Pharmacy Blog – Dr Vibore

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.

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.

Albendazole does not alter bioavailability of praziquantel.Praziquantel markedly increases bioavailability of albendazole sulfoxide in fasted subjects, but much less so when albendazole is given with a meal, as recommended. None of these changesappears to have adverse consequences.

Clinical evidence,mechanism, importance and management

In a study in Sudanese men, AUC of albendazole sulfoxide (the active metabolite of albendazole), was increased 4.5-fold when a single 400mg dose of albendazole was given with praziquantel 40 mg/kg to fasting subjects. However,this difference was much less marked (only a 1.5-fold increase) when drugs were given with food (See reference number 1). The reasons for these changes and their practical consequences are not known, but increases in albendazole sulfoxide levels seemed not to cause any problems (See reference number 1). If both drugs are given with food,as may be advisable (see Albendazole + Food interaction, above), any interaction is modest. On basis of these studies there do not seem to be any obvious reasons why concurrent use of these two drugs should be avoided.

In a study,21 children treated for giardiasis were given a single 400mg dose of albendazole either alone or with a single 20-mg/kg dose of praziquantel. It was found that pharmacokinetics of albendazole were not significantly affected by praziquantel when drugs were given with 200 mL of milk, one hour after breakfast. There were wide inter-individual variations in plasma levels and AUC of active metabolite, albendazole sulfoxide, but these were similar whether albendazole was given alone or with praziquantel.(See reference number 2)

Homeida M,Leahy W, Copeland S, Ali MMM, Harron DWG. Pharmacokinetic interaction between praziquantel and albendazole in Sudanese men. Ann Trop Med Parasitol (1994) 88, 551–9.

Pengsaa K,Na-Bangchang K, Limkittikul K, Kabkaew K, Lapphra K, Sirivichayakul C, Wisetsing P, Pojjaroen-Anant C, Chanthavanich P, Subchareon A. Pharmacokinetic investigation ofalbendazole and praziquantel in Thai children infected with Giardia intestinalis. Ann Trop Med Parasitol (2004) 98, 349–57.

table 1 below, lists drugs covered in this section by therapeutic group and drug class. If anti-infective is drug causing interaction, interaction is generally dealt with under affected drug. Also note that drugs such as 5-nitroimidazoles (e.g. metronidazole),which have actions against more than one type of organism (e.g. bacteria and protozoa) are covered under Antibacterials.

Intravenous amphotericin B causes important pharmacodynamic interactions via additive nephrotoxicity and myelotoxicity, and may increase cardiotoxicity of other drugs because of amphotericin-induced hypokalaemia. No important pharmacokinetic interactions are known. Lipid formulations such as liposomal amphotericin are less nephrotoxic than conventional amphotericin,and would therefore be expected to interact less frequently. Orally administered amphotericin is not absorbed systemically,and no interactions are known.

The most important interactions affecting and caused by azole antifungals are those resulting from inhibition and induction of cytochrome P450 isoenzymes

Fluconazole is principally (80%) excreted unchanged in urine, so is less affected by enzyme inducers and inhibitors than some other azoles. Fluconazole is a potent inhibitor of CYP2C9 and CYP2C19,and generally only inhibits CYP3A4 at high doses (greater than 200mg daily). Interactions are less likely with single doses used for genital candidiasis than with longer term use.

Itraconazole is extensively metabolised by CYP3A4,and its metabolism may become saturated with multiple dosing. Itraconazole and its major metabolite,hydroxy-itraconazole are potent inhibitors of CYP3A4.

Ketoconazole is extensively metabolised,particularly by CYP3A4. It is also a potent inhibitor of CYP3A4.

Miconazole is a potent inhibitor of CYP2C9. Because this azole is generally used topically as pessaries, skin cream, or an oral gel, it is less likely to cause interactions, although it should be noted that interactions with warfarin, , have been reported, particularly for oral gel.

Posaconazole is metabolised via UDP glucuronidation,and may also be a substrate for P-glycoprotein. Posaconazole is an inhibitor of CYP3A4.

Voriconazole is metabolised by CYP2C19,CYP2C9, and to a lesser extent by CYP3A4. Voriconazole is an inhibitor of CYP2C9,CYP2C19 and CYP3A4.

An number of other azole antifungals are only used topically in form of skin creams or intravaginal preparations, and have not been associated with drug interactions, presumably since their systemic absorption is so low, see Azoles; Topical + Miscellaneous interaction.

Fluconazole, ketoconazole and voriconazole have been associated with prolongation of QT interval, although generally not to a clinically relevant extent. However, they may also raise levels of other drugs that prolong QT interval, and these combinations are often contraindicated, see Antihistamines + Azoles interaction.

1. Venkatakrishnan K,von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet (2000) 38, 111–80.

table 1 below Anthelmintics,antifungals and antimalarials and other antiprotozoals

Albendazole,Flubendazole, Mebendazole, Tiabendazole (Thiabendazole)

Diethylcarbamazine,Ivermectin, Levamisole, Niclosamide, Oxamniquine, Piperazine, Praziquantel, Pyrantel

Naftifine,Terbinafine

Bifonazole,* Butoconazole,* Chlormidazole,* Clotrimazole,* Econazole,* Fenticonazole,* Isoconazole,* Ketoconazole,Miconazole, Oxiconazole,* Sertaconazole,* Sulconazole,* Tioconazole*

Fluconazole,Itraconazole, Posaconazole, Terconazole,* Voriconazole

Anidulafungin,Caspofungin

Amphotericin B,Natamycin,* Nystatin*

Amorolfine,* Butenafine,* Ciclopirox,* Flucytosine,Griseofulvin, Tolnaftate*

Amodiaquine,Chloroquine, Hydroxychloroquine

Mefloquine,Quinine

Artemether,Artemotil, Artesunate, Atovaquone, Halofantrine, Lumefantrine, Proguanil, Pyrimethamine, Sulfadoxine

Metronidazole,Ornidazole, Tinidazole

Furazolidone,Nifurtimox

Atovaquone,Diiodohydroxyquinoline, Diloxanide furoate, Eflornithine, Mepacrine, Pentamidine, Suramin

Anthelmintics,Antifungals and Antiprotozoals 209

Table 1 Anthelmintics, antifungals and antimalarials and other antiprotozoals
Group	Drugs
Anthelmintics
Benzimidazole derivatives	Albendazole, Flubendazole, Mebendazole, Tiabendazole (Thiabendazole)
Organophosphorous compounds	Metrifonate (Metriphonate)
Other	Diethylcarbamazine, Ivermectin, Levamisole, Niclosamide, Oxamniquine, Piperazine, Praziquantel, Pyrantel
Antifungals
Allylamines	Naftifine, Terbinafine
Azoles:
Imidazoles	Bifonazole,* Butoconazole,* Chlormidazole,* Clotrimazole,* Econazole,* Fenticonazole,* Isoconazole,* Ketoconazole, Miconazole, Oxiconazole,* Sertaconazole,* Sulconazole,* Tioconazole*
Triazoles	Fluconazole, Itraconazole, Posaconazole, Terconazole,* Voriconazole
Echinocandins	Anidulafungin, Caspofungin
Polyene antibiotics	Amphotericin B, Natamycin,* Nystatin*
Other	Amorolfine,* Butenafine,* Ciclopirox,* Flucytosine, Griseofulvin, Tolnaftate*
Antimalarials
4-aminoquinolines	Amodiaquine, Chloroquine, Hydroxychloroquine
8-aminoquinolines	Primaquine
4-methanolquinolines	Mefloquine, Quinine
Other	Artemether, Artemotil, Artesunate, Atovaquone, Halofantrine, Lumefantrine, Proguanil, Pyrimethamine, Sulfadoxine
Antiprotozoals
Antimony compounds	Sodium stibogluconate
Arsenicals	Melarsoprol
5-nitroimidazoles†	Metronidazole, Ornidazole, Tinidazole
Nitrofuran	Furazolidone, Nifurtimox
Other	Atovaquone, Diiodohydroxyquinoline, Diloxanide furoate, Eflornithine, Mepacrine, Pentamidine, Suramin

Table 2 Anthelmintics, antifungals and antimalarials and other antiprotozoals
Group	Drugs
Anthelmintics
Benzimidazole derivatives	Albendazole, Flubendazole, Mebendazole, Tiabendazole (Thiabendazole)
Organophosphorous compounds	Metrifonate (Metriphonate)
Other	Diethylcarbamazine, Ivermectin, Levamisole, Niclosamide, Oxamniquine, Piperazine, Praziquantel, Pyrantel
Antifungals
Allylamines	Naftifine, Terbinafine
Azoles:
Imidazoles	Bifonazole,* Butoconazole,* Chlormidazole,* Clotrimazole,* Econazole,* Fenticonazole,* Isoconazole,* Ketoconazole, Miconazole, Oxiconazole,* Sertaconazole,* Sulconazole,* Tioconazole*
Triazoles	Fluconazole, Itraconazole, Posaconazole, Terconazole,* Voriconazole
Echinocandins	Anidulafungin, Caspofungin
Polyene antibiotics	Amphotericin B, Natamycin,* Nystatin*
Other	Amorolfine,* Butenafine,* Ciclopirox,* Flucytosine, Griseofulvin, Tolnaftate*
Antimalarials
4-aminoquinolines	Amodiaquine, Chloroquine, Hydroxychloroquine
8-aminoquinolines	Primaquine
4-methanolquinolines	Mefloquine, Quinine
Other	Artemether, Artemotil, Artesunate, Atovaquone, Halofantrine, Lumefantrine, Proguanil, Pyrimethamine, Sulfadoxine
Antiprotozoals
Antimony compounds	Sodium stibogluconate
Arsenicals	Melarsoprol
5-nitroimidazoles†	Metronidazole, Ornidazole, Tinidazole
Nitrofuran	Furazolidone, Nifurtimox
Other	Atovaquone, Diiodohydroxyquinoline, Diloxanide furoate, Eflornithine, Mepacrine, Pentamidine, Suramin

Clinical evidence,mechanism, importance and management

In a steady-state study,23 healthy subjects were given modafinil 200mg daily for 7 days, followed by 400mg daily for 3 weeks. During last week, 10 of subjects were also given dexamfetamine 20mg daily, 7 hrs after their modafinil dose. Dexamfetamine caused no significant change in pharmacokinetics of modafinil and combination was well tolerated. In addition, pharmacokinetics of dexamfetamine did not appear to be affected by modafinil, when compared with values reported in literature (See reference number 1). Similar results were found in a single dose study (See reference number 2). No additional precautions appear to be necessary on concurrent use.

Hellriegel ET,Arora S, Nelson M, Robertson P. Steady-state pharmacokinetics and tolerabilityof modafinil administered alone or in combination with dextroamphetamine in healthy volunteers. J Clin Pharmacol (2002) 42, 448–58.

Wong YN,Wang L, Hartman L, Simcoe D, Chen Y, Laughton W, Eldon R, Markland C, Grebow P. Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers. J Clin Pharmacol (1998) 38, 971–8.

Fenfluramine and dexfenfluramine have generally been withdrawn worldwide because of occurrence of serious and sometimes fatal valvular heart disease (aortic, mitral, tricuspid ormixed valve disease). Pulmonary hypertension has also sometimes been seen. These serious adverse effects occurred when these drugs were taken alone,and when combined with phentermine as Fen-phen and Dexfen-phen, but not with phentermine alone.(See reference number 1-5)There is also an isolated case of cardiomyopathy attributed to theuse of fenfluramine with mazindol.(See reference number 6)Before withdrawal of drug from market, manufacturer of fenfluramine recommended that concurrent use with other centrally acting anorecticsshould be avoided.(See reference number 7)

Committee on Safety of Medicines/Medicines Control Agency. Fenfluramine and dexfenfluramine withdrawn. Current Problems (1997) 23,12.

Food and Drugs Administration. FDA announces withdrawal fenfluramine and dexfenfluramine (Fen-Phen). September 15th,1997.

Connolly HM,Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV.Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med (1997) 337, 581–8.

Mark EJ,Patalas ED, Chang HT, Evans RJ, Kessler SC. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl J Med (1997) 337, 602–6.

Graham DJ,Green L. Further cases of valvular heart disease associated with fenfluraminephentermine. N Engl J Med (1997) 337, 635.

Gillis D,Wengrower D, Witztum E, Leitersdorf E. Fenfluramine and mazindol: acute reversible cardiomyopathy associated with their use. Int J Psychiatry Med (1985) 15, 197–200.

Ponderax Pacaps (Fenfluramine). Servier Laboratories Limited. ABPI Compendium of Datasheets and Summaries of Product Characteristics 1997–8,1307.

This section covers drugs used in management of obesity (such as orlistat and sibutramine) as well as older drugs, such as amfetamines, which are now no longer widely indicated for this condition, and are now more generally considered as drugs of abuse. However, it should not be forgotten that amfetamines (largely dexamfetamine) still have a limited therapeutic role in management of narcolepsy. Ecstasy (MDMA,methylenedioxymethamfetamine), a drug of abuse that is structurally related to amfetamine, is also included in this section. The amfetamines are sympathomimetics,a diverse group, which have a number of interactions. The mechanism of action and classification of sympathomimetics is discussed in Cardiovascular drugs,miscellaneous, . Other stimulant drugs (such as atomoxetine; and methylphenidate,another sympathomimetic) have a role in attention deficit hyperactivity disorder (ADHD) and are also discussed in this section.

Rifampicin increases metabolism of paracetamol. An isolatedreport describes hepatic failure,which may have been due to aninteraction between paracetamol and rifampicin.

Clinical evidence,mechanism, importance and management

The metabolite to paracetamol ratio for glucuronides was twice as high in 10 patients treated with rifampicin 600mg daily than in 14 healthy control subjects. In contrast ratio for sulfates did not differ between two groups.(See reference number 1)In a crossover study in healthy subjects, rifampicin 600mg daily for 1 week, given before paracetamol 500 mg, had no effect on formation of N-acetyl-p-benzoquinone imine (NAPQI) or recovery of thiol metabolites formed by conjugation of NAPQI with glutathione.(See reference number 2) These studies suggest that rifampicin induces glucuronidation of paracetamol, but that it does not increase formation of hepatotoxic metabolites of paracetamol, .

However,a 32-year-old woman, who had taken paracetamol 2 to 4 g daily for several weeks, and who had not responded to doxycycline or clarithromycin for suspected cat scratch fever, became confused and agitated 2 days after starting to take rifampicin 600mg twice daily. Her INR increased from 1.1 to 5.2 and her liver enzymes became raised. Rifampicin and paracetamol were stopped,and she was treated with vitamin K and acetylcysteine, and liver function returned to normal. Paracetamol hepatotoxicity, in doses not normally associated with such effects, occurred only after addition of rifampicin. It was suggested that rifampicin, which alone may cause hepatitis, had in this case induced metabolism of paracetamol to hepatotoxic metabolites (See reference number 3).

The clinical importance of studies awaits further study, but they suggest that rifampicin may reduce efficacy of paracetamol.

Bock KW,Wiltfang J, Blume R, Ullrich D, Bircher J. Paracetamol as a test drug to determineglucuronide formation in man. Effects of inducers and of smoking. Eur J Clin Pharmacol (1987) 31, 677–83.

Manyike PT,Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A toacetaminophen reactive metabolite formation. Clin Pharmacol Ther (2000) 67, 275–82.

Stephenson I,Qualie M, Wiselka MJ. Hepatic failure and encephalopathy attributed to an interaction between acetaminophen and rifampicin. Am J Gastroenterol (2001) 96, 1310–1.

Propranolol may slightly increase bioavailability of paracetamol, but this is unlikely to be clinically significant.

Clinical evidence,mechanism, importance and management

In a study in 10 healthy subjects, propranolol 80mg twice daily for 4 days increased half-life of a single 1.5-g dose of paracetamol by 25 % and lowered its clearance by 14%. The partial clearance of paracetamol to its cysteine and mercapturate derivatives was decreased by 16 % and 32%, respectively, and clearance to glucuronide conjugate was decreased by 27%, but sulfate was not significantly affected (See reference number 1). Similarly, an earlier study found that propranolol 40mg four times daily for one week increased maximum plasma level of a single 1.5-g dose of paracetamol and reduced time to peak plasma level. However, increased rate of absorption of paracetamol was not thought to be clinically important (See reference number 2). In contrast, a study in 6 subjects found that a relatively small dose of propranolol (80 mg daily for 6 days) did not affect pharmacokinetics of paracetamol (See reference number 3). Another study found that long-term propranolol use in patients with chronic liver disease did not influence clearance of total or unconjugated paracetamol (See reference number 4).

The changes described here appear to be small,and therefore unlikely to be clinically significant. Note that, it has been postulated, based on studies in animals, that propranolol may have a protective effect on paracetamol hepatic toxicity by inhibiting oxidative metabolism of paracetamol to toxic metabolites (See reference number 1,5).

Baraka OZ,Truman CA, Ford JM, Roberts CJC. The effect of propranolol on paracetamol metabolism in man. Br J Clin Pharmacol (1990) 29, 261–4.

Clark RA,Holdsworth CD, Rees MR, Howlett PJ. The effect on paracetamol absorption ofstimulation and blockade of :5.5pt; font-weight:normal; color:#000000″>β-adrenoceptors. Br J Clin Pharmacol (1980) 10, 555–9.

Sanchez-Martinez V,Tucker GT, Jackson PR, Lennard MS, Bax NDS, Woods HF. Lack of effect of propranolol on the kinetics of paracetamol in man. Br J Clin Pharmacol (1985) 20, 548P.

Hayes PC,Bouchier IAD. Effect of acute and chronic propranolol administration on antipyrineand paracetamol clearance in patients with chronic liver disease. Am J Gastroenterol (1989) 84, 723–6.

Auty RM,Branch RA. Paracetamol toxicity and propranolol. Lancet (1973) 2, 1505.

Probenecid reduces clearance of paracetamol

Clinical evidence,mechanism, importance and management

A metabolic study in 10 healthy subjects found that clearance of paracetamol 1.5 g was almost halved (from 6.23 to 3.42 mL/minute per kg) when it was taken 1 hour after a 1-g dose of probenecid. The amount of unchanged paracetamol in urine stayed same, but glucuronide metabolite fell sharply (See reference number 1). Another study in 11 subjects also found that probenecid 500mg every 6 hrs almost halved (from 329 to 178 mL/minute) clearance of a 650mg intravenous dose of paracetamol. The urinary excretion of glucuronide metabolite was decreased by 68 % and excretion of sulfate metabolite increased by 49 % (See reference number 2). These studies suggest that probenecid inhibits paracetamol glucuronidation,possibly by inhibiting glucuronyltransferase. See also paracetamol,. The practical consequences of this interaction are uncertain but there seem to be no adverse reports.

Kamali F. The effect of probenecid on paracetamol metabolism and pharmacokinetics. Eur J Clin Pharmacol (1993) 45,551–3.

Abernethy DR,Greenblatt DJ, Ameer B, Shader RI. Probenecid impairment of acetaminophenand lorazepam clearance: direct inhibition of ether glucuronide formation. J Pharmacol Exp Ther (1985) 234, 345–9.