Pharmacy Blog – Dr Vibore

Fluoxetine modestly raised levels of ritonavir, and ritonavir ispredicted to raise levels of fluoxetine, paroxetine and sertraline. Afew cases of serotonin syndrome have been attributed to theuse of fluoxetine and ritonavir. The concurrent use of escitalopram and ritonavir do not appear to affect pharmacokineticsof either drug.

Clinical evidence,mechanism, importance and management

In a single-dose study involving 18 healthy subjects,no significant pharmacokinetic interaction was seen when ritonavir was given with escitalopram (See reference number 1).

Ritonavir 600mg was given to 16 healthy subjects before and after 8 days of treatment with fluoxetine 30mg twice daily. The maximum plasma levels of ritonavir were unaffected,but its AUC rose by 19%. These changes were not considered large enough to warrant changing dose of ritonavir (See reference number 2). The study was criticised for not achieving steady state before assessing pharmacokinetics and thus possibly underestimating interaction (See reference number 3). However, authors point out that fluoxetine levels were equivalent to those seen at steady state, and multiple dosing of ritonavir is likely to induce its own metabolism, so if anything, interaction would be lessened at steady state (See reference number 4).

The UK manufacturers of ritonavir predict that it may raise levels of SSRIs (fluoxetine, paroxetine, sertraline) due to inhibitory effect of ritonavir on cytochrome P450 isoenzymes CYP2D6 (See reference number 5). The US manufacturers do not mention any specific SSRIs (See reference number 6). Both manufacturers suggest careful monitoring of adverse effects when these drugs are used with ritonavir; a dose reduction of SSRI may be required (See reference number 5,6).

Two cases of serotonin syndrome were attributed to adding ritonavir to established fluoxetine treatment. In one patient this was managed by halving fluoxetine dose, and in other ritonavir was withdrawn. Other cases of serotonin syndrome have been seen in patients taking ritonavir or indinavir with fluoxetine. One involved additional use of trazodone, , and other involved large quantities of grapefruit, .

Gutierrez,MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and the cytochrome P450 3A4 inhibitor ritonavir. Clin Ther (2003) 25, 1200–10.

Ouellet D,Hsu A, Qian J, Lamm JE, Cavanaugh JH, Leonard JM, Granneman GR. Effect offluoxetine on the pharmacokinetics of ritonavir. Antimicrob Agents Chemother (1998) 42, 3107–12.

Bellibas SE. Ritonavir-fluoxetine interaction. Antimicrob Agents Chemother (1999) 43,1815.

Ouellet D,Hsu A. Ritonavir-fluoxetine interaction. Antimicrob Agents Chemother (1999) 43, 1815.

Norvir (Ritonavir). Abbott Laboratories Ltd. UK Summary of product characteristics,May2007.

Norvir (Ritonavir). Abbott Laboratories. US Prescribing information,January 2006.

Citalopram, escitalopram, paroxetine and sertraline levels aremoderately increased by cimetidine but only clinically relevant effect appears to be a slight increase in adverse effects withsertraline.

Twelve healthy subjects were given citalopram 40mg daily for 21 days and then for next 8 days they were also given cimetidine 400mg twice daily. The cimetidine caused a 29 % decrease in oral clearance of citalopram, a 39 % rise in its maximum serum levels and a 43 % increase in its AUC. Some changes in renal clearance of citalopram metabolites were also seen (See reference number 1).

Cimetidine 400mg twice daily increased mean plasma level of escitalopram by about 70%. There was also a 22 % increase in maximum plasma level of citalopram, but this was not considered to be clinically significant (See reference number 2).

Cimetidine 200mg four times daily for 8 days did not affect mean pharmacokinetic values or bioavailability of a single 30mg dose of paroxetine in 10 healthy subjects. However,2 subjects had AUC increases of 55 % and 81%, respectively, while taking cimetidine and 4 others also had some minor increases (See reference number 3). Another study in 11 healthy subjects found that cimetidine 300mg three times a day increased AUC of paroxetine 30mg daily by 50 % after 1 week of concurrent use (See reference number 4).

In a randomised,two-way, crossover study, 12 healthy subjects were given a single 100mg oral dose of sertraline after taking either cimetidine 800mg or a placebo at bedtime for 7 days. Cimetidine increased AUC of sertraline by 50%, maximum serum levels of sertraline by 24%, and half-life by 26 % (See reference number 5,6). There was a small increase in sertraline adverse effects (not specified) while taking cimetidine (See reference number 5).

The apparent reason for all these changes is that cimetidine inhibits activity of cytochrome P450 so that metabolism of SSRIs is reduced, and as a result their serum levels rise.

The authors of citalopram study say that while cimetidine certainly causes an increase in serum levels of citalopram, extent is only moderate and because drug is well tolerated and there are very considerable pharmacokinetic variations between individual subjects, they consider that there is no need to reduce citalopram dosage (See reference number 1). This advice is most likely applicable to escitalopram, S-isomer of citalopram. However, manufacturer of escitalopram suggests caution, and advises that a reduction in dose of escitalopram may be necessary (based on monitoring of adverse effects) during concurrent treatment (See reference number 7).

Information on concurrent use of cimetidine and paroxetine or sertraline seems to be limited and clinical significance of changes in clearance is not known. However, it would be prudent to monitor outcome for excessive adverse effects (dry mouth, nausea, diarrhoea, dyspepsia, tremor, ejaculatory delay, sweating) if cimetidine is used with either of these SSRIs and reduce sertraline or paroxetine dosage if necessary. If suggested mechanism of interaction is true, one of other H2-re

ceptor antagonists that lack enzyme inhibitory activity,such as ranitidine or famotidine, might be a non-interacting alternative for cimetidine. This needs confirmation.

Priskorn M,Larsen F, Segonzac A, Moulin M. Pharmacokinetic interaction study of citalopramand cimetidine in healthy subjects. Eur J Clin Pharmacol (1997) 52, 241–2.

Malling D,Poulsen MN, Søgaard B. The effect of cimetidine or omeprazole on the pharmacokinetics of escitalopram in healthy subjects. Br J Clin Pharmacol (2005) 60, 287–90.

Greb WH,Buscher G, Dierdorf H-D, Köster FE, Wolf D, Mellows G. The effect of liver enzyme inhibition by cimetidine and enzyme induction by phenobarbitone on the pharmacokinetics of paroxetine. Acta Psychiatr Scand (1989) 80 (Suppl 350), 95–8.

Bannister SJ,Houser VP, Hulse JD, Kisicki JC, Rasmussen JGC. Evaluation of the potentialfor interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin. Acta Psychiatr Scand (1989) 80 (Suppl 350), 102–6.

Invicta Pharmaceuticals. Phase 1 study to assess the potential of cimetidine to alter the disposition of sertraline in normal,healthy male volunteers. Data on file (Study 050-019), 1991.

Zoloft (Sertraline hydrochloride). Pfizer Inc. US Prescribing information,June 2007.

Cipralex (Escitalopram oxalate). Lundbeck Ltd. UK Summary of product characteristics,December 2005.

Anorexia developed in a patient taking fluoxetine when itraconazole was started, and it disappeared when itraconazole wasstopped. The pharmacokinetics of citalopram in healthy subjectswere not affected by ketoconazole. The clearance of escitalopramwas not affected by ketoconazole in an in vitro study.

Clinical evidence,mechanism, importance and management

In a double-blind, placebo-controlled, crossover study in 18 healthy subjects, a single 200mg dose of ketoconazole did not affect pharmacokinetics of citalopram 40mg (See reference number 1). Ketoconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4,which, in part, metabolises citalopram, but as several other cytochrome P450 isoenzymes are also involved in citalopram metabolism it would seem that inhibition of only one pathway does not result in clinically significant effects. Similarly,escitalopram is metabolised by CYP3A4, CYP2C19, and CYP2D6, and it has been suggested that its clearance is also unlikely to be affected by impaired activity of only one CYP isoform (See reference number 2).

A man taking fluoxetine 20mg daily,diazepam and several anti-asthma drugs (salbutamol (albuterol), salmeterol, budesonide, theophylline) was given itraconazole 200mg daily for allergic bronchopulmonary aspergillosis. Within 1 to 2 days he developed anorexia without nausea. He stopped itraconazole after a week, and anorexia resolved 1 to 2 days later. The author of report suggested that itraconazole, a potent enzyme inhibitor, increased levels of fluoxetine metabolite, norfluoxetine, which resulted in anorexia (See reference number 3). Anorexia is a recognised adverse effect of fluoxetine. However,drug levels were not taken, so this suggestion has not been confirmed.

This report and conclusions reached are uncertain, but they draw attention to possibility of an interaction between fluoxetine and itraconazole. Consider this interaction if fluoxetine adverse effects are troublesome.

Gutierrez M,Abramowitz W. Lack of effect of a single dose of ketoconazole on the pharmacokinetics of citalopram. Pharmacotherapy (2001) 21, 163–8.

Von Moltke LL,Greenblatt DJ, Giancarlo GM, Granda BW, Harmatz JS, Shader RI. Escitalopram (S-citalopram) and its metabolites in vitro: cytochromes mediating biotransformation, inhibitory effects, and comparison to R-citalopram. Drug Metab Dispos (2001) 29, 1102–9.

Black PN. Probable interaction between fluoxetine and itraconazole. Ann Pharmacother (1995) 29,1048–9.

There are isolated reports of psychosis, mania and seizures associated with use of bupropion and fluoxetine and an isolated report of serotonin syndrome with bupropion and sertraline.Hypersexuality has also been reported with bupropion and fluoxetine or sertraline.

The day after stopping fluoxetine 60mg daily,a 41-year-old man was started taking 75mg and later 100mg of bupropion three times daily. After 10 days he became edgy and anxious and after 12 days he developed myoclonus. After 14 days he became severely agitated and psychotic,with delirium and hallucinations. His behaviour returned to normal 6 days after bupropion was stopped (See reference number 1). Another patient taking lithium carbonate for bipolar disorder developed anxiety,panic and eventually mania a little over a week after stopping fluoxetine and starting bupropion (See reference number 2).

A 35-year old woman taking fluoxetine 40mg daily was given low-dose bupropion (100 mg daily) to treat fluoxetine-induced sexual dysfunction. Despite a good initial response,hypersexuality developed leading to discontinuation of bupropion (See reference number 4).

A 62-year-old woman treated with therapeutic doses of bupropion and sertraline experienced upper extremity tremor,clumsiness and gait difficulties, with fluctuating symptoms of confusion, forgetfulness, and alternating agitation and lethargy, which started after a few days on this regimen. Venlafaxine was then added and clinical picture worsened with deterioration of mental status, hallucinations, insomnia, myoclonic jerks, postural and balance difficulties, incoordination and incontinence. The medications were discontinued and symptoms, which were indicative of serotonin syndrome, gradually resolved (See reference number 5).

An isolated case describes spontaneous orgasm with combined use of bupropion and sertraline. Bupropion had been successfully used to treat SSRI-induced impaired sexual function,but after 6 weeks of combined therapy she experienced a sudden-onset, spontaneous orgasm; this occurred again on rechallenge with bupropion (See reference number 6).

Several mechanisms have been proposed. Bupropion inhibits cytochrome P450 isoenzyme CYP2D6, which may interfere with metabolism of some SSRIs, causing an increase in plasma levels and increased toxicity. However,a small study found no statistically significant changes in plasma levels of fluoxetine or paroxetine when combined with bupropion (See reference number 7). An in vitro study demonstrated that several SSRIs (paroxetine, sertraline, norfluoxetine, and fluvoxamine) could inhibit CYP2B6, isoenzyme involved in bupropion hydroxylation,(See reference number 8)and in one of cases described above it was suggested that residual fluoxetine may have inhibited metabolism of bupropion, leading to toxic levels (See reference number 1). A pharmacodynamic mechanism has also been proposed. Bupropion can cause seizures and antidepressants may further lower seizure threshold, see Bupropion + Miscellaneous interaction.

Information is very limited but these reports suggest that if concurrent or sequential use is thought appropriate, outcome should be well monitored and reduced doses should be considered. The UK and US manufacturers recommend that drugs that are metabolised by CYP2D6 should be given with bupropion with caution and initiated at lower end of dose range. If bupropion is added to treatment of a patient already taking a drug metabolised by CYP2D6, need to decrease dose of this drug should be considered (See reference number 9,10). The UK manufacturers specifically name paroxetine and US manufacturers additionally name fluoxetine and sertraline. In addition, manufacturers advise extreme caution if bupropion is given with antidepressants that lower seizure threshold(See reference number 10) and recommend reducing dose of bupropion to a maximum of 150mg daily (See reference number 9).

van Putten T,Shaffer I. Delirium associated with bupropion. J Clin Psychopharmacol (1990) 10, 234.

Zubieta JK,Demitrack MA. Possible bupropion precipitation of mania and a mixed affective state. J Clin Psychopharmacol (1991) 11, 327–8.

Ciraulo DA,Shader RI. Fluoxetine drug-drug interactions.II. J Clin Psychopharmacol (1990) 10, 213–17.

Chollet CAS,Andreatini R. Effect of bupropion on sexual dysfunction induced by fluoxetine:a case report of hypersexuality. J Clin Psychiatry (2003) 64, 1268–9.

Munhoz RP. Serotonin syndrome induced by a combination of bupropion and SSRIs. Clin Neuropharmacol (2004) 27,219–22.

Grimes JB,Labbate LA. Spontaneous orgasm with the combined use of bupropion and sertraline. Biol Psychiatry (1996) 40, 1184–5.

Kennedy SH,McCann SM, Masellis M, McIntyre RS, Raskin J, McKay G, Baker GB. Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report onpharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry (2002) 63, 181–6.

Hesse LM,Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, Greenblatt DJ. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactionswith other antidepressants. Drug Metab Dispos (2000) 28, 1176–83.

Zyban (Bupropion hydrochloride). GlaxoSmithKline UK. UK Summary of product characteristics,October 2006.

Zyban (Bupropion hydrochloride). GlaxoSmithKline. US Prescribing information,August2007.

The sedative effects of mirtazapine may be increased by benzodiazepines

Clinical evidence,mechanism, importance and management

A single-dose study in 12 healthy subjects found that pharmacokinetics of mirtazapine and diazepam were not affected by concurrent use, but diazepam further impaired action of mirtazapine on objectively measured skill performance; combined actions were mostly additive (See reference number 1). The impairment of psychomotor performance and learning caused by diazepam is increased by mirtazapine and therefore manufacturers warn that sedative effects of benzodiazepines in general may be potentiated by concurrent use with mirtazapine (See reference number 2,3).

Mattila M,Mattila MJ, Vrijmoed-de Vries M, Kuitunen T. Actions and interactions of psychotropic drugs on human performance and mood: single doses of ORG 3770, amitriptyline anddiazepam. Pharmacol Toxicol (1989) 65, 81–8.

Zispin (Mirtazapine). Organon Laboratories Ltd. UK Summary of product characteristics,September 2005.

Remeron (Mirtazapine). Organon USA Inc. US Prescribing information,June 2005.

The manufacturers issue warnings about concurrent use ofbupropion with alcohol, amantadine, levodopa, drugs that canlower convulsive threshold, drugs metabolised by cytochrome P450 isoenzyme CYP2D6, drugs which affect CYP2B6,and also use of nicotine.

Clinical evidence,mechanism, importance and management

The manufacturers report rare adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during bupropion treatment. They recommend that consumption of alcohol should be minimised or avoided (See reference number 1,2). For comment on increased risk of seizures with alcohol see (d), below.

The manufacturers say that concurrent use of bupropion and levodopa or amantadine should be undertaken with caution because limited clinical data suggest a higher incidence of undesirable effects (nausea, vomiting, excitement, restlessness, postural tremor) in patients given bupropion with either drug. Good monitoring is therefore appropriate and patients should be given small initial bupropion doses,which are increased gradually (See reference number 1,2).

The manufacturers advise caution if bupropion is used with drugs such as clopidogrel,cyclophosphamide, ifosfamide, orphenadrine, and ticlopidine as bupropion is metabolised to its major metabolite hydroxybupropion by CYP2B6 and these drugs are also metabolised by this isoenzyme (See reference number 1,2). However,there is no evidence to suggest that this is a problem in practice.

The manufacturers of bupropion predict that it may inhibit metabolism of drugs by cytochrome P450 isoenzyme CYP2D6, which might result in a rise in their plasma levels. They name haloperidol,risperidone, thioridazine, flecainide, propafenone. The recommendation is that if any of these drugs is added to treatment with bupropion, doses at lower end of range should be used. If bupropion is added to existing treatment,decreased dosages should be considered (See reference number 1,2). This seems a prudent precaution as bupropion raises levels of desipramine, , dextromethorphan, , metoprolol, , all of which are metabolised by this isoenzyme.

(e) Drugs and circumstances that can lower convulsive threshold

There is a small dose-related risk of seizures with bupropion. At a daily dose of 300mg of sustained-release formulation risk is 0.1%,which increases to 0.4 % at a dose of 450mg of immediate-release formulation, and increases tenfold between doses of 450 and 600mg daily (See reference number 2). The manufacturers caution use of other drugs that lower convulsive threshold, concern being that these drugs might further increase risk of seizures. The UK(See reference number 1) and US(See reference number 2) manufacturers list antipsychotics,antidepressants (see SSRIs, and tricyclics,), systemic steroids, , and theophylline. The UK manufacturers additionally list antimalarials,tramadol, quinolones and sedating antihistamines. A maximum dose of 150mg of bupropion should be considered for patients prescribed such drugs (See reference number 1). Caution is also urged with regard to circumstances that may lower convulsive threshold, including use of anorectics or stimulants, , excessive use of alcohol or sedatives, addiction to cocaine or opiates. Bupropion is contraindicated during abrupt withdrawal from alcohol or any drug known to be associated with seizures on withdrawal (See reference number 1,2).

Nicotine transdermal patches are reported not to affect pharmacokinetics of bupropion or its metabolites (See reference number 1). The manufacturers of bupropion say that limited data suggest that giving up smoking is more easily achieved if bupropion is taken while using a nicotine transdermal system, but a higher rate of treatment-emergent hypertension has been noted with combined treatment (See reference number 1,2). They recommend weekly monitoring to check for any evidence of a blood pressure increase (See reference number 1). The same warning would also seem to be applicable to use of nicotine in any other form (oral or nasal).

For a report of acute myocardial ischaemia attributed to combined use of bupropion,nicotine (from smoking) and pseudoephedrine, see ‘Bupropion

+ Pseudoephedrine’,below.

Zyban (Bupropion hydrochloride). GlaxoSmithKline UK. UK Summary of product characteristics,October 2006.

Zyban (Bupropion hydrochloride). GlaxoSmithKline. US Prescribing information,August 2007.

Clinical evidence,mechanism, importance and management

A case report describes a patient taking bupropion,who experienced a severe, prolonged seizure 24 hrs after receiving methylprednisolone 30mg for subacromial bursitis (See reference number 1). The author notes that there could be a risk of seizures in patients taking bupropion who are given prophylactic oral steroids (See reference number 1). This is in line with manufacturers’ suggestion that systemic steroids could increase risk of seizures, see Bupropion + Miscellaneous interaction.

1. White P. Interaction of intra-articular steroids and bupropion. Clin Radiol (2002) 57,235.

Zileuton raises theophylline levels and increases incidence ofadverse effects

In a double-blind,crossover study, 13 healthy subjects were given 200mg of theophylline (Slo-Phyllin) four times daily for 5 days and either zileuton 800mg twice daily or a placebo. Zileuton caused a 73 % rise in mean steady-state peak serum levels of theophylline (from 12 to 21 mg/L), a 92 % increase in its AUC, and halved its apparent plasma clearance. During use of zileuton incidence of adverse effects increased (headache, gastrointestinal effects), which was attributed to theophylline toxicity, and this caused 3 of original 16 subjects to withdraw from study (See reference number 1).

Not fully established but it seems highly likely that zileuton inhibits metabolism of theophylline by cytochrome P450 enzymes (probably isoenzymes CYP1A2 and CYP3A) so that its serum levels rise

Information is limited but interaction appears to be established and of clinical importance. Concurrent use need not be avoided but monitor theophylline levels and reduce dosage of theophylline as necessary. The report quoted above suggests that a typical asthma patient may initially need theophylline dosage to be halved, and this dose reduction is recommended by US manufacturers (See reference number 2). Similarly, dose of theophylline should be reduced if it is given to a patient already taking zileuton, and adjusted according to theophylline levels (See reference number 2). This is based on results of a study in over 1000 patients taking zileuton 600mg four times daily without apparent problems when this course of action was followed (See reference number 1).

Granneman GR,Braeckman RA, Locke CS, Cavanaugh JH, Dubé LM, Awni WM. Effect ofzileuton on theophylline pharmacokinetics. Clin Pharmacokinet (1995) 29 (Suppl 2), 77–83.

Zyflo (Zileuton). Critical Therapeutics Inc. US Prescribing information,November 2005.

Tobacco smokers, and non-smokers heavily exposed to tobaccosmoke, may need more theophylline than non-smokers to achievethe same therapeutic benefits, because theophylline is clearedfrom body more quickly. This may also occur in those whochew tobacco or take snuff but not if they chew nicotine gum.

A study found that mean half-life of theophylline (given as a single oral dose of aminophylline) was 4.3 hrs in a group of tobacco smokers (20 to 40 cigarettes a day) compared with 7 hrs in a group of non-smokers, and that theophylline clearance was higher (mean 126%) and more variable in smokers (See reference number 1). Almost identical results were found in an earlier study,(See reference number 2) and a number of later studies in subjects given oral or intravenous theophylline or aminophylline confirm these findings (See reference number 3-7). The ability of smoking to increase theophylline clearance occurs irrespective of gender,(See reference number 3,6) and in presence of congestive heart failure or liver impairment (See reference number 7). The effects of ageing on induction of theophylline metabolism by tobacco smoking is less clear. One study has found that in both young subjects (less than 30-years-old) and elderly subjects (more than 67-yearsold) smoking decreased half-life and increased clearance of theophylline, when compared with non-smokers. The effect was greater in young subjects (See reference number 4). However, another study found no difference in pharmacokinetics of theophylline between asthmatic and healthy smokers and non-smokers aged over 65 years (See reference number 8). A similar high clearance of theophylline (given as intravenous aminophylline) has been seen in a patient who chewed tobacco (1.11 mL/kg per minute compared with more usual

0.59 mL/kg per minute) (See reference number 9). The half-life of theophylline (given as intravenous aminophylline) in passive smokers (non-smokers regularly exposed to tobacco smoke in air they breathe, for 4 hrs a day in this study) is reported to be shorter than in non-smokers (6.93 hrs compared with

In one study,3 of 4 patients who stopped smoking for 3 months (confirmed by serum thiocyanate levels) had a longer theophylline half-life, but only 2 had a slight decrease in theophylline clearance (See reference number 1). In another study,ex-smokers who had stopped heavy smoking 2 years previously had values for theophylline clearance and half-life that were intermediate between non-smokers and current heavy smokers (See reference number 3). In another study,7 hospitalised smokers who abstained from smoking for 7 days had a 35.8 % increase in theophylline half-life and a 37.6 % decrease in clearance (although clearance after abstinence was still higher than values usually found in non-smokers) (See reference number 12).

Tobacco smoke contains polycyclic hydrocarbons, which act as inducers of cytochrome P450 isoenzyme CYP1A2, and this results in a more rapid clearance of theophylline from body. Both N-demethylation and 8-hydroxylation of theophylline is induced (See reference number 13). Ageing appears to offset effects of smoking on theophylline metabolism (See reference number 8).

An established interaction of clinical importance. Heavy smokers (20 to 40 cigarettes daily) may need much greater theophylline dosage than nonsmokers,(See reference number 1) and increased doses are likely for those who chew tobacco or take snuff,(See reference number 9) but not for those who chew nicotine gum (See reference number 12,14). In patients who stop smoking, a reduction in theophylline dosage of up to 25 to 33 % may be needed after one week,(See reference number 12)but full normalisation of hepatic function appears to take many months or even years (See reference number 1,3). Investigators of possible interactions of theophylline with other drugs should take smoking habits into account when selecting their subjects (See reference number 6,10,11). Note that effects of cannabis, , may be additive with those of tobacco smoking.

Hunt SN,Jusko WJ, Yurchak AM. Effect of smoking on theophylline disposition. Clin Pharmacol Ther (1976) 19, 546–51.

Jenne J,Nagasawa H, McHugh R, MacDonald F, Wyse E. Decreased theophylline half-lifein cigarette smokers. Life Sci (1975) 17, 195–8.

Powell JR,Thiercelin J-F, Vozeh S, Sansom L, Riegelman S. The influence of cigarettesmoking and sex on theophylline disposition. Am Rev Respir Dis (1977) 116, 17–23.

Cusack B,Kelly JG, Lavan J, Noel J, O’Malley K. Theophylline kinetics in relation to age:the importance of smoking. Br J Clin Pharmacol (1980) 10, 109–14.

Jusko WJ,Schentag JJ, Clark JH, Gardner M, Yurchak AM. Enhanced biotransformation oftheophylline in marihuana and tobacco smokers. Clin Pharmacol Ther (1978) 24, 406–10.

Jennings TS,Nafziger AN, Davidson L, Bertino JS. Gender differences in hepatic inductionand inhibition of theophylline pharmacokinetics and metabolism. J Lab Clin Med (1993) 122, 208–16.

Harralson AF,Kehoe WA, Chen J-D. The effect of smoking on theophylline disposition inpatients with hepatic disease and congestive heart failure. J Clin Pharmacol (1996) 36, 862.

Samaan S,Fox R. The effect of smoking on theophylline kinetics in healthy and asthmaticelderly males. J Clin Pharmacol (1989) 29, 448–50.

Rockwood R,Henann N. Smokeless tobacco and theophylline clearance. Drug Intell Clin Pharm (1986) 20, 624–5.

Matsunga SK,Plezia PM, Karol MD, Katz MD, Camilli AE, Benowitz NL. Effects of passivesmoking on theophylline clearance. Clin Pharmacol Ther (1989) 46, 399–407.

Mayo PR. Effect of passive smoking on theophylline clearance in children. Ther Drug Monit (2001) 23,503–5.

Lee BL,Benowitz NL, Jacob P. Cigarette abstinence, nicotine gum, and theophylline disposition. Ann Intern Med (1987) 106, 553–5.

Grygiel J,Birkett DJ. Cigarette smoking and theophylline clearance and metabolism. Clin Pharmacol Ther (1981) 30, 491–6.

Benowitz NL,Lee BL, Jacob P. Nicotine gum and theophylline metabolism. Biomed Pharmacother (1989) 43, 1–3.

Theophylline serum levels can be markedly and rapidly increasedby fluvoxamine. Toxicity will develop if theophylline dosage isnot suitably reduced. Some preliminary clinical evidence suggeststhat fluoxetine and citalopram may not interact,and in vitro evidence suggests that paroxetine and sertraline are also unlikely tointeract.

In a study in 13 healthy subjects citalopram 40mg daily for 21 days (to achieve steady-state) did not affect pharmacokinetics of a single 300mg oral dose of theophylline (See reference number 1)

The pharmacokinetics of theophylline were unchanged in 8 healthy subjects when they were given a 6-mg/kg infusion of aminophylline over 30 minutes,8 hrs after a single 40mg dose of fluoxetine (See reference number 2).

The effect of fluvoxamine on theophylline pharmacokinetics has been characterised in two studies in healthy subjects. In first study AUC of theophylline (given as a single 442mg oral dose of aminophylline) was increased almost threefold, clearance was reduced by 62 % and half-life was prolonged from 7.4 to 32.1 hrs by fluvoxamine 50mg daily for 3 days then 100mg daily for 13 days (See reference number 3). In second study, clearance of theophylline (given as a single 300mg oral dose of aminophylline) was reduced by about 70 % and half-life was increased from 6.6 to 22 hrs by fluvoxamine 50 to 100mg daily for 7 days (See reference number 4). This interaction was shown to be reduced in patients with mild and severe liver cirrhosis (Child class A and C, respectively), whereas clearance of a single 4-mg/kg dose of theophylline elixir was reduced by 62%, 52%, and 10.5 % in healthy subjects,patients with mild cirrhosis, and patients with severe cirrhosis, respectively. The half-life of theophylline was increased by 13.6 hrs in healthy subjects compared with 10.5 hrs in patients with mild cirrhosis and 1 hour in patients with severe cirrhosis, demonstrating reduced metabolic capabilities of cirrhotic liver (See reference number 5).

A number of case reports have described fluvoxamine-induced theophylline toxicity. Agitation and tachycardia (120 bpm) developed in an 83-year-old man taking theophylline 600mg daily (Theostat) about a week after he started to take fluvoxamine 100mg daily. His serum theophylline levels were found to have risen from under 15 mg/L to 40 mg/L (See reference number 6). A 70-year-old man similarly developed theophylline toxicity,with theophylline levels of about 32 mg/L (reference range 10 to 20 mg/L), when fluvoxamine was added. Subsequently theophylline concentrations were found to parallel a number of changes in fluvoxamine dosage (See reference number 7). The clearance of theophylline in an 84-year-old man was approximately halved while he was taking fluvoxamine (See reference number 8). An 11-year-old boy complained of headaches,tiredness and vomiting within a week of starting to take fluvoxamine. His serum theophylline levels were found to have doubled,from 14.2 to 27.4 mg/L (See reference number 9). A 78-year-old woman became nauseous within 2 days of starting to take fluvoxamine 50mg daily, and by day 6, when fluvoxamine was stopped, her serum theophylline levels were found to have increased about threefold. She experienced a seizure,became comatose, and had supraventricular tachycardia (200 bpm) requiring intravenous digoxin and verapamil. She recovered uneventfully (See reference number 10). A patient taking fluvoxamine 100mg daily developed nausea,vomiting, confusion, reduced sleep and a poor appetite 5 days after she began to take theophylline 300mg twice daily for COPD. Her theophylline level was found to be

In vitro studies with human liver microsomes have shown that fluvoxamine inhibits cytochrome P450 isoenzyme CYP1A2, principal enzyme responsible for metabolism of theophylline (See reference number 12,13). This results in raised theophylline levels and toxicity. This metabolic function,and hence interaction, appears to be severely reduced in patients with severe cirrhosis, probably due to reduced hepatic expression of CYP1A2 and reduced uptake of fluvoxamine (See reference number 5). The other SSRIs,citalopram, fluoxetine, paroxetine and sertraline only weakly inhibited CYP1A2 in vitro, and consequently would not be expected to interact (See reference number 12,13).

The interaction between fluvoxamine and theophylline is established and clinically important. The CSM in UK advise that concurrent use should usually be avoided, but that if this is not possible, reduce theophylline dosage by half when fluvoxamine is added and monitor theophylline levels (See reference number 14). . There is evidence to suggest that extent of this interaction is markedly reduced in patients with liver cirrhosis, particularly severe Child class C, despite higher levels of fluvoxamine,(See reference number 5) although caution should still be applied with concurrent use in this patient group as they are more likely to have high levels of theophylline due to reduced metabolism. There is good in vitro evidence to suggest that fluvoxamine is only SSRI likely to interact (because it is only one that significantly affects CYP1A2). This would seem to be borne out by lack of studies and case reports in literature describing problems with any of other SSRIs.

Møller SE,Larsen F, Pitsiu M, Rolan PE. Effect of citalopram on plasma levels of oral theophylline. Clin Ther (2000) 22, 1494–1501.

Mauro VF,Mauro LS, Klions HA. Effect of single dose fluoxetine on aminophylline pharmacokinetics. Pharmacotherapy (1994) 14, 367.

Donaldson KM,Wright DM, Mathlener IS, Harry JD. The effect of fluvoxamine at steadystate on the pharmacokinetics of theophylline after a single dose in healthy male volunteers.Br J Clin Pharmacol (1994) 37, 492P.

Rasmussen BB,Jeppesen U, Gaist D, Brøsen K. Griseofulvin and fluvoxamine interactionswith the metabolism of theophylline. Ther Drug Monit (1997) 19, 56–62.

Orlando R,Padrini R, Perazzi M, De Martin S, Piccoli P, Palatini P. Liver dysfunction markedly decreases the inhibition of cytochrome P450 1A2-mediated theophylline metabolism byfluvoxamine. Clin Pharmacol Ther (2006) 79, 489–99.

Diot P,Jonville AP, Gerard F, Bonnelle M, Autret E, Breteau M, Lemarie E, Lavandier M. Possible interaction entre théophylline et fluvoxamine. Therapie (1991) 46, 170–71.

Thomson AH,McGovern EM, Bennie P, Caldwell G, Smith M. Interaction between fluvoxamine and theophylline. Pharm J (1992) 249, 137. Correction. ibid. (1992) 249, 214.

Puranik A,Fitzpatrick R, Ananthanarayanan TS. Monitor serum theophylline. Care Elder (1993) 5, 237.

Sperber AD. Toxic interaction between fluvoxamine and sustained release theophylline in an11-year-old boy. Drug Safety (1991) 6,460–2.

van den Brekel AM,Harrington L. Toxic effects of theophylline caused by fluvoxamine. Can Med Assoc J (1994) 151, 1289–90.

DeVane CL,Markowitz JS, Hardesty SJ, Mundy S, Gill HS. Fluvoxamine-induced theophylline toxicity. Am J Psychiatry (1997) 154, 1317–18.

Brøsen K,Skjelbo E, Rasmussen BB, Poulsen HE, Loft S. Fluvoxamine is a potent inhibitorof cytochrome P4501A2. Biochem Pharmacol (1993) 45, 1211–14.

Rasmussen BB,Mäenpää J, Pelkonen O, Loft S, Poulsen HE, Lykkesfeldt J, Brøsen K. Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol (1995) 39, 151–9.

Committee on Safety of Medicines/Medicines Control Agency. Fluvoxamine increases plasma theophylline levels. Current Problems (1994) 20,12.