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Rifampin and Rifabutin Drug Interactions an Update

Rifampin and Rifabutin Drug Interactions an Update

REVIEW ARTICLE Rifampin and Drug Interactions An Update

Christopher K. Finch, PharmD; Cary R. Chrisman, PharmD; Anne M. Baciewicz, PharmD, MBA; Timothy H. Self, PharmD

ifampin is a potent inducer of cytochrome P-450 oxidative enzymes. A few examples of well-documented clinically significant interactions include interactions with , oral contraceptives, cyclosporine, glucocorticoids, or , the- ophylline, sulfate, digitoxin or , verapamil hydrochloride, human im- Rmunodeficiency virus–related protease inhibitors, , mesylate, , and . Recent reports have demonstrated clinically relevant interactions with numerous other drugs, such as hydrochloride, zolpidem tartrate, , propafenone hydrochloride, , ondansetron hydrochloride, and opiates. Rifabutin reduces serum concentrations of an- tiretroviral agents, but less so than rifampin. To avoid a reduced therapeutic response, therapeutic failure, or toxic reactions when rifampin is added to or discontinued from medication regimens, cli- nicians need to be cognizant of these interactions. Enhanced knowledge of known interactions will continue to develop, including research on the induction of specific cytochrome P-450 isoenzymes and on the importance of the P-glycoprotein transport system. New rifampin and rifabutin interac- tions will be discovered with further investigations. Arch Intern Med. 2002;162:985-992

Rifampin is a potent inducer of the hepatic nificant effect on the and site and intestinal cytochrome P-450 (CYP) distribution of many drugs. Hoffmeyer et enzyme system and the P-glycoprotein al7 discovered that patients with specific (P-gp) transport system, which results in nu- polymorphisms of MDR1 had signifi- merous clinically significant drug interac- cantly different levels of P-gp activity in tions.1-4 Schuetz et al5 found that rifampin the duodenum. Moreover, the ability of rif- intracellular concentrations and, there- ampin to induce P-gp and thereby lower fore, the extent by which rifampin was able digoxin levels (described later) was greatly to induce CYP3A was strongly correlated governed by these polymorphisms of the with P-gp levels. MDR1 gene. This may partially explain the P-glycoprotein is a transmembrane wide interpatient variability in CYP3A in- protein that is a member of the adeno- duction by rifampin. The subject of P-gp sine triphosphate–binding cassette fam- as a mechanism for drug interactions has ily, a group of molecules that control con- been recently reviewed.6 centrations of endogenous and exogenous As the number of new agents mar- substances across cell membranes by func- keted increases, the potential for clini- tioning as cellular efflux pumps.6 The gene cally significant drug interactions height- that encodes this protein is the multi- ens. Since the last review of this topic in gene (MDR1). MDR1 ex- the ARCHIVES,4 several new interactions in- pression manifested as P-gp is widely dis- volving rifampin have been reported. In tributed throughout the body, and is found addition, because of the importance of at many sites that are key to drug bioavail- rifabutin in treating in pa- ability and distribution, such as the intes- tients with the acquired immunodefi- tinal lumen, the , the kidney, and the ciency syndrome (AIDS),8 interactions blood-brain barrier.6 Interpatient and in- with this agent are included. trapatient variability in the expression of A summary of previously reviewed the gene product of MDR1, P-gp, has a sig- rifampin interactions1-4 that are well docu- Author affiliations are listed at the end of this article. mented and of major clinical significance

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 Table 1. Rifampin Drug Interactions of Major Clinical Significance*

Type of Drug Comments Oral anticoagulants Monitor international normalized ratio; increased anticoagulant dose will likely be needed Oral contraceptives Use alternative form(s) of birth control; counsel patient and document in medical record Cyclosporine Monitor serum cyclosporine concentrations; increased dosage will likely be needed Digitoxin Monitor arrhythmia control, signs and symptoms of , and serum digitoxin concentrations Glucocorticoids Increase dose of glucocorticoid 2- to 3-fold Itraconazole Prefer to avoid use with rifampin; if must use, increase dose and monitor response Ketoconazole Avoid concomitant use if possible; if must use, increase dose and monitor response; space ketoconazole and rifampin doses by 12 h Methadone hydrochloride Increase methadone dose with concomitant rifampin therapy; monitor and control withdrawal symptoms Midazolam or Prefer to avoid use with rifampin; use another agent if possible Monitor serum phenytoin concentrations and seizure activity; increase dosage if needed Quinidine Monitor serum quinidine concentrations and arrhythmia control; increase dosage if needed Theophylline Monitor serum theophylline concentrations; increase dosage if needed Verapamil Use an alternative agent to verapamil because large oral verapamil doses may not be adequate; monitor patient for clinical response†

*Data adapted from Baciewicz and coworkers,1,2 Borcherding et al,3 and Strayhorn et al.4 Carefully adjust doses when rifampin use is discontinued. The enzyme induction effect is gradually reduced during a 1- to 2-week period or longer. †See also data on diltiazem and nifedipine in Table 2.

Table 2. Rifampin Drug Interactions*

Type of Drug Comments ␤-Adrenergic blocking agents Monitor patient for clinical response; increased hydrochloride or metoprolol dose may be needed † Monitor serum chloramphenicol concentrations; may need to increase dosage Monitor signs and symptoms of ; more study needed Monitor clinical response; dosage increase may be necessary; additional study needed when used for Pneumocystis carinii prophylaxis; monitor for hematologic toxic effects † Monitor clinical response; may need to increase diazepam dosage Digoxin (oral) Monitor arrhythmia control and signs and symptoms of heart failure; monitor digoxin serum concentrations Diltiazem† Use alternative agent if possible because large oral doses of diltiazem may be ineffective; monitor clinical response‡ Disopyramide 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 Haloperidol† Monitor clinical response; increase dosage if needed potassium Monitor patient for clinical response; may need to increase dosage Nifedipine Alternative class of agents should be considered; monitor clinical response; dosage increase may be needed† Nortriptyline hydrochloride Monitor clinical response and serum nortriptyline concentrations Moderate rifampin induction effect; pending further research, no dosage adjustment recommended Sulfonylureas Monitor blood glucose levels; base any dosage adjustments on blood glucose control Tacrolimus Monitor serum tacrolimus concentrations and clinical response; increased dose may be needed or use another agent if possible Tocainide Monitor arrhythmia control; increase dosage if needed

*Data adapted from Baciewicz and coworkers,1,2 Borcherding et al,3 and Strayhorn et al.4 Additional study is needed to clearly establish clinical significance. Carefully adjust doses when rifampin use is discontinued. The enzyme induction effect is gradually reduced during a 1- to 2-week period or longer. †Probably of clinical significance. ‡See also data on verapamil in Table 1.

is given in Table 1, while rifampin coccal skin infection, concurrently symptoms if inducers of CYP3A4 are interactions that may be clinically with sertraline, 200 mg/d. After 7 used during sertraline therapy. relevant but less well documented days of rifampin therapy, the pa- are listed in Table 2. tient reported feeling anxious and Nortriptyline Hydrochloride excessively worried. Subsequent PSYCHOTROPIC AGENTS blood samples revealed that sertra- Two prior case reports have docu- line concentrations increased 3-fold mented a decrease in nortriptyline Sertraline Hydrochloride (from 18 to 55 ng/mL) 1 week after levels when used concomitantly with discontinuation of rifampin, and the rifampin.4 Although nortriptyline is Sertraline is a commonly used se- active metabolite of sertraline was predominantly metabolized by lective serotonin reuptake inhibi- increased greater than 2-fold. The CYP2D6, Venkatakrishnan et al10 tor that is thought to undergo ex- treatment of the patient was later found that CYP3A4 contributes to the tensive first-pass by the changed to another agent after symp- hydroxylation of nortriptyline. Cyto- CYP3A4 isoenzyme. Markowitz and toms were still present 1 week after chrome P-4503A4 is characterized as DeVane9 described a 34-year-old discontinuing rifampin. These re- having a low affinity and a low ca- man receiving rifampin, 600 mg/d, searchers suggest the potential for pacity for nortriptyline metabolism. as part of treatment for a staphylo- therapeutic failure or withdrawal However, the authors suggest that the

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 contribution by CYP3A4 increases as Zolpidem Tartrate placebo-controlled, crossover study nortriptyline concentrations in- to examine the effects of rifampin on crease because of impaired CYP2D6 Zolpidem, a short-acting hypnotic the of simvastatin. function (eg, poor metabolizers [PMs] agent, is predominantly metabo- After a 5-day course of rifampin, 600 or patients treated with CYP2D6 in- lized by CYP3A4. In a randomized, mg/d, simvastatin, 40 mg, was given hibitors) or concomitant administra- balanced, placebo-controlled, cross- on day 6. Rifampin reduced the AUC tion with an inducer of the CYP3A4 over study by Villikka et al,14 8 vol- of simvastatin and simvastatin acid by isoenzyme. unteers were used to examine the 87% and 93%, respectively. The Cmax possible interaction between rif- of both agents was decreased by 90% Buspirone Hydrochloride ampin and zolpidem. Rifampin, 600 byrifampin.Basedontheresultsofthis mg/d, was administered for 5 days, study, it is likely that concomitant use Buspirone, a common anxiolytic with zolpidem, 20 mg, given on day of rifampin with simvastatin may sig- agent, undergoes extensive first- 6. Rifampin reduced the AUC and nificantly reduce the - pass metabolism via the CYP3A4 iso- the Cmax of zolpidem by 73% and lowering effect of simvastatin. The re- enzyme. Lamberg et al11 conducted a 58%, respectively, and the half-life searchers postulate that rifampin may randomized, placebo-controlled, was decreased from 2.5 to 1.6 hours. interact with and atorvas- crossover study of the effects of rif- The pharmacodynamic effects tatincalciumbecauseoftheirCYP3A4 ampin on buspirone pharmacokinet- (drowsiness) of zolpidem were also activity, but further investigation is ics. Ten healthy volunteers received reduced and shortened during the warranted. According to the manufac- rifampin, 600 mg/d, for 5 days and rifampin phase. These findings sug- turer of fluvastatin sodium, rifampin buspirone, 30 mg, on day 6. During gest that this interaction is likely to reduces the AUC and Cmax of the agent the rifampin phase, the area under the be clinically relevant. by 51% and 59%, respectively.18 concentration-time curve (AUC) of buspirone decreased by 89.6%. The Midazolam Digoxin maximum concentration (Cmax) and half-life decreased by 83.7% and Reports of the induction of mid- There have been previous reports1,2 52.8%, respectively. No subjects in the azolam metabolism by rifampin have of a digoxin-rifampin interaction that rifampin arm had measurable buspi- already been reviewed,4 and the re- involved patients with renal failure rone concentrations at 6, 8, or 10 sults of a new study15 are consistent or a moderate decline in renal func- hours after taking the therapeutic with the previous findings. When tion. In patients with normal renal agent. These results indicate an in- midazolam, 15 mg, was adminis- function, digoxin is eliminated from crease in presystemic and systemic tered orally on days 1 and 4 after a the body almost entirely as un- clearance of buspirone. 5-day course of rifampin, 600 mg/d, changed drug. Nonrenal clearance The same group of investiga- the AUC of midazolam was de- mechanisms of this interaction have tors12 studied the effects of rifampin creased by 97.7% and 86.8%, respec- not been clearly defined. 19 on the active metabolite of tively, and the Cmax was decreased Greiner et al examined the role buspirone. Using samples from their by 94.6% and 79.8%, respectively. of intestinal P-gp in the interaction of previous study,11 plasma concentra- Concentrations of the active met- digoxinandrifampinin8healthymen tions of the piperazine metabolite abolite were also reduced by 20% to givena2-weekcourseofrifampin,600 were not significantly affected by rif- 40% of the control during the rif- mg/d, and then digoxin, 1 mg, either ampin. Based on the results of these ampin phase. The researchers also orally or intravenously (IV). After rif- studies, concomitant administration concluded that if switching from in- ampin administration, the AUC and of buspirone with rifampin should be hibition (in this study, with itra- Cmax of oral digoxin decreased by 43% avoided because of the potential for conazole) to induction of CYP3A4 and 58%, respectively. The oral bio- therapeutic failure. enzymes, a 400-fold change in the availability of digoxin decreased by pharmacokinetics of oral mid- 30.1% during rifampin therapy. Rif- azolam may be observed. Using mid- ampin also increased intestinal P-gp azolam as a substrate during rif- levels 3.5-fold. These results suggest Joos et al13 described a 33-year-old ampin induction, Gorski et al16 found thatP-gpregulatesdigoxindisposition, schizophrenic patient who was stable that intestinal CYP3A4 may be pref- whichcanleadtoaltereddrugconcen- while receiving clozapine, 400 mg/d, erentially altered by rifampin. trations. Patients should be closely for 2 years. After 31⁄2 weeks of treat- monitored for arrhythmia control and ment with rifampin, 600 mg/d, as part CARDIOVASCULAR DRUGS signs and symptoms of heart failure of treatment for pulmonary tubercu- during concurrent rifampin adminis- losis, the patient began experiencing Simvastatin tration. increased restlessness and paranoid thoughts. Subsequent clozapine se- Simvastatin, a widely used agent for Propafenone Hydrochloride rum concentrations were dramati- hypercholesterolemia, and its active cally reduced by 600%. On discon- metabolite, simvastatin acid, are me- While one previous case report3 tinuation of rifampin, clozapine tabolized to inactive metabolites by suggested a clinically important serum concentrations increased to the CYP3A4. Kyrklund et al17 enrolled interaction between rifampin and therapeutic level within 3 days. 10 healthy patients in a randomized, propafenone, 2 recent controlled tri-

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Nelfinavir Delavirdine Mesylate Mesylate Ritonavir and Mesylate Rifampin 89 82 84 82 35 75 25 37 96 Rifabutin 32 32 40 15 0 0 0 16 80

*Data adapted from previously published guidelines.25 AUC indicates area under the concentration-time curve; PI, protease inhibitor; and NNRTI, nonnucleoside reverse transcriptase inhibitor.

als verify the importance of this inter- potent, followed by and hibitors, a between action. Dilger et al20 studied the con- rifabutin.22 Initial clinical evidence a nucleoside and has only sequences of rifampin treatment on indicated that rifabutin has less pro- been reported with zidovudine. Rif- propafenone disposition in CYP2D6 pensity than rifampin to cause an im- abutin and rifampin decreased the zi- extensive metabolizer (EM) and PM portant induction of drug metabo- dovudine AUC by 32% and 47%, re- phenotypes.Twelvevolunteers(6EMs lism, and these reports have been spectively.29,30 A dramatic reduction and6PMs)ingestedrifampin,600mg/ reviewed.23 Consequently, the drug (25%-96%) in the AUC of PIs and d, for 9 days, followed by a single IV interactions between rifabutin and nonnucleoside reverse transcriptase infusion of unlabeled propafenone, protease inhibitors (PIs) and non- inhibitors occurs when rifampin is 140 mg, and a single dose of labeled nucleoside reverse transcriptase in- coadministered because of CYP3A/ oral propafenone, 300 mg. There were hibitors, drugs with narrow thera- P-gp induction (Table 3). The most no significant differences in the phar- peutic ranges, are easier to manage recent Centers for Disease Control macokinetics of IV propafenone be- than those with rifampin.24,25 The PIs and Prevention guidelines state that foreandafterrifampinadministration; and the nonnucleoside reverse tran- rifampin should only be adminis- however, the bioavailability of oral scriptase inhibitors not only are tered in individuals undergoing propafenone decreased by 67% and CYP3A substrates but are also inhibi- HAART in 3 situations: (1) if the pa- 41% in the EM and PM groups, re- tors and inducers of this same iso- tient is taking efavirenz, (2) if the pa- spectively. The propafenone metabo- form, with the net result being ei- tient is taking ritonavir, or (3) if the lism mediated by CYP2D6 was not ther an increase or a decrease of the patient is taking ritonavir plus sa- enhanced; however, clearance via rifabutin levels, frequently necessi- quinavir mesylate. However, more re- CYP3A4/1A2andglucuronidationand tating rifabutin and PI dosage adjust- cent evidence suggests that these sulfation were greatly increased by rif- ment.24 The extent and effect of the guidelines may require modifica- ampin. These results indicate a 67% inhibition of rifabutin metabolism by tion. While the ritonavir-saquinavir and 71% reduction in active propafe- amprenavir were demonstrated in a combination dosed at 400 mg each noneconcentrationsintheEMandPM recent study by Polk et al.26 When twice daily given with rifampin re- groups, respectively. Such reductions combined with amprenavir in healthy sulted in adequate levels of saquina- in propafenone concentrations may volunteers, rifabutin given at the stan- vir, newer methods of dosing this cause a loss of arrhythmia control. dard dose of 300 mg/d was associ- combination (ritonavir, 100 mg/d, The same group of research- ated with poor tolerability and re- and saquinavir, 1600 mg/d; or rito- ers21 found similar data when evalu- sulted in leukopenia in 7 of 11 navir, 100 mg, and saquinavir, 1000 ating the effects of rifampin on the subjects. This abnormally high rate of mg, both twice daily) are being used, pharmacokinetics and pharmacody- adverse reactions could have been which may result in a different mag- namics of propafenone in elderly per- caused by the nearly 3-fold increase nitude of interaction with rifampin. sons. Bioavailability decreased by in rifabutin’s AUC. For this reason, the Indeed,DeGastetal31 found that rif- 87% and 52% in the EMs and PMs, rifabutin dose must be decreased ampin administered with 100 mg of respectively, during rifampin induc- and/or the dosing interval increased ritonavir and 800 mg of indinavir, tion. They also found that during en- when coadministered with a PI.24 twice daily, resulted in a greatly re- zyme induction, maximum QRS pro- Spradling et al27 found that even af- duced indinavir AUC. In addition, the longation decreased significantly after ter adjusting the rifabutin and anti- most recent Centers for Disease Con- oral propafenone therapy. Induc- retroviral agent doses, rifabutin lev- trol and Prevention guidelines24 state tion of gut wall metabolism may play els were suboptimal among many that no dosage adjustment is neces- a major role because gastrointesti- patients taking more than one PI or sary when efavirenz is given with rif- nal extraction of propafenone in- PIs combined with efavirenz. How- ampin. However, efavirenz levels were creased almost 4-fold during rif- ever, Narita et al28 found that after rif- significantly lowered when given with ampin administration. abutin and PI doses were adjusted, rif- rifampin at the usual efavirenz dose abutin levels were only marginally of 600 mg, but were increased to the ANTIRETROVIRAL AGENTS lower in patients receiving either in- normal range when the efavirenz dose dinavir or mesylate based was increased to 800 mg, a strategy The 3 commercially available rifamy- on highly active antiretroviral therapy that proved successful in treating cin derivatives have different CYP3A (HAART), a reduction that was not patients coinfected with the human induction potencies. In vitro data clinically significant. Among the virus (HIV) and demonstrate that rifampin is the most nucleoside reverse transcriptase in- tuberculosis.32,33

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 COMMONLY same individuals while taking only because of the risk of therapeutic USED AS TREATMENT one of these drugs. Likewise, the me- failure. OR PROPHYLAXIS OF tabolites 14-OH-clarithromycin and OPPORTUNISTIC 25-O-desacetyl-rifabutin were in- IMMUNOSUPPRESSANTS IN PATIENTS WITH creased by 57% and 357%, respec- HIV OR AIDS tively. While these mean values are Two case reports suggestive of significant, interpatient variability clinically relevant interactions of rif- Dapsone was high, with some patients expe- ampin with tacrolimus (a substrate for riencing much larger (Ͼ150%) in- CYP3A4 and P-gp) have been previ- In 7 HIV-positive patients receiving creases in the rifabutin AUC. The re- ously summarized.4 Hebert et al40 100 mg of dapsone twice weekly for searchers concluded that the elevated evaluated the pharmacokinetics of ta- Pneumocystis carinii pneumonia pro- AUC of rifabutin that occurs when crolimus in 6 healthy volunteers. Sub- phylaxis, rifampin increased dap- given with clarithromycin is likely the jects were treated with either a single sone clearance by 69% to 122% (de- cause of the increased incidence of oral dose (0.1 mg/kg) or an IV dose pending on which pharmacokinetic uveitis observed in patients receiv- (0.025 mg/kg) of tacrolimus, before models were used), a magnitude that ing this combination therapy. and after 18 days of rifampin, 600 would most likely be clinically sig- mg/d. With coadministration of rif- nificant.34 The investigators be- Fluconazole and/or ampin, the clearance of tacrolimus in- lieved that the increased clearance of Clarithromycin creased nearly 50%. Oral bioavail- dapsone was largely because of a sig- ability also decreased 50% during nificant first-pass effect. Moreover, Researchers38 found, in 10 HIV- concomitant rifampin therapy. they observed that monoacetyldap- infected patients, that when rifabu- Chenhsu et al41 described a 61-year- sone was undetectable in plasma. tin, 300 mg/d, was administered with old kidney transplant recipient in either clarithromycin, 500 mg/d, or whom tacrolimus therapy was main- Azithromycin fluconazole, 200 mg/d, the rifabutin tained. Rifampin was prescribed as AUC was increased by 76%. When part of tuberculosis therapy, and sub- Two different dosing regimens of clarithromycin and fluconazole were sequent tacrolimus serum concen- azithromycin and rifabutin were administered simultaneously with rif- trations decreased from 5 to 8 to 1.5 evaluated in HIV-positive and HIV- abutin at the previously mentioned ng/mL. A 10-fold increase in the ta- negative volunteers.35 Fifty study sub- doses, the metabolic inhibitory effect crolimus dose was needed to main- jects received either 1200 mg of was additive, with a 152% increase tain pre-rifampin serum concentra- azithromycin plus 600 mg of rifabu- in the rifabutin AUC. These authors tions. These results are consistent with tin daily or 600 mg of azithromycin caution that in real clinical situa- previous reports and warrant the need plus 300 mg of rifabutin daily. While tions, many drugs are given concomi- for careful monitoring of tacrolimus no significant drug interactions were tantly and the extent of drug inter- trough concentrations when rif- found between the 2 drugs, the rate actions is difficult to predict based on ampin is added to either IV or oral ta- of was quite high at 66%, pharmacokinetic studies only exam- crolimus therapy. as were the rates of gastrointestinal ad- ining 2 drugs. Although the highly signifi- verse reactions. Whether these ad- cant rifampin-cyclosporine interac- verse reactions would occur to the Itraconazole tion has been previously reviewed,2 same degree with the standard dose the effects of rifampin on cyclospor- of azithromycin, 1200 mg /wk, used Itraconazole and rifampin are com- ine disposition continue to be evalu- for avium-intracellu- monly used together in HIV-in- ated.42 Kim et al43 found that doses lare complex prophylaxis is not fected patients, and literature4 reveal- of cyclosporine had to be increased known. A study36 in healthy volun- ing an interaction between these 2 2.5- to 3-fold to maintain satisfac- teers given concomitant rifabutin and agents has been reviewed. A new tory blood concentrations. either azithromycin or clarithromy- study has emerged to further substan- cin also revealed the risk of neutro- tiate evidence of an interaction. Jaru- ANTIEMETIC AGENTS penia, which occurred in all 12 sub- ratanasirikul and Sriwiriyajan39 stud- jects given either agent with rifabutin. ied 6 healthy patients and 3 patients Ondansetron Hydrochloride with AIDS to evaluate the effect of rif- Clarithromycin ampin on the pharmacokinetics of A randomized crossover study44 in 10 itraconazole. All subjects received healthy volunteers suggested that rif- The pharmacokinetics of clarithro- rifampin, 600 mg, for 2 weeks fol- ampin may cause a clinically signifi- mycin, dosed at 500 mg twice daily, lowed by a single 200-mg dose of oral cant interaction with ondansetron, a plus rifabutin, dosed at 300 mg/d, itraconazole. On concomitant admin- potent antiemetic agent. Ondanse- were evaluated in 34 patients with istration, itraconazole serum concen- tron, 8 mg IV and orally, was admin- HIV or AIDS.37 A 44% reduction in trations were undetectable in all but istered before and after rifampin, the clarithromycin AUC was ob- one healthy volunteer, whose levels 600 mg/d, for 5 days. The AUC of oral served, along with a 99% increase in were quite low. Based on these data, and IV ondansetron was reduced by the rifabutin AUC, when compared the concurrent use of rifampin and 65% and 48%, respectively, after rif- with those values obtained in the itraconazole should be avoided ampin administration. Rifampin de-

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Downloaded From: https://jamanetwork.com/ on 09/28/2021 creased the Cmax of oral ondansetron diated by CYP2D6) to morphine and tionshasyettobedetermined,thedos- by 50% and increased IV ondanse- N-demethylation to an inactive age of tamoxifen and toremifene may tron clearance by 83%. Based on these metabolite. While rifampin induced need significant adjustment during results, concomitant use of rifampin O-demethylation only in EMs, it in- concomitant use of rifampin. with ondansetron may result in a re- creased N-demethylation to a greater The highly important rifampin– duced antiemetic effect. degree (relative to baseline values), oral contraceptive interaction (in- with a resultant decrease in morphine duction of and progester- Dolasetron Mesylate concentrations. Decreased morphine one metabolism) has already been concentrations observed in EMs was reviewed,1 and a new study50 evalu- Dimmitt et al45 studied the pharma- associated with attenuation of co- ating rifampin and rifabutin effects cokinetic disposition of dolasetron, deine’s respiratory and psychomotor on oral contraception has been con- 200 mg, and its active metabolite, hy- effects but not the miotic effect. These ducted. Although the effects of rif- drodolasetron, in 18 healthy men be- pharmacodynamic changes did not ampin were significantly greater than fore and after the administration of rif- occur in PMs. Because of reduced those of rifabutin, an alternate form ampin, 600 mg/d, for 1 week. Dolas- morphine concentrations in EMs due of birth control should be used, etron plasma concentrations were to this interaction, some patients may along with patient counseling and below the detectable limit throughout have a diminished effect. documentation with either agent. allphasesofthestudy,butduringcon- A study48 was conducted evalu- Nolan et al51 described a 50-year- current rifampin treatment, the clear- ating the ethnic variability in the effect old man with a history of hypothy- ance of hydrodolasetron increased by of rifampin on codeine disposition roidism who was stable while taking 39%. Although the researchers sug- and pharmacodynamics. Codeine me- sodium, 0.025 mg/d. gested that no dosage adjustment is tabolism via O-demethylation to mor- Rifampin, 600 mg/d, was added as necessary during concomitant rif- phine and N-demethylation to an in- part of therapy for persistent infec- ampin administration, studies in pa- active metabolite was assessed. Caraco tion with methicillin sodium– tients are needed to verify that no dos- et al48 found that morphine’s AUC in resistant Staphylococcus aureus. Af- age increases will be required. Chinese volunteers was not altered ter 2 weeks of rifampin therapy, the during rifampin therapy, while there patient’s thyrotropin level increased OPIATES was a significant decrease in the mor- by 202% (9.44 mmol/L) from the phine AUC in white persons. Based most recent pretreatment thyrotro- Fromm et al46 discussed a loss of the on these observations, rifampin’s pref- pin value (4.67 mmol/L). Thyrotro- analgesic effect of morphine sulfate erential induction of codeine to in- pin levels returned to baseline 9 days in 10 healthy volunteers because of active metabolite over morphine is after discontinuation of rifampin the coadministration of rifampin. ethnically dependent. Clinical signifi- therapy. The researchers suggested Morphine, 10 mg orally, was admin- cance is still to be determined. that this interaction may be due to en- istered before and near the end of 13 hanced hepatic clearance of the levo- days of treatment with rifampin, 600 OTHER DRUGS thyroxine. mg/d. Rifampin therapy resulted in Rifampin decreases the plasma a significant reduction in the AUC Theantiestrogenagents,tamoxifenci- concentrations and effects of repaglin- 52 (28%) and the Cmax (41%) of mor- trate and toremifene citrate, undergo ide, an oral hypoglycemic agent ex- phine. Using the cold pressor test to metabolism mediated by CYP3A4. tensivelymetabolizedbyCYP3A4.Re- determine pain sensation, the admin- Kivisto et al49 conducted 2 random- paglinide, 0.5 mg, was administered istration of rifampin resulted in no ized, placebo-controlled, crossover to 9 healthy volunteers before and af- analgesic effect of morphine. Be- studies to evaluate the effects of rif- ter a 5-day course of rifampin, 600 cause a major drug interaction was ampin on the pharmacokinetics of ta- mg/d. Concomitant treatment with observed between morphine and rif- moxifen and toremifene in 10 and 9 rifampin significantly decreased the ampin, the assessment of pain should healthy volunteers, respectively. Vol- mean AUC of by 57% and be performed more frequently dur- unteerstookeither600mgofrifampin the Cmax by 41%. Subsequently, blood ing rifampin therapy to determine a or placebo orally once a day for 5 days; glucoseconcentrationswereincreased loss of the analgesic effect. The need on the sixth day, 80 mg of tamoxifen significantly during rifampin admin- for increased morphine doses should or 120 mg of toremifene was admin- istration. These researchers suggested be anticipated. istered.Rifampinsignificantlyreduced that blood glucose concentrations Caracoetal47 evaluatedtheeffects the plasma concentrations of tamox- should be closely monitored and that of rifampin on codeine phosphate ifen and toremifene, with the AUC re- the repaglinide dosage should be ad- pharmacokinetics and pharmaco- duced by 86% and 87%, respectively. justed appropriately during CYP3A4 dynamics in 15 healthy men (9 EMs The Cmax and half-life of both agents induction. This same group of inves- and 6 PMs). Single-dose oral codeine, were also decreased by 55% and 44%, tigators studied the effect of rifampin 120 mg, was administered before and respectively, with rifampin treatment. onthepharmacokineticsandpharma- 3 weeks after rifampin therapy, 600 The pharmacokinetic variables of the codynamics of glyburide and glipi- mg/d. The codeine plasma AUC was active metabolites for each agent zide in 10 healthy subjects. Consistent decreased by a mean of 79% (in EMs) changed significantly vs placebo dur- with initial case reports previously and 83% (in PMs). Codeine is me- ing rifampin therapy. Although the reviewed,3,4 these investigators found tabolized by O-demethylation (me- clinical significance of these interac- that rifampin, 600 mg/d orally for 5

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Type of Drug Comments Controlled Drug Interaction Studies

Selective serotonin receptor (5-HT3) Monitor clinical response; increase dose if needed; use another agent if needed antagonist44,45 Buspirone hydrochloride11,12 Monitor clinical response; increased dose will likely be needed or use another agent if possible 3-Hydroxy-3-methylglutaryl coenzyme A Monitor lipid panel; increased dose will likely be needed for simvastatin; further research needed for other reductase inhibitors17,18 agents in this class Metronidazole55 Monitor for decreased clinical response; increase dose if needed or use another agent if possible Opiates (morphine or codeine)46-48 Monitor pain control and clinical response; increased dose may be needed in extensive metabolizers; use another agent if possible; may be associated with ethnic variability Propafenone hydrochloride20,21 Monitor clinical response; increased dose may be needed or use another agent if possible Tamoxifen citrate or toremifene citrate49 Monitor clinical response; increased dose likely needed Zolpidem tartrate14 Monitor clinical response; increased dose may be needed or use another agent if possible Potential Interactions Based on Case Reports† Clozapine13 Monitor clinical response; increase dose if needed or use another agent if possible Levothyroxine sodium51 Monitor thyrotropin level; increased dose likely needed Sertraline hydrochloride9 Monitor clinical response; increase dose if needed

*Carefully adjust dosage when rifampin use is initiated and discontinued. The enzyme induction effect is gradually reduced during a 1- to 2-week periodor longer when rifampin therapy is discontinued. Based on the small number of reports, further studies are needed for most of these agents. †Controlled study is needed to establish the importance and extent of the interaction.

days, significantly affects glyburide of rifampin; however, food signifi- Pharmacy, Franklin, Tenn (Dr Chris- plasma concentrations (decreased cantly reduced the Cmax by 36% and man);andDepartmentofPharmacySer- the AUC by 39%).53 The maximum increased the time to peak concen- vices,UniversityHospitalsofCleveland, decrease in blood glucose concentra- tration by 103%. These findings sug- Cleveland, Ohio (Dr Baciewicz). Dr tions due to this interaction was 36%. gest that rifampin should be taken on Finch is now with the Department of Rifampin decreased glipizide’s AUC an empty stomach to avoid these ki- PharmacyPractice,AuburnUniversity, by 22%.53 netic changes. Auburn, Ala, and Dr Chrisman is now Hamman et al54 studied the ef- withtheDepartmentofPharmacy,Meth- fects of rifampin, 600 mg/d for 6 days, CONCLUSIONS odist Medical Center of Oak Ridge, Oak on the disposition of a single dose of Ridge, Tenn. Dr Chrisman has no type fexofenadine hydrochloride, 60 mg, Rifampin has numerous well- of investment of involvement with in 24 healthy volunteers. After rif- documented clinically significant anypharmaceuticalcompaniesviastock ampin therapy, all of the subjects had drug interactions associated with its or mutual funds. He has consultant ar- a significant increase in the oral clear- use. Since the initial discovery of sev- rangements for which he receives no ance, with individual increases rang- eral important rifampin interactions compensation, financial or otherwise, ing from 1.3- to 5.3-fold. There was more than 25 years ago, new inter- withthefollowingpharmaceuticalcom- also a significant reduction in the actions continue to be found. Up- panies: Merck & Co, Inc, Whitehouse peakserumconcentrationoffexofena- dated information on rifampin inter- Station, NJ; Roche, Nutley, NJ; Bristol- dine. Because fexofenadine is elimi- actions is summarized in Table 4. Myers Squibb, Wallingford, Conn; natedasunchangeddrug,theresearch- As rifabutin use continues to in- and Agouron Pharmaceuticals, Inc, La ers concluded that the increased crease in patients with HIV or AIDS, Jolla, Calif. Dr Baciewicz owns drug clearance and decreased concentra- drug interactions with this agent are company stocks (including stocks for tions are caused by an induction of in- increasingly being reported. Al- GlaxoSmithKline, Research Triangle testinal P-gp. The clinical relevance of though rifabutin interactions are Park, NC; Merck & Co, Inc; Pfizer Inc, this study has yet to be determined. generally less dramatic than rif- New York, NY; and Bristol-Myers Djojosaputroetal55 evaluatedthe ampin interactions, many are clini- Squibb) in addition to drug company elimination kinetics of IV metronida- cally relevant. Table 3 offers a com- stocks via mutual funds. Dr Self receives zole, 500 and 1000 mg, after pretreat- parison of rifabutin and rifampin standardspeaking/consultinghonoraria ment with rifampin, 450 mg/d for 7 interactions. Whenever clinicians pre- from GlaxoSmithKline; Merck & Co, days, in 10 healthy volunteers. Pre- scribe therapy with either rifampin or Inc; and other pharmaceutical compa- treatment with rifampin increased the rifabutin, it is prudent to screen for nies related to his expertise on asthma clearanceofmetronidazoleby44%and drug interactions. As these agents therapy. (These companies may have decreased the AUC by 33% for both continue to be used, discovery of new products discussed in this review.) Dr doses. interactions should be anticipated. Self has received investigator-initiated Although most of the literature grantsfromGlaxoSmithKlineforasthma focuses on the effects of rifampin on Accepted for publication September 6, clinical investigations. He also owns other drugs, some agents have ef- 2001. stock in several pharmaceutical compa- fects on rifampin.4 In a study56 of 14 From the Department of Clinical nies, primarily via mutual funds. volunteers, coadministra- Pharmacy, University of Tennessee, Corresponding author and re- tion had no effect on the absorption Memphis (Drs Finch and Self); Secure prints: Timothy H. Self, PharmD, De-

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