Adenosine + Dipyridamole - Drug Interactions

Dipyridamole reduces bolus dose of adenosine necessary toconvert supraventricular tachycardia to sinus rhythm by aboutfourfold

Adenosine by rapid intravenous bolus (10 to 200 micrograms/kg in stepwise doses) was found to restore sinus rhythm in 10 of 14 episodes of tachycardia in 7 patients with supraventricular tachycardia (SVT). The mean dose was 8.8mg compared with only 1mg in two patients also taking oral dipyridamole (See reference number 1). Another study in 6 patients found that dipyridamole (560 microgram/kg intravenous bolus, followed by a continuous infusion of 5 micrograms/kg/minute) reduced minimum effective bolus dose of intravenous adenosine required to stop SVT from 68 to 17 micrograms/kg in 5 patients. In other patient, dipyridamole alone stopped SVT (See reference number 2).

Other studies in healthy subjects have clearly shown that dipyridamole reduces dose of adenosine required to produce an equivalent cardiovascular effect by fourfold(See reference number 3) or six- to sixteenfold (See reference number 4). A brief report describes a woman with paroxysmal SVT who lost ventricular activity for 18 seconds when given adenosine 6mg intravenously. She was also taking dipyridamole [dose unstated], which was considered to have contributed to loss of ventricular function (See reference number 5). Another report describes 3 of 4 patients who had heart block of 3,9 and 21-second duration respectively when given adenosine 3 to 6mg by central venous bolus. The patient with most profound heart block was also being treated with dipyridamole, which was thought to have contributed to reaction (See reference number 6).

A 79-year-old woman taking a combination of low-dose aspirin and extended-release dipyridamole (Aggrenox) became profoundly bradycardic (36 bpm), dizzy and almost fainted 2 minutes after start of an adenosine infusion for radionuclide myocardial imaging. Adenosine was stopped,and she recovered within 2 minutes. The last dose of Aggrenox had been taken 12 hrs previously (See reference number 7). However,note that bradycardia is a known adverse effect of adenosine (See reference number 8,9).

Part of explanation is that dipyridamole increases plasma levels of endogenous adenosine by inhibiting its uptake into cells

Patients will need much less adenosine to treat arrhythmias while taking dipyridamole. It has been suggested that initial dose of adenosine should be reduced by twofold(See reference number 5) or fourfold (See reference number 2). The UK manufacturers actually advise avoidance of adenosine in patients taking dipyridamole. If it must be used for supraventricular tachycardia in a patient taking dipyridamole, they recommend that adenosine dose should be reduced about fourfold (See reference number 8).

The UK manufacturers advise avoidance of adenosine in patients taking dipyridamole. If adenosine is considered necessary for myocardial imaging in a patient taking dipyridamole, they suggest that dipyridamole should be stopped 24 hrs before, or dose of adenosine should be greatly reduced (See reference number 9). This may be insufficient for extended-release dipyridamole preparations: authors of above report recommend several days (See reference number 7). Xanthines,such as intravenous aminophylline, have been used to terminate persistent adverse effects of adenosine infusion given for myocardial imaging (See reference number 9). Consider also Adenosine + Xanthines interaction,below.

Watt AH,Bernard MS, Webster J, Passani SL, Stephens MR, Routledge PA. Intravenous adenosine in the treatment of supraventricular tachycardia: a dose-ranging study and interactionwith dipyridamole. Br J Clin Pharmacol (1986) 21, 227–30.

Lerman BB,Wesley RC, Belardinelli L. Electrophysiologic effects of dipyridamole on atrioventricular nodal conduction and supraventricular tachycardia. Role of endogenous adenosine. Circulation (1989) 80, 1536–43.

Biaggioni I,Onrot J, Hollister AS, Robertson D. Cardiovascular effects of adenosine infusionin man and their modulation by dipyridamole. Life Sci (1986) 39, 2229–36.

Conradson T-BG,Dixon CMS, Clarke B, Barnes PJ. Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole. Acta Physiol Scand (1987) 129, 387–91.

Mader TJ. Adenosine: adverse interactions. Ann Emerg Med (1992) 21,453.

McCollam PL,Uber WE, Van Bakel AB. Adenosine-related ventricular asystole. Ann Intern Med (1993) 118, 315–16.

Littmann L,Anderson JD, Monroe MH. Adenosine and Aggrenox: a hazardous combination.Ann Intern Med (2002) 137, W1.

Adenocor (Adenosine). Sanofi-Aventis. UK Summary of product characteristics,January2005.

Adenoscan (Adenosine). Sanofi-Aventis. UK Summary of product characteristics,September 2005.

German DC,Kredich NM, Bjornsson TD. Oral dipyridamole increases plasma adenosine levels in human beings. Clin Pharmacol Ther (1989) 45, 80–4.

Quinine + Rifampicin (Rifampin) - Drug Interactions

Rifampicin induces metabolism of quinine, which may resultin subtherapeutic quinine levels.

Clinical evidence,mechanism, importance and management

A study in 9 healthy subjects found that clearance of a single 600mg dose of quinine sulfate was increased more than sixfold by pretreatment with rifampicin 600mg daily for 2 weeks

A report describes a patient with myotonia, controlled with quinine, whose symptoms worsened within 3 weeks of starting to take rifampicin for treatment of tuberculosis. Peak quinine levels were found to be low, but rose again when rifampicin was stopped. Control of myotonia was regained 6 weeks later (See reference number 2).

The effect of adding rifampicin to quinine was investigated in patients with uncomplicated falciparum malaria. They were taking quinine sulfate 10 mg/kg three times daily either alone (30 patients) or with rifampicin 15 mg/kg daily (29 patients) for 7 days. Peak plasma levels of quinine during monotherapy were attained within 2 days of treatment and remained within therapeutic range for 7-day treatment period. Levels of main metabolite of quinine, 3-hydroxyquinine, followed a similar pattern. In patients taking quinine with rifampicin, quinine was more extensively metabolised and, after second day of treatment, quinine levels were sharply reduced to below therapeutic levels. Acute malaria reduces metabolic clearance of quinine (by a reduction in hepatic mixed function oxidase activity, mainly by cytochrome P450 isoenzyme CYP3A4) and recovery is associated with a sharp decline in quinine levels. Rifampicin induces cytochrome P450 isoenzymes and this probably more than countered their inhibition during acute malaria and resulted in increased metabolism of quinine. Although patients who received rifampicin with quinine had shorter parasite clearance times than those who received quinine alone, suggesting rifampicin may enhance antimalarial activity of quinine, recrudescence rates were 5 times, higher suggesting increased resistance. [Note, recrudescence is reappearance of disease after a period of inactivity.] The authors suggest that rifampicin should not be given with quinine for treatment of malaria. Patients receiving rifampicin who also require quinine for malaria may need increased doses of quinine (See reference number 3).

Wanwimolruk S,Kang W, Coville PF, Viriyayudhakorn S, Thitiarchakul S. Marked enhancement by rifampicin and lack of effect of isoniazid on the elimination of quinine in man. Br J Clin Pharmacol (1995) 40, 87–91.

Osborn JE,Pettit MJ, Graham P. Interaction between rifampicin and quinine: case report.Pharm J (1989) 243, 704.

Pukrittayakamee S,Prakongpan S, Wanwimolruk S, Clemens R, Looareesuwan S, White NJ.Adverse effect of rifampin on quinine efficacy in uncomplicated falciparum malaria. Antimicrob Agents Chemother (2003) 47, 1509–13.

Metrifonate + Antacids or H2-receptor antagonists - Drug Interactions

Clinical evidence,mechanism, importance and management

1. Heinig R,Boettcher M, Herman-Gnjidic Z, Pierce CH. Effects of magnesium/aluminium hydroxide–containing antacid, cimetidine or ranitidine on the pharmacokinetics of metrifonateand its metabolite DDVP. Clin Drug Invest (1999) 17, 67–77.

Praziquantel + Chloroquine - Drug Interactions

Chloroquine reduces bioavailability of praziquantel, whichwould be expected to reduce its efficacy in systemic worm infections such as schistosomiasis.

Clinical evidence,mechanism, importance and management

A single 40-mg/kg oral dose of praziquantel was given to 8 healthy subjects alone,and 2 hrs after chloroquine 600 mg. The chloroquine reduced praziquantel AUC by 65 % and maximum serum levels by 59%. The reasons for this effect are not understood. There were large individual variations in levels,and one subject was not affected. The effect of this interaction could be that some patients will not achieve high enough serum praziquantel levels to treat systemic worm infections such as schistosomiasis. After taking chloroquine, praziquantel serum levels of 4 out of 8 subjects (50%) did not reach threshold of

0.3 micrograms/mL for about 6 hrs (which is required to effectively kill schistosomes), compared with only 2 of 8 (25%) during control period. The authors conclude that an increased dosage of praziquantel should be considered if chloroquine is given (they do not suggest how much),particularly in anyone who does not respond to initial treatment with praziquantel (See reference number 1). More study of this interaction is needed.

The interaction is of no importance when praziquantel is used for intestinal worm infections (where its action is a local effect on worms in gut)

1. Masimirembwa CM,Naik YS, Hasler JA. The effect of chloroquine on the pharmacokineticsand metabolism of praziquantel in rats and in humans. Biopharm Drug Dispos (1994) 15, 33–

43.

Mefloquine + Ampicillin - Drug Interactions

Although ampicillin modestly increases plasma levels of mefloquine and reduces its half-life, these effects are probably notclinically relevant.

Clinical evidence,mechanism, importance and management

In a study,8 healthy subjects were given ampicillin 250mg four times daily for 5 days, with a single 750mg dose of mefloquine on day 2. The maximum plasma level and 5-day AUC of mefloquine were increased by 34 % and 49%, respectively, although AUC0–:6.2pt; font-weight:normal; color:#000000″>∞ was not significantly increased. The half-life and volume of distribution of mefloquine were reduced from 17.7 to 15.3 days and by 27%, respectively, by ampicillin. No increase in adverse events was seen. The effects may be due to an increase in mefloquine bioavailability and a reduction in its enterohepatic recycling (See reference number 1). The clinical relevance of these changes is uncertain, but au-

Anthelmintics,Antifungals and Antiprotozoals 231

thors consider that changes in elimination are unlikely to be clinically significant, since these occur after resolution of infection (See reference number 1).

1. Karbwang J,Na Bangchang K, Back DJ, Bunnag D. Effect of ampicillin on mefloquine pharmacokinetics in Thai males. Eur J Clin Pharmacol (1991) 40, 631–3.

Halofantrine + Miscellaneous - Drug Interactions

Halofantrine prolongs QT interval and therefore should notbe used with other drugs that can prolong QT interval because of increased risk of cardiac arrhythmias. The concurrent and sequential use of halofantrine and mefloquine markedlyincreased risk of clinically important increases in QT interval. Pyrimethamine/sulfadoxine and tetracycline have been shown toincrease halofantrine levels,and may therefore increase its toxicity. Diltiazem, erythromycin, ketoconazole, mefloquine, quinine,and quinidine might also increase toxicity of halofantrine because they have been shown to inhibit its metabolism in vitro. The manufacturer has therefore recommended caution with concurrent use of potent CYP3A4 inhibitors. Fatty food markedlyincreases halofantrine levels,consequently it is recommendedthat halofantrine is taken on an empty stomach. Grapefruit juicehas a similar effect. Note that halofantrine is no longer widelymarketed.

Clinical evidence,mechanism, importance and management

A study in animals found that ketoconazole roughly doubled AUC of halofantrine and inhibited its metabolism to equipotent metabolite, desbutylhalofantrine (See reference number 1). In in vitro studies, ketoconazole markedly inhibited metabolism of halofantrine by CYP3A4 (See reference number 2,3). It has been suggested that rise in halofantrine levels could reasonably be expected to increase toxicity (See reference number 2,3). Other CYP3A4 inhibitors, diltiazem and erythromycin, also inhibited metabolism of halofantrine in vitro, and might therefore do so clinically (See reference number 3). The manufacturer recommended caution with concurrent use of potent CYP3A4 inhibitors (See reference number 4). Further study is needed of these potential pharmacokinetic interactions. Mefloquine, quinine and quinidine may also inhibit metabolism of halofantrine by CYP3A4, see (b) below.

(b) Drugs that prolong QT interval

Halofantrine, in therapeutic doses, can prolong QT interval in majority of patients, causing ventricular arrhythmias in a very small number. The effect is increased if halofantrine is taken with fatty foods because of marked increase in absorption, see (d) below. By 1993,worldwide, 14 cases of cardiac arrhythmias associated with halofantrine had been reported, and 8 patients were known to have died. In order to reduce likelihood of arrhythmias, in 1994 UK Committee on Safety of Medicines advised that halofantrine should not be taken with meals, or with certain other drugs that may induce arrhythmias. They list chloroquine,mefloquine, quinine, tricyclic antidepressants, antipsychotics, certain antiarrhythmics, terfenadine and astemizole, as well as drugs causing electrolyte disturbances (See reference number 5). Although not listed, it would seem prudent to avoid other drugs that prolong QT interval. For a list,see table 1 below,’.

In addition to possible additive QT-prolonging effects, quinidine and quinine have been shown in vitro to inhibit metabolism of halofantrine by CYP3A4, and so may increase halofantrine levels, which could reasonably be expected to increase toxicity (See reference number 2,3). Animal studies found that although mefloquine alone did not significantly alter QTc interval, it enhanced effects of halofantrine by increasing blood levels (See reference number 6). Similarly, a study in patients with malaria found that risk of clinically relevant QT prolongation was increased twofold when halofantrine was used after mefloquine failure (7 of 10 patients) when compared with use as primary treatment (18 of 51 patients). However, authors note that their population had longer baseline QT intervals than average population, which may have made them more susceptible to effects of halofantrine(See reference number 7) The manufacturers of mefloquine(See reference number 8,9) and halofantrine,(See reference number 4) therefore contraindicated concurrent use, and use of halofantrine after mefloquine.

A study in 6 healthy subjects found that maximum plasma levels and AUC of a single 250mg dose of halofantrine were increased by about 6.6-fold and 2.9-fold,respectively, when given with a fatty meal rather than in a fasting state. The AUC of metabolite desbutylhalofantrine was also increased (See reference number 10). Animal data suggest that fats may reduce presystemic metabolism of halofantrine (See reference number 1). As this is likely to increase risk of halofantrine-induced arrhythmias, halofantrine should not be taken with meals, but should be taken on an empty stomach.

A crossover study in 12 healthy subjects given halofantrine 500mg with 250 mL of either water, orange juice or grapefruit juice (standard strength), found that grapefruit juice increased AUC and peak plasma levels of halofantrine by 2.8-fold and 3.2-fold,respectively. The QTc interval increased by 17 milliseconds with halofantrine,and by 31 milliseconds when grapefruit juice was also given. Orange juice did not affect pharmacokinetics or pharmacodynamics of halofantrine (See reference number 11). These data suggest that grapefruit juice should be avoided by patients taking halofantrine due to increased risk of arrhythmias (See reference number 11).

In a preliminary study in healthy subjects, pyrimethamine/sulfadoxine (Fansidar) raised AUC0-6 and peak plasma levels of halofantrine by about 1.6-fold, without changing overall AUC. This might lead to an increased incidence of arrhythmias,(See reference number 12) see also (b) above.

A study in 8 healthy subjects found that tetracycline 500mg twice daily for 7 days increased maximum plasma levels, AUC and elimination half-life of a single 500mg dose of halofantrine by 146%, 99%, and 73%, respectively. Increases in major metabolite of halofantrine also occurred in presence of tetracycline (See reference number 13). As both halofantrine and tetracycline are excreted into bile, competition for this elimination route may result in increased plasma levels. There may be an increased risk of halofantrine toxicity if it is used with higher doses of tetracycline (See reference number 13). In contrast, in vitro studies found that doxycycline does not inhibit metabolism of halofantrine (See reference number 2).

1.

Khoo S-M,Porter CJH, Edwards GA, Charman WN. Metabolism of halofantrine to its equipotent metabolite, desbutylhalofantrine, is decreased when orally administered with ketoconazole. J Pharm Sci (1998) 87, 1538–41.

2.

Baune B,Furlan V, Taburet AM, Farinotti R. Effect of selected antimalarial drugs and inhibitors of cytochrome P-450 3A4 on halofantrine metabolism by human liver microsomes.Drug Metab Dispos (1999) 27, 565–8.

3.

Baune B,Flinois JP, Furlan V, Gimenez F, Taburet AM, Becquemont L, Farinotti R. Halofantrine metabolism in microsomes in man: major role of CYP 3A4 and CYP 3A5. J Pharm Pharmacol (1999) 51, 419–26.

4.

Halfan (Halofantrine). SmithKline Beecham Pharmaceuticals. US Prescribing information,October 2001.

5.

Committee on Safety of Medicines/Medicines Control Agency. Cardiac arrhythmias withhalofantrine (Halfan). Current Problems (1994) 20,6.

6.

Lightbown ID,Lambert JP, Edwards G, Coker SJ. Potentiation of halofantrine-induced QTcprolongation by mefloquine: correlation with blood concentrations of halofantrine. Br J Pharmacol (2001) 132, 197–204.

7.

Nosten F,ter Kuile FO, Luxemburger C, Woodrow C, Kyle DE, Chongsuphajaisiddhi T,White NJ. Cardiac effects of antimalarial treatment with halofantrine. Lancet (1993) 341, 1054–6.

8.

Lariam (Mefloquine hydrochloride). Roche Products Ltd. UK Summary of product characteristics,September 2005.

9.

Lariam (Mefloquine hydrochloride). Roche Pharmaceuticals. US Prescribing information,May 2004.

Milton K,Edwards G, Ward SA, Orme ML’E, Breckenridge AM. Pharmacokinetics of halofantrine in man: effects of food and dose size. Br J Clin Pharmacol (1989) 28, 71–7.

Charbit B,Becquemont L, Lepère B, Peytavin G, Funck-Brentano C. Pharmacokinetic andpharmacodynamic interaction between grapefruit juice and halofantrine. Clin Pharmacol Ther (2002) 72, 514–23.

Hombhanje FW. Effect of a single dose of Fansidar(See reference number TM) on the pharmacokinetics of halofantrine in healthy volunteers: a preliminary report. Br J Clin Pharmacol (2000) 49,283–4.

Bassi PU,Onyeji CO, Ukponmwan OE. Effects of tetracycline on the pharmacokinetics ofhalofantrine in healthy volunteers. Br J Clin Pharmacol (2004) 58, 52–5.

Table 1 Drugs causing QT prolongation and torsade de pointes
High risk Some risk
Amisulpride Clarithromycin (increase in QTc interval less than 5 milliseconds; rare case reports of torsade de pointes)
Antiarrhythmics, class Ia (ajmaline, cibenzoline, disopyramide, hydroquinidine, procainamide, quinidine) Chlorpromazine (rare case reports of torsade de pointes)
Antiarrhythmics, class III (amiodarone, azimilide, cibenzoline, dofetilide,† ibutilide,† sotalol†) Erythromycin oral (see also high risk)
Arsenic trioxide (40% of patients had a QTc interval greater than 500 milliseconds) Gatifloxacin (increase in QTc interval less than 10 milliseconds)
Artemisinin derivatives (artemisinin, artemether/lumefantrine -5% of patients had an asymptomatic prolongation of QTc intervals by greater than 30 milliseconds, with an actual QTc of greater than 450 milliseconds in males and greater than 470 milliseconds in females) Levofloxacin (rare case reports of torsade de pointes)
Astemizole† (if metabolism inhibited) Lithium (greater risk if levels raised)
Cisapride† (if metabolism inhibited) Methadone (in doses greater than 100 mg)
Droperidol† Moxifloxacin (increase in QTc interval less than 10 milliseconds)
Erythromycin intravenous (see also some risk) Pentamidine intravenous (case reports of torsade de pointes)
Halofantrine† Quinine (greater risk with higher doses and intravenous use)
Haloperidol (also increased in high doses and with intravenous use) Spiramycin
Ketanserin (30% of patients had an increase of greater than 30 milliseconds in a clinical trial) Tricyclics (prolongation of QTc interval greater than 10 milliseconds, most notable risk occurs with clomipramine, risk with other tricyclics largely seems to be in overdose)
Mesoridazine†
Pimozide†
Ranolazine (dose-related QTc interval prolonged by up to 15 milliseconds, or more if metabolism inhibited)
Sertindole†
Sparfloxacin (10 millisecond increase in clinical trials)
Terfenadine† (if metabolism inhibited)
Thioridazine†

Azoles; Voriconazole + St John’s wort (Hypericum perforatum) - Drug Interactions

St John’s wort, taken for two weeks, halved levels of a singledose of voriconazole, which may be clinically relevant.

Clinical evidence,mechanism, importance and management

A single 400mg dose of oral voriconazole was given alone and on first and last day of St John’s wort (Jarsin, Lichtwer Pharma) given at a dose of 300mg three times daily for 15 days to 17 healthy subjects. One day of St John’s wort had no effect on voriconazole AUC0-:6.2pt; font-weight:normal; color:#000000″>∞, but slightly increased maximum serum level and AUC0-10 by 22%. However, when voriconazole was given on day 15, AUC of voriconazole was decreased by 59 % and there was a 2.4-fold increase in oral clearance (See reference number 1).

These results suggest that short-term effect of St John’s wort is to slightly enhance absorption of voriconazole, whereas longer-term effect is to induce absorption-limiting transport proteins and intestinal metabolism via cytochrome P450 isoenzymes (See reference number 1).

The slight increase in voriconazole absorption with a single dose of St John’s wort is not clinically relevant. However, reduction in voriconazole levels after 15 days of St John’s wort could impact on clinical efficacy. This suggests that patients requiring voriconazole should be asked about current or recent use of St John’s wort, since this may indicate need to use an increased voriconazole dose, at least initially. Patients taking voriconazole should be advised not to take St John’s wort.

1. Rengelshausen J,Banfield M, Riedel KD, Burhenne J, Mikus G, et al. Opposite effects ofshort-term and long-term St John’s wort on voriconazole pharmacokinetics. Clin Pharmacol Ther (2005) 78, 25–33.

Azoles + Rifabutin - Drug Interactions

Rifabutin levels are increased by fluconazole,posaconazole, voriconazole, and possibly itraconazole. Patients taking this combination are at increased risk of rifabutin toxicity,specifically uveitis,and should be closely monitored. Rifabutin markedly reduces theplasma levels of itraconazole,posaconazole, and voriconazole.These azoles should be used cautiously with rifabutin,if at all. Rifabutin does not affect metabolism of fluconazole.

Twelve HIV positive patients were given zidovudine 500mg daily from day 1 to 44,fluconazole 200mg daily from days 3 to 30 and rifabutin 300mg daily from days 17 to 44. Rifabutin did not significantly affect pharmacokinetics of fluconazole,(See reference number 1) but fluconazole increased AUC of rifabutin by 82%, and AUC of rifabutin metabolite LM565 was increased by 216 % (See reference number 1). In another study in 10 patients with HIV infection, fluconazole 200mg daily increased AUC of rifabutin 300mg daily by 76 % and maximum level by 91%. When patients were also given clarithromycin 500mg daily, AUC of rifabutin was further increased to 152 % (See reference number 2). There is some evidence that fluconazole increases prophylactic efficacy of rifabutin against M. avium complex disease,although there was also an increase in incidence of leucopenia (See reference number 3). Uveitis developed in 6 HIV positive patients taking rifabutin 450 to 600mg daily and fluconazole,5 of whom were also taking clarithromycin,(See reference number 4)which is also known to increase rifabutin levels, see Macrolides + Rifamycins interaction. Uveitis has been attributed to concurrent use of rifabutin and fluconazole in other reports (See reference number 5,6). Rifabutin does not appear to significantly affect metabolism of fluconazole (See reference number 7,8).

Itraconazole serum levels reduced. In a three-period study,6 HIV positive patients were given itraconazole 200mg daily for 14 days, rifabutin 300mg daily for 10 days, and then both drugs for 14 days. It was found that rifabutin reduced peak plasma levels of itraconazole by 71 % and reduced its AUC by 74 % (See reference number 9).

Because of low plasma levels after 3 weeks itraconazole dose was increased to 900mg daily. A week later patient developed anterior uveitis. It was found that itraconazole trough serum levels were normal but rifabutin trough serum levels were raised to 153 nanograms/mL (expected to be less than 50 nanograms/mL after 24 hours). Rifabutin was stopped and uveitis was treated

In a study in healthy subjects concurrent use of posaconazole 200mg once daily and rifabutin 300mg once daily for 10 days increased AUC of rifabutin by 72 % and decreased AUC of posaconazole by 51 % when compared with either drug alone (See reference number 11)

Rifabutin 300mg daily decreased AUC and maximum plasma levels of voriconazole 200mg twice daily by 79 % and 67%, respectively. Increasing dose of voriconazole to 350mg twice daily in presence of ri-

Anthelmintics,Antifungals and Antiprotozoals 219

fabutin gave an AUC of 68 % of that achieved with voriconazole 200mg twice daily alone while maximum plasma levels were more or less same (See reference number 12,13). At a dose of 400mg twice daily, voriconazole increased maximum plasma level and AUC of rifabutin 300mg twice daily by about threefold and fourfold, respectively (See reference number 12,13).

Rifabutin increases metabolism of itraconazole, posaconazole and voriconazole, probably, at least in part, by inducing their metabolism by cytochrome P450 CYP3A subfamily. Fluconazole is largely excreted unchanged in urine and so it is not affected. The azoles apparently increase rifabutin levels by inhibiting its metabolism,probably by CYP3A4. Raised rifabutin levels can cause uveitis.

The interaction between rifabutin and fluconazole is established, general picture being that concurrent use can be advantageous. However, because of increased risk of uveitis, UK Committee on Safety of Medicines says that full consideration should be given to reducing dosage of rifabutin to 300mg daily. The rifabutin should be stopped if uveitis develops and patient referred to an ophthalmologist (See reference number 14). A later review suggests this 300mg dose is associated with a reduced risk of uveitis and maintains efficacy (See reference number 15). The combination should be well monitored. Note that effects of clarithromycin, , are additive with those of fluconazole.

Information on interaction between itraconazole and rifabutin is very limited, but monitor for reduced antifungal activity, raising itraconazole dosage as necessary, and watch for increased rifabutin levels and toxicity (in particular uveitis). More study is needed. Note that manufacturers recommend that combination should be avoided (See reference number 16,17).

The manufacturer of ketoconazole suggests that levels of both drugs may be affected if rifabutin is also taken. They suggest that rifabutin dose may need to be reduced (See reference number 18)

On basis of interaction between rifabutin and posaconazole, manufacturer suggests that combination be avoided unless benefit to patient outweighs risk (See reference number 19). If combination is used, monitor efficacy of posaconazole and toxicity of rifabutin, particularly full blood counts and uveitis.

The manufacturer in US contraindicates combination of voriconazole and rifabutin (See reference number 13). However, UK manufacturer permits concurrent use if benefits outweigh risks (See reference number 12). If used together, it is recommended that oral dose of voriconazole be increased from 200mg twice daily to 350mg twice daily (and from 100 to 200mg twice daily in patients under 40 kg). The intravenous dose should also be increased from 4 to 5 mg/kg twice daily. Importantly, manufacturer advises careful monitoring for rifabutin adverse effects (e.g. check full blood counts,monitor for uveitis) (See reference number 12).

Trapnell CB,Narang PK, Li R, Lavelle JP. Increased plasma rifabutin levels with concomitant fluconazole therapy in HIV-infected patients. Ann Intern Med (1996) 124, 573–6.

Jordan MK,Polis MA, Kelly G, Narang PK, Masur H, Piscitelli SC. Effects of fluconazoleand clarithromycin on rifabutin and 25-O-desacetylrifabutin pharmacokinetics. Antimicrob Agents Chemother (2000) 44, 2170–2.

Narang PK,Trapnell CB, Schoenfelder JR, Lavelle JP, Bianchine JR. Fluconazole and enhanced effect of rifabutin prophylaxis. N Engl J Med (1994) 330, 1316–17.

Becker K,Schimkat M, Jablonowski H, Häussinger D. Anterior uveitis associated with rifabutin medication in AIDS patients. Infection (1996) 24, 34–6.

Fuller JD,Stanfield LED, Craven DE. Rifabutin prophylaxis and uveitis. N Engl J Med (1994) 330, 1315–16.

Kelleher P,Helbert M, Sweeney J, Anderson J, Parkin J, Pinching A. Uveitis associated withrifabutin and macrolide therapy for Mycobacterium avium intracellulare infections in AIDS patients. Genitourin Med (1996) 72, 419–21.

Mycobutin (Rifabutin). Pfizer Inc. US Prescribing information,February 2006.

Mycobutin (Rifabutin). Pharmacia Ltd. UK Summary of product characteristics,October2006.

Smith JA,Hardin TC, Patterson TF, Rinaldi MG, Graybill JR. Rifabutin (RIF) decreases itraconazole (ITRA) plasma levels in patients with HIV-infection. Am Soc Microbiol 2nd NatConf. Human retroviruses and related infections. Washington DC, Jan 29—Feb 2 1995, 77.

Lefort A,Launay O, Carbon C. Uveitis associated with rifabutin prophylaxis and itraconazoletherapy. Ann Intern Med (1996) 125, 939–40.

Courtney RD,Statkevich P, Laughlin M, Radwanski E, Lim J, Clement RP, Batra VK. Potential for a drug interaction between posaconazole and rifabutin. Intersci Conf Antimicrob Agents Chemother (2001) 41, 4–5.

VFEND (Voriconazole). Pfizer Ltd. UK Summary of product characteristics,July 2007.

VFEND (Voriconazole). Pfizer Inc. US Prescribing information,November 2006.

Committee on Safety of Medicines/Medicines Control Agency. Stop Press: Rifabutin (Mycobutin) — uveitis. Current Problems (1994) 20,4.

Committee on the Safety of Medicines/Medicines Control Agency. Revised indications anddrug interactions of rifabutin. Current Problems (1997) 23,14.

Sporanox Capsules (Itraconazole). Janssen-Cilag Ltd. UK Summary of product characteristics,March 2004.

Sporanox Capsules (Itraconazole). Janssen. US Prescribing information,June 2006.

Nizoral Tablets (Ketoconazole). Janssen-Cilag Ltd. UK Summary of product characteristics,October 2006.

Noxafil (Posaconazole). Schering-Plough Ltd. UK Summary of product characteristics,October 2006.

Atovaquone + Proguanil - Drug Interactions

Clinical evidence,mechanism, importance and management

Atovaquone did not affect pharmacokinetics of proguanil in a comparative study of 4 patients taking proguanil 200mg twice daily for 3 days and 12 patients taking proguanil 200mg twice daily with atovaquone 500mg twice daily for 3 days (See reference number 1)

In contrast,in a longer study 13 healthy subjects were given a single 250/100-mg dose of atovaquone/proguanil, then after an interval of one week they were given daily doses for 13 days. There was no change in AUC of atovaquone from single dose to steady state, indicating that accumulation did not occur. However, AUC of proguanil was modestly increased at steady state, and AUC of active metabolite cycloguanil was modestly decreased, in 9 subjects who were extensive metaboliser phenotypes for cytochrome P450 isoenzyme CYP2C19 (see Genetic factors, ). It was suggested that atovaquone may have inhibited production of cycloguanil by CYP3A4. However,since this study had no arm with each drug alone, it is impossible to determine whether these changes in pharmacokinetics were due to an interaction or not (See reference number 3).

A pharmacokinetic interaction is not established, and is anyway of little clinical relevance, since efficacy of combination product for malaria prophylaxis up to 12 weeks is established. The enhanced activity of combination may, in part, be due to proguanil lowering effective concentration at which atovaquone collapses mitochondrial potential in malaria parasites (See reference number 4).

Edstein MD,Looareesuwan S, Viravan C, Kyle DE. Pharmacokinetics of proguanil in malariapatients treated with proguanil plus atovaquone. Southeast Asian J Trop Med Public Health (1996) 27, 216–20.

Gillotin C,Mamet JP, Veronese L. Lack of pharmacokinetic interaction between atovaquoneand proguanil. Eur J Clin Pharmacol (1999) 55, 311–15.

Thapar MM,Ashton M, Lindegardh N, Bergqvist Y, Nivelius S, Johansson I, Bjorkman A.Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis. Eur J Clin Pharmacol (2002) 58, 19–27.

Srivastava IK,Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquoneand proguanil. Antimicrob Agents Chemother (1999) 43, 1334–9.

Atovaquone + Co-trimoxazole - Drug Interactions

Clinical evidence,mechanism, importance and management

As part of a larger study, 6 HIV-positive subjects received atovaquone 500mg once daily, co-trimoxazole 960mg (trimethoprim/sulfamethoxazole 160/800 mg) twice daily, or combination, taken with food. There was no change in steady-state atovaquone levels but there was a minor 17 % decrease in steady-state trimethoprim levels and a minor 8 % decrease in sulfamethoxazole levels when both drugs were given together (See reference number 1).

1. Falloon J,Sargent S, Piscitelli SC, Bechtel C, LaFon SW, Sadler B, Walker RE, Kovacs JA,Polis MA, Davey RT, Lan HC, Masur H. Atovaquone suspension in HIV-infected volunteers:pharmacokinetics, pharmacodynamics, and TMP-SMX interaction study. Pharmacotherapy (1999) 19, 1050–6.