is currently the medication of choice for Pneumocystis carinii pneumonia (PCP) and toxoplasmosis. Ribera et al52 studied 10 HIV-positive patients (9 men) 132

receiving PCP prophylaxis with TMP/SMX and admitted for tuberculosis. All patients received TMP/ SMX 160/800 mg daily for 1 month before the tuberculosis therapy being initiated, which included rifampin (600 mg daily) as part of the 4 drug regimen. After 12 days of concomitant administration of rifampin and TMP/SMX, significant reductions of each TMP/SMX component were noted (47% and 23%, respectively). These data are consistent with results from an earlier study by the same group that found a potential association with rifampin use and breakthrough toxoplasmosis during TMP/SMX prophylaxis.53 Since serum concentrations for TMP/ SMX prophylaxis of PCP and toxoplasmosis have not been established, the authors do not make recommendations regarding dose alterations. However, clinical experience would suggest that breakthrough infections could be severe and warrant a dosage escalation. Caspofungin An open-label, randomized, parallel-panel study54 of healthy male subjects was performed to investigate the potential effects of concomitant administration of rifampin and caspofungin. Study A consisted of 20 subjects receiving either caspofungin, 50 mg intravenous (IV) daily for 14 days (n ⫽ 10), or caspofungin plus rifampin, 600 mg orally daily for 14 days (n ⫽ 10). Rifampin co-administration led to increases in caspofungin’s AUC and trough concentration of 61% and 170%, respectively, on day 1. However, by day 14, no difference was found in these measurements. Rifampin is not recognized as a potential inhibitor of drug metabolism, thus the mechanism behind this finding has yet to be elucidated. This model suggests that combination therapy started simultaneously leads to early onset caspofungin inhibition with subsequent induction occurring later in therapy. The authors indicate that the transient elevation in caspofungin concentrations on day 1 would not be clinically relevant. Study B consisted of 26 healthy male subjects receiving either caspofungin, 50 mg IV daily for 14 days (n ⫽ 12), or rifampin, 600 mg orally daily for 28 days plus caspofungin 50 mg IV daily on the final 14 days (n ⫽ 14). After receiving rifampin for 14 days, there were no significant alterations in caspofungin AUC or maximum concentrations on days 1 and 14. However, a statistically significant decrease in trough concentrations was found on days 1 and 14 (29% and 31%, respectively). This study also evaluated the effects of caspofungin on rifampin pharmacokinetics and no significant differences were noted. The study suggests that when rifampin reaches maximal induction potential, a clinically meaningful reduction in caspofungin trough concentration may occur. Thus, the authors conclude that an increase in caspofungin dose to 70 mg should be considered when given concomitantly with rifampin. February 2008 Volume 335 Number 2

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Azole Antifungals Forty Thai patients were enrolled in a study to determine the effect of rifampin on fluconazole therapy in patients with AIDS-related cryptococcal meningitis.55 Before the fluconazole (400 mg daily) maintenance therapy, patients either received at least 2 weeks of rifampin (600 mg daily) for tuberculosis (n ⫽ 20) or had no exposure to rifampin within the previous 3 months (n ⫽ 20). After 8 days of concomitant administration, patients receiving rifampin had significant reductions in fluconazole AUC (22%), Cmax (17%), and an increase in fluconazole elimination rate constant (39%). On day 8, all serum concentration measured throughout the dosing interval was significantly lower in the rifampin/fluconazole group. The authors noted no significant differences in the conversion rates of cerebrospinal fluid (CSF). When patients showed negative CSF cultures, their fluconazole regimen was reduced to prophylaxis doses of 200 mg/day; however, patients continued to receive rifampin therapy. When this lower dose of fluconazole was utilized, serum concentrations of fluconazole were found to be mostly lower than the MIC of Cryptococcus neoformans. Therefore clinicians should consider increasing the dosage of fluconazole by 30% for treatment of serious infections with concomitant rifampin therapy. The effect of rifampin on itraconazole disposition is well documented, and this combination should be avoided to prevent therapeutic failure with itraconazole.4,5 Todd et al56 describe 2 HIV-positive patients with possible itraconazole failure after the addition of rifampin. Other Drugs Chung et al8 evaluated the effect of rifampin on the pharmacokinetics and pharmacodynamics of IV lorazepam in 24 healthy volunteers. This evaluation was part of a study aimed at assessing UGT genetic polymorphisms (UGT2B15*1/*1 and UGT2B15*2/ *2). Rifampin 600 mg daily for 10 days was administered prior to lorazepam 2 mg intravenously. Lorazepam mean systemic clearance increased by 140% after rifampin. Percentage changes in clearance from baseline did not significantly differ by genotype. Rifampin pretreatment also had a significant effect on lorazepam pharmacodynamics measured by visual analog scale (decreased sedative effect) in the UGT2B15*1/*1 group compared with baseline. Since lorazepam is cleared primarily by glucuronidation, this study adds to a limited body of evidence that rifampin induces conjugation mechanisms of drug clearance as well as oxidative metabolism by CYP enzymes and the transporter system P-gp. Kukoyi et al57 reported a case suggestive of decreased effect of citalopram associated with rifampin therapy. However, serum concentrations of citalopram or its active metabolite were not obtained. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

Another report of an apparent interaction of rifampin and the serotonin selective reuptake inhibitor (SSRI) sertraline did include serum concentrations and was summarized in our previous review.5 Controlled studies are needed to determine the effect of rifampin on various SSRIs. Pukrittayakamee et al58 assessed rifampin’s effect on quinine efficacy in uncomplicated falciparum malaria. Thirty patients received quinine sulfate 10 mg/kg 3 times a day orally alone while 20 patients received a combination of quinine with rifampin, 15 mg/kg orally daily for 7 days. The parasite clearance time was reduced by 15% in the quinine-rifampin (QR) treated group but patients in this group had a 5 time higher recurrence rate. QR treated patients had a higher conversion of quinine to 3 hydroxyquinine and also had a significantly lower (75%) median AUC for quinine. If possible rifampin should not be combined with quinine for malaria treatment. Ridtitid et al59 studied the effect of rifampin on the plasma concentrations of the antimalarial drug mefloquine in an open, 2-phase crossover study in 7 healthy Thai males. Pharmacokinetics of a single dose of mefloquine (500 mg) were compared before and 7 days after rifampin (600 mg daily). Mefloquine’s AUC was reduced by 68% after rifampin administration and mean Cmax was reduced by 19%. The authors suggested that concomitant rifampin and mefloquine administration be avoided. Ridtitid and coworkers60 investigated the pharmacokinetics of praziquantel and rifampin in a randomized, 2-phase crossover design of single and multiple doses of praziquantel. Ten healthy male volunteers received single (40 mg/kg) and multiple (25 mg/kg every 8 hours for 3 doses) praziquantel alone and after pretreatment with rifampin (600 mg) orally daily for 5 days. Rifampin reduced the plasma praziquantel concentrations to undetectable in the single and multiple dose studies in 70% and 50% of subjects, respectively. Rifampin through CYP3A4 induction can render praziquantel therapy nonefficacious in treatment of liver flukes and tuberculosis. Simultaneously administration of these drugs should be avoided. Jokenen et al61 evaluated the effect of rifampin on the disposition of ropivacaine. In a randomized, crossover study of 10 healthy nonsmokers and 8 healthy smokers, subjects received 5 days of rifampin (600 mg) or placebo. On day 6, subjects received ropivacaine (0.6 mg/kg IV) with plasma samples collected over the next 12 hours and urine samples taken over 24 hours. Rifampin reduced the plasma AUC of ropivacaine in smokers by 38% and in nonsmokers by 52%. Although rifampin is documented to induce several CYP isoenzymes,4 in this study the CYP3A4 mediated metabolism of ropivacaine was increased, while CYP1A2 mediated metabolism was decreased, as measured by 2 urinary metabolites. These findings are unlikely to be clini133

Update on Rifampin and Rifabutin Drug Interactions

Table 4. Updated Rifampin Drug Interactions Comments Controlled Drug Interaction Studies

Drug/Drug Class Sulfonylureas (Gliclazide, Glimepiride) Meglitinides (Repaglinide, Nateglinide) Thiazolidinediones (Rosiglitazone, Pioglitazone) HMG-CoA reductase inhibitors (Atorvastatin, Pravastatin) Everolimus Nilvadipine Opiates (Fentanyl) Cyclooxygenase (COX) 2 Inhibitors (Celecoxib, Rofecoxib) Caspofungin Fluconazole Clarithromycin Trimethoprim/Sulfamethoxazole Lorazepam Quinine Praziquantel Mefloquine Imatinab Gefitinib Mycophenolate mofentil Citalopram

Monitor blood glucose levels and clinical response; dosage adjustments made on blood glucose control Monitor blood glucose levels and clinical response; dosage adjustments made on blood glucose control Monitor blood glucose levels and clinical response; dosage adjustment made on blood glucose control Monitor cholesterol levels; dosage adjustment may be needed with select patients and drugs (see Table 1 for simvastatin interaction) Monitor serum concentrations and clinical response; increase dose probably will be needed; Or use alternative agent if possible Monitor clinical response; increase dose if needed Monitor clinical response; increase dose if needed Monitor clinical response; increase dose if needed Monitor clinical response; increase dose to 70 mg daily Monitor clinical response and microbiologic cure; increase dose if needed Prefer to avoid use; if must use then increase dose and monitor response Monitor clinical response; increase dose if needed Monitor clinical response; increase dose if needed Monitor clinical response; consider alternative agent if possible Consider alternative agent if possible; monitor clinical response; Consider avoiding combination; larger study needed Avoid combination; if must use, increase dose Avoid combination; if must use, increase dose Potential Interactions Based on Case Reports Monitor serum concentrations; increase dose if needed Monitor clinical response; controlled study needed to verify interaction

cally significant because ropivacaine is administered locally near the nerves to be desensitized. Bolton et al62 assessed the effect of rifampin on the pharmacokinetics of imatinab in 14 healthy adult subjects. The effect of rifampin on imatinib clearance was dramatic with a 385% increase; Cmax was reduced by 54%, and 24-hour AUC was decreased by 68%. The authors suggested avoiding concomitant rifampin and imatinib. Swaisland et al63 studied the effect of rifampin on the disposition of gefitinib in 18 healthy men. Rifampin caused a 65% reduction in Cmax and 83% decrease in the AUC of gefitinib. A series of small studies did not reveal any clinically significant interactions with rifampin combined with the quinolones, ciprofloxacin or pefloxacin.64 – 67 A single case report suggested a modest effect of rifampin on the disposition of irinotecan.68 Ahn and Lee69 have further validated the established interaction of rifampin on theophylline. Paine et al70 added to the body of knowledge regarding rifampin as an inducer of intestinal P-gp. Conclusions Rifampin and rifabutin have numerous well documented, clinically relevant drug interactions associated with their use. After 35 years of use in the 134

United States, new rifampin interactions continue to be discovered. Updated information on rifampin interactions is summarized in Table 4. Whenever these agents are prescribed, it is prudent to carefully monitor for drug interactions. Considering the clinical importance of many of these interactions, appropriate management of them is essential for safe and efficacious therapy. References 1. Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med 1984;144:1667–71. 2. Baciewicz AM, Self TH, Bekemeyer WB. Update on rifampin drug interactions. Arch Intern Med 1987;147:565–8. 3. Borcherding SM, Baciewicz AM, Self TH. Update on rifampin drug interactions II. Arch Intern Med 1992;152: 711–6. 4. Strayhorn VA, Baciewicz AM, Self TH. Update on rifampin drug interactions III. Arch Intern Med 1997;157: 2453–8. 5. Finch CK, Chrisman CR, Baciewicz AM, et al. Rifampin and rifabutin drug interactions. Arch Intern Med 2002;162: 985–92. 6. Kliewer SA, Moore JT, Wade L, et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 1998;92:73–82. 7. Tirona RG, Leake BF, Wolkoff AW, et al. Human organic anion transporting polypeptide-C (SLC21A6) is a major de-

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27. Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P4502C8 substrate rosiglitazone. Clin Pharmacol Ther 2004;76:239–49. 28. Jaakkola T, Backman JT, Neuvonen M, et al. Effect of rifampicin on the pharmacokinetics of pioglitazone. Br J Clin Pharmacol 2006;61:70–8. 29. Takane H, Nosaka A, Wakushima H, et al. Rifampin reduces the analgesic effect of transdermal fentanyl (letter). Ann Pharmacother 2005;39:2139–40. 30. Kharasch ED, Whittington D, Hoffer C. Influence of hepatic and intestinal cytochrome P4503A activity on the acute disposition and effects of oral transmucosal fentanyl citrate. Anesthesiology 2004;101:729–37. 31. Jayasagar G, Krishna Kumar M, Chandrasekhar K, et al. Influence of rifampicin pretreatment on the pharmacokinetics of celecoxib in healthy male volunteers. Drug Metabol Drug Interact 2003;19:287–95. 32. Vioxx package insert. Whitehouse Station, NJ: Merck & Co, Inc; August 2003. 33. Stephenson I, Qualie M, Wiselka MJ. Hepatic failure and encephalopathy attributed to an interaction between acetaminophen and rifampicin (letter). Am J Gastroenterol 2001; 98:1310–1. 34. Boyd MA, Zhang X, Dorr A, et al. Lack of enzyme-inducing effect of rifampicin on the pharmacokinetics of enfuvirtide. J Clin Pharmacol 2003;43:1382–91. 35. Droste JAH, Verweij-van Wissen CPWGM, Kearney BP, et al. Pharmacokinetic study of tenofovir disoproxil fumarate combined with rifampin in healthy volunteers. Antimicrob Agents Chemother 2005;49:680–4. 36. Tattevin P, Revest M, Dupont M, et al. A regimen containing rifabutin for the treatment of tuberculosis in patients intolerant to rifampin. Clin Infect Dis 2003;36:127–8. 37. Vernon A, Burman W, Benator D, et al. Acquired rifamycin monoresistance in patients with HIV related tuberculosis treated with once-weekly rifapentine and isoniazid: Tuberculosis Trials Consortium. Lancet 1999;353:1843–7. 38. Weiner M, Benator D, Burman W, et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis 2005;40:1481–91. 39. la Porte CJL, Colbers EPH, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother 2004;48:1553–60. 40. Gurumurthy P, Ramachandran G, Hemanth Kumar AK, et al. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 2004;48:4473–5. 41. Ribera E, Azuaje C, Lopez RM, et al. Once-daily regimen of saquinavir, ritonavir, didanosine, and lamivudine in HIVinfected patients with standard tuberculosis therapy (TBQD Study). J Acquir Immune Defic Syndr 2005;40:317–23. 42. (DHHS) Panel on Clinical Practices for Treatment of HIV Infection. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Washington, DC: US Department of Health and Human Services; 2006. 43. Edelstein HE, Cuadros Y. Failure of treatment of tuberculous adenitis due to an unexpected drug interaction with rifabutin and efavirenz. AIDS 2004;18:1741–9. 44. Spradling P, Drociuk D, McLaughlin S, et al. Drug-drug interactions in inmates treated for human immunodeficiency virus and mycobacterium tuberculosis infection or disease: an Institutional Tuberculosis Outbreak. Clin Infect Dis 2002;35:1106–12.

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45. Burger D, van der Heiden I, la Porte C, et al. Interpatient variability in the pharmacokinetics of the HIV nonnucleoside reverse transcriptase inhibitor efavirenz: the effect of gender, race, and CYP2B6 polymorphism. Br J Clin Pharmacol 2006;61:148–54. 46. Manosuthi W, Kiertiburanakul S, Sungkanuparph S, et al. Efavirenz 600 mg/day versus efavirenz 800 mg/day in HIV-infected patients with tuberculosis receiving rifampicin: 48 weeks results. AIDS 2006;20:131–2. 47. Lopez-Cortes LF, Ruiz-Valderas R, Ruiz-Morales J, et al. Efavirenz trough levels are not associated with virological failure throughout therapy with 800 mg daily and a rifampicincontaining antituberculosis regimen. J Antimicrob Chemother 2006;58:1017–23. 48. Sheehan NL, Richter C, Koopmans P, et al. Efavirenz 600 mg is not associated with subtherapeutic efavirenz concentrations when given concomitantly with rifampin Poster 2.21 6th International Workshop on Clinical Pharmacology of HIV Therapy Que´bec City, Canada April 28 – 30, 2005. 49. Manosuthi W, Ruxrungtham K, Likanonsakul S, et al. Nevirapine levels after discontinuation of rifampicin therapy and 60-week efficacy of nevirapine-based antiretroviral therapy in HIV-infected patients with tuberculosis. Clin Infect Dis 2007;44:141–4. 50. Ramachandran G, Hemanthkumar AK, Rajasekaran S, et al. Increasing nevirapine dose can overcome reduced bioavailability due to rifampicin coadministration. J Acquir Immune Defic Syndr 2006;41:36–41. 51. Yamamoto F, Harada S, Mitsuyama T, et al. Concentration of clarithromycin and 14-R-hydroxy-clarithromycin in plasma of patients with Mycobacterium avium complex infection, before and after the addition of rifampicin. Jpn J Antibiot 2004;57:124–33. 52. Ribera E, Pou L, Fernandez-Sola A, et al. Rifampin reduces concentrations of trimethoprim and sulfamethoxazole in serum in human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2001;45:3238–41. 53. Ribera E, Fernandez-Sola A, Juste C, et al. Comparison of high and low doses of trimethoprim-sulfamethoxazole for primary prevention of toxoplasmic encephalitis in human immunodeficiency virus-infected patients. Clin Infect Dis 1999;29:1461–6. 54. Stone JA, Migoya EM, Hickey L, et al. Potential for interactions between caspofungin and nelfinavir or rifampin. Antimicrob Agents Chemother 2004;48:4306–14. 55. Ayudhya DPN, Thanompuangseree N, Tansuphaswadikul S. Effect of rifampicin on the pharmacokinetics of fluconazole in patients with AIDS. Clin Pharmacokinet 2004;43:725–32.

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56. Todd JR, Arigala MR, Penn RL, et al. Possible clinically significant interaction of itraconazole plus rifampin. AIDS Patient Care STDS 2001;15:505–10. 57. Kukoyi O, Argo TR, Carnahan RM. Exacerbation of panic disorder with rifampin therapy in a patient receiving citalopram. Pharmacotherapy 2005;25:435–7. 58. Pukrittayakamee S, Prakongpan S, Wanwimolruk S, et al. Adverse effect of rifampin on quinine efficacy in uncomplicated falciparum malaria. Antimicrob Agents Chemother 2003;47:1509–13. 59. Ridtitid W, Wongnawa M, Mahatthanatrakul W, et al. Effect of rifampin on plasma concentrations of mefloquine in healthy volunteers. J Pharm Pharmacol 2000;52:1265–9. 60. Ridtitid W, Wongnawa M, Mahatthanatrakul W, et al. Rifampin markedly decreases plasma concentrations of praziquantel in healthy volunteers. Clin Pharmacol Ther 2002;72:505–13. 61. Jokinen MJ, Olkkola KT, Ahonen J, et al. Effect of rifampin and tobacco smoking on the pharmacokinetics of ropivacaine. Clin Pharmacol Ther 2001;70:344–50. 62. Bolton AE, Peng B, Hubert M, et al. Effect of rifampicin on the pharmacokinetics of imatinib mesylate (Gleevec, STI571) in healthy subjects. Cancer Chemother Pharmacol 2004;53: 102–6. 63. Swaisland HC, Ranson M, Smith RB, et al. Pharmacokinetic drug interactions of gefitinib with rifampicin, itraconazole and metoprolol. Clin Pharmacokinet 2005;44:1067–81. 64. Orisakwe OE, Agbasi PU, Afonne OJ, et al. Rifampicin pharmacokinetics with and without ciprofloxacin. Am J Ther 2001;8:151–3. 65. Orisakwe OE, Afonne OJ, Agbasi PU, et al. Urinary excretion of rifampicin in the presence of ciprofloxacin. Am J Ther 2004;11:171–4. 66. Orisakwe OE, Akunyili DN, Agbasi PU, et al. Some plasma and saliva pharmacokinetics parameters of rifampicin in the presence of pefloxacin. Am J Ther 2004;11:283–7. 67. Orisakwe OE, Agbasi PU, Ofoefule SI, et al. Effect of pefloxacin on the urinary excretion of rifampicin. Am J Ther 2004;11:13–6. 68. Yonemori K, Takeda Y, Toyota E, Kobayashi N, Kudo K. Potential interactions between irinotecan and rifampin in a patient with small-cell lung cancer. Int J Clin Oncol 2004;9:206–9. 69. Ahn HC, Lee YC. The clearance of theophyllines increased during the initial period of tuberculosis treatment. Int J Tuberc Lung Dis 2003;7:587–91. 70. Paine MF, Wagner DA, Hoffmaster KA, et al. Cytochrome P450 3A4 and P-glycoprotein mediate the interaction between an oral erythromycin breath test and rifampin. Clin Pharmacol Ther 2002;72:524–35.

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