Pharmacy Blog – Dr Vibore

Duloxetine increased maximum levels of tolterodine by 64%,but this was not considered to be clinically significant

Clinical evidence,mechanism, importance and management

In a placebo-controlled,crossover study, 14 healthy subjects received duloxetine 40mg twice daily and tolterodine 2mg twice daily for 5 days. Duloxetine increased steady-state AUC of tolterodine by 71 % and its maximum level by 64%. However, duloxetine had no effect on pharmacokinetics of 5-hydroxymethyl-tolterodine active metabolite of tolterodine (See reference number 1).

Duloxetine is an inhibitor of cytochrome P450 isoenzyme CYP2D6, by which tolterodine is metabolised.

The increases in tolterodine levels were not considered to be clinically relevant,and no routine dosage adjustment of tolterodine dosage was considered necessary when given with duloxetine (See reference number 1). Consider also Urinary antimuscarinics; Tolterodine + Fluoxetine interaction.

1. Hua TC,Pan A, Chan C, Poo YK, Skinner MH, Knadler MP, Gonzales CR, Wise SD. Effect of duloxetine on tolterodine pharmacokinetics in healthy volunteers. Br J Clin Pharmacol (2004) 57, 652–6.

Rifampicin moderately decreases plasma concentrations oftizanidine

Clinical evidence,mechanism, importance and management

In a placebo-controlled, crossover study in 10 healthy subjects, pre-treatment with rifampicin 600mg daily for 5 days moderately reduced AUC and peak level of a single 4mg dose of tizanidine given on day 6 by about 50%, without altering half-life (See reference number 1).

Rifampicin appears to be only a weak inducer of cytochrome P450 isoenzyme CYP1A2, by which tizanidine is metabolised (See reference number 1).

Rifampicin moderately reduces levels and effects of tizanidine. Because tizanidine dose is titrated to effect,this is probably not that clinically important. A small increase in dose might be required.

1. Backman JT,Granfors MT, Neuvonen PJ. Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol (2006) 62, 451–61.

Fluvoxamine causes a very marked 33-fold increase in tizanidinelevels with a consequent increase in hypotensive and sedative effects. The combination is potentially hazardous and should beavoided. Ciprofloxacin markedly increases tizanidine levels andadverse effects,and particular caution is required if this combination is considered essential. Combined oral contraceptivesincrease tizanidine levels fourfold and might increase adverse effects. Other inhibitors of CYP1A2 are predicted to interact similarly.

In a placebo-controlled, crossover study in 10 healthy subjects ciprofloxacin 500mg twice daily for 3 days markedly increased AUC of a single 4mg dose of tizanidine by tenfold and maximum level by sevenfold, without significantly affecting half-life. The hypotensive and sedative effects of tizanidine were also markedly increased by ciprofloxacin (See reference number 1).

A 45-year-old Japanese woman with multiple sclerosis taking tizanidine 3mg daily had a reduction in blood pressure (from 124/88 to 102/74 mmHg) and heart rate (from 86 to 58 bpm) shortly after starting to take ciprofloxacin 400mg daily. After 2 days she complained of drowsiness and her blood pressure was 92/54 mmHg (See reference number 2). Retrospective analysis revealed 8 patients who had received tizanidine and ciprofloxacin concurrently. In these patients, mean reduction in blood pressure on starting ciprofloxacin was 21.3/15.4 mmHg, and heart rate reduction was 14.9 bpm. Adverse effects attributable to tizanidine occurred in three of patients (See reference number 2).

In a placebo-controlled, crossover study in 10 healthy subjects fluvoxamine 100mg once daily for 4 days very markedly increased AUC of a single 4mg dose of tizanidine by 33-fold and maximum level by 12-fold. The elimination half-life was prolonged from 1.5 to 4.3 hours. The hypotensive and sedative effects of tizanidine were also markedly increased by fluvoxamine, with all of 10 subjects somnolent and dizzy for 3 to 6 hrs (See reference number 3).

A 70-year-old Japanese woman started taking tizanidine 3mg daily 15 days after starting fluvoxamine 100mg increased to 150mg daily. Her heart rate dropped from about 85 bpm to a range of 56 to 60 bpm. After tizanidine was stopped, symptoms improved immediately (See reference number 4). Retrospective analysis revealed 23 patient who had received tizanidine with fluvoxamine. Of these patients,6 had adverse effects including low heart rate, dizziness, drowsiness and hypotension. The patients with adverse effects were,on average, taking higher doses of fluvoxamine and tizanidine than those without adverse effects (See reference number 4).

In a study in 15 healthy women taking a combined oral contraceptive (ethinylestradiol/gestodene), AUC of a single 4mg dose of tizanidine was 3.9-fold higher than in 15 healthy women not taking an oral contraceptive, without any difference in elimination half-life. In addition, blood pressure-lowering effect of tizanidine was increased by 12/8 mmHg in oral contraceptive users (See reference number 5). The manufacturer also notes that retrospective analysis of population pharmacokinetic data showed that clearance of tizanidine is about 50 % lower in women taking oral contraceptives (See reference number 6,7).

In a placebo-controlled, crossover study in 9 healthy subjects rofecoxib 25mg daily for 4 days markedly increased AUC of a single 4mg dose of tizanidine by 13.6-fold and maximum level by 6.1-fold. The hypotensive and sedative effects of tizanidine were also markedly increased by rofecoxib. There was no evidence of QT prolongation in this study (See reference number 8).

An otherwise healthy 59-year-old woman developed extreme sinus bradycardia (30 bpm) with chest pain and acute right heart failure while taking tizanidine,diclofenac and rofecoxib. This resolved promptly after stopping medication (See reference number 9). Note that rofecoxib was generally withdrawn worldwide in 2004 because of its cardiovascular adverse effects,but these data are included here for completeness.

Tizanidine is a substrate of cytochrome P450 isoenzyme CYP1A2, which undergoes substantial presystemic metabolism by this isoenzyme. Ciprofloxacin appears to inhibit mainly presystemic metabolism leading to increased absorption, as reflected by increase in maximum level without a change in elimination half-life. Rofecoxib and fluvoxamine inhibited both presystemic metabolism and elimination phase. Fluvoxamine, which is a known potent inhibitor of CYP1A2, had most marked effect. The contraceptive steroids were modest inhibitors of CYP1A2 by comparison.

These pharmacokinetic interactions are well established,and clinically important. The common adverse effects of tizanidine, such as hypotension and sedation, are dose related, and consequently manufacturers recommend starting with a low dose of tizanidine (2 or 4 mg) and carefully titrating to usual maximum of 24mg daily, and not exceeding 36mg daily (See reference number 6,7). This represents a maximum 18-fold variation in dosage. Fluvoxamine increases exposure to tizanidine by a mean of 33-fold, which, broadly speaking, changes a 2mg dose into a 66mg dose, which is far higher than maximum recommended dose. For this reason, authors of one of studies conclude that combination is potentially hazardous and should be avoided (See reference number 3). The US manufacturer also contraindicates combination (See reference number 7). Given available data this is sensible advice. Note that other SSRIs are generally not considered to inhibit CYP1A2,see Theophylline + SSRIs interaction, and may therefore be suitable alternatives to fluvoxamine.

For ciprofloxacin,there is a marked tenfold increase in exposure to tizanidine, with a consequent increase in adverse effects. Some authors recommend that this combination be avoided,(See reference number 2) whereas others recommend caution (See reference number 1). The US manufacturer contraindicates combination,(See reference number 7) whereas UK manufacturers do not mention this potential interaction (See reference number 6). If ciprofloxacin is considered most appropriate antibacterial to use in a patient already taking tizanidine, anticipate need to reduce tizanidine dose before starting ciprofloxacin, and closely monitor adverse effects: starting ciprofloxacin may cause marked hypotension, bradycardia, and sedation. Other quinolones also inhibit CYP1A2,but to varying degrees, see table 1 below,.

For combined oral contraceptives, increase in exposure to tizanidine is a more moderate fourfold. The manufacturer states that clinical response or adverse effects might occur at lower doses of tizanidine in patients taking oral contraceptives,(See reference number 6) and that during dose titration,individual doses should be reduced (See reference number 7). Care is needed (See reference number 7).

In addition, US manufacturer also recommends caution if tizanidine is given with other inhibitors of CYP1A2, of which they mention amiodarone, mexiletine, propafenone, cimetidine and ticlopidine (See reference number 7). For a list of clinically important CYP1A2 inhibitors,see table 2 below,.

Granfors MT,Backman JT, Neuvonen M, Neuvonen PJ. Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther (2004) 76, 598–606.

Momo K,Homma M, Kohda Y, Ohkoshi N, Yoshizawa T, Tamaoka A. Drug interaction oftizanidine and ciprofloxacin: case report. Clin Pharmacol Ther (2006) 80, 717–9.

Granfors MT,Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ. Fluvoxamine drasticallyincreases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther (2004) 75, 331–41.

Momo K,Doki K, Hosono H, Homma M, Kohda Y. Drug interaction of tizanidine and fluvoxamine. Clin Pharmacol Ther (2004) 76, 509–10.

Granfors MT,Backman JT, Laitila J, Neuvonen PJ. Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clin Pharmacol Ther (2005) 78, 400–11.

Zanaflex (Tizanidine hydrochloride). Cephalon Ltd. UK Summary of product characteristics,December 2006.

Zanaflex (Tizanidine hydrochloride). Acorda Therapeutics,Inc. US Prescribing information,July 2006.

Backman JT,Karjalainen MJ, Neuvonen M, Laitila J, Neuvonen PJ. Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol (2006) 62, 345–57.

Kick A,Bertoli R, Moschovitis G, Caduff Janosa P, Cerny A. [Extreme sinus bradycardia(30/min) with acute right heart failure under tizanidine (Sirdalud). Possible pharmacologicalinteraction with rofecoxib (Vioxx)]. Med Klin (2005) 100, 213–16.

Table 1 Effect of quinolones on theophylline pharmacokinetics in order of magnitude of the potential interaction
Quinolone (daily dose)	Increase in theophylline level	Increase in AUC	Decrease in clearance	Refs
Enoxacin 600 to 1200mg	72 to 243 %	84 to 248 %	42 to 74 %	1–8
Pipemidic acid 800 to 1500mg	71%	76 to 79 %	49%	3, 9
Clinafloxacin 400 to 800mg			46 to 69 %	10
Grepafloxacin 200 to 600mg	28 to 82 %	93 to 113 %	33 to 54 %	11, 12
Ciprofloxacin 600 to 1500mg	17 to 50 %	22 to 52 %	18 to 31 %	2, 3, 13–18
Pazufloxacin 500mg	up to 27 %	up to 33 %	25%	19
Pefloxacin 400 to 800mg	17 to 20 %	19 to 53 %	29%	2, 3
Norfloxacin 600 to 800mg	up to 22 %	up to 17 %	up to 15 %	7, 16, 20–23
Prulifloxacin 600mg		16%	15%	24
Ofloxacin 400 to 600mg	up to 10 %	up to 10 %	up to 12 %	2, 3, 7, 22, 25– 27
Trovafloxacin 200 to 300mg		up to 8 %		28, 29
Fleroxacin 400mg	No significant change	up to 8 %	up to 6 %	30–33
Flumequine 1200mg	No significant change	No significant change	No significant change	34
Gatifloxacin 400mg	No significant change	No significant change		35
Gemifloxacin 400 to 600mg	No significant change	No significant change		36
Levofloxacin 300 to 1000mg	No significant change	No significant change	No significant change	11, 37, 38
Lomefloxacin 400 to 800mg	No significant change	No significant change	No significant change	9, 15, 39–42
Moxifloxacin 200mg to 400mg	No significant change	No significant change	No significant change	43
Nalidixic acid 400 to 600mg		No significant change	No significant change	2, 16
Rufloxacin 200 to 400mg	No significant change	No significant change	No significant change	44, 45
Sparfloxacin 200 to 400mg	No significant change	No significant change	No significant change	46–49

Table 2 Drugs affecting or metabolised by the cytochrome P450 isoenzyme CYP1A2
Inhibitors	Cimetidine Fluoroquinolones Ciprofloxacin Enoxacin Grepafloxacin Fluvoxamine	Ipriflavone Mexiletine Rofecoxib Tacrine Ticlopidine Zileuton
Inducers	Barbiturates Phenytoin	Tobacco smoke
Substrates	Caffeine Clozapine Duloxetine Flecainide Olanzapine Rasagiline Ropinirole Tacrine Theophylline*	Tizanidine* Tricyclic antidepressants Amitriptyline Clomipramine Imipramine Triptans Frovatriptan Zolmitriptan R-Warfarin

It is unclear whether tizanidine prolongs QT interval inhumans

Clinical evidence,mechanism, importance and management

One of most common adverse effects of tizanidine is somnolence or drowsiness (occurring in up to 50 % of patients(See reference number 1)) for which reason manufacturers warn about possibility of increased sedation with other sedative drugs, and alcohol (See reference number 2,3). In addition to additive sedative effects, alcohol increased AUC of tizanidine by about 20 % and its maximum level by 15%, which was associated with an increase in adverse effects of tizanidine (See reference number 3). Patients should be warned.

The UK manufacturers say that concurrent use of digoxin may potentiate bradycardia (See reference number 2)

(c) Drugs that prolong QT interval

The US manufacturer information states that prolongation of QT interval and bradycardia were noted in chronic toxicity studies in dogs at doses equal to maximum dose (See reference number 3). The UK information states that caution should be exercised when tizanidine is prescribed with drugs known to increase QT interval (See reference number 2). In one pharmacological interaction study in healthy subjects,there was no evidence of QT prolongation either with tizanidine 4 mg, or almost 14-fold increased tizanidine levels caused by rofecoxib, , despite increased bradycardia and hypotension (See reference number 4). This suggests that a clinically significant interaction resulting in QT-prolongation is unlikely.

In 20 healthy subjects,no clinically significant interaction occurred between 325mg of paracetamol (acetaminophen) and 4mg of tizanidine (See reference number 1).

Wagstaff AJ,Bryson HM. Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders. Drugs (1997) 53, 435–52.

Zanaflex (Tizanidine hydrochloride). Cephalon Ltd. UK Summary of product characteristics,December 2006.

Zanaflex (Tizanidine hydrochloride). Acorda Therapeutics,Inc. US Prescribing information,July 2006.

Backman JT,Karjalainen MJ, Neuvonen M, Laitila J, Neuvonen PJ. Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjects. Br J Clin Pharmacol (2006) 62, 345–57.

Clinical evidence,mechanism, importance and management

A woman with Turner’s syndrome,who had undergone a total thyroidectomy and who was being treated with levothyroxine 100 micrograms daily, had a marked fall in serum levothyroxine levels and free levothyroxine index with a dramatic rise in TSH levels when given rifampicin. However, no symptoms of clinical hypothyroidism developed, and drop in serum levothyroxine occurred prior to starting rifampicin, which may reflect clinical picture of an acute infection (See reference number 1). Another case describes a fall in TSH levels when rifampicin was discontinued (See reference number 2).

A possible reason for changes is that rifampicin, a potent enzyme inducer, can markedly increase metabolism of many drugs and thereby reduce their effects. Rifampicin has been found to reduce endogenous serum thyroxine levels in healthy subjects(See reference number 3) and possibly in patients (See reference number 2).

There seem to be no reports of adverse effects in other patients given both drugs and evidence for this interaction is by no means conclusive. Although rifampicin can affect thyroid hormones,it appears that healthy individuals can compensate for this. Since hypothyroid patients may not be able to compensate in same way, bear this interaction in mind if rifampicin is given to a patient taking levothyroxine.

Isley WL. Effect of rifampin therapy on thyroid function tests in a hypothyroid patient on replacement L-thyroxine. Ann Intern Med (1987) 107,517–18.

Nolan SR,Self TH, Norwood JM. Interaction between rifampin and levothyroxine. South Med J (1999) 92, 529–31.

Ohnhaus EE,Studer H. A link between liver microsomal enzyme activity and thyroid hormonemetabolism in man. Br J Clin Pharmacol (1983) 15, 71–6.

Clinical evidence,mechanism, importance and management

Retrospective analysis of 11 patients taking levothyroxine and with thyroid cancer found that 8 patients who had previously undergone a total thyroidectomy developed markedly elevated TSH levels and were clinically hypothyroid after receiving treatment with imatinib. Despite a mean increase in dose of levothyroxine of about 200%, hypothyroidism was reversed in only 3 patients. Thyroid function tests normalised on discontinuing imatinib. Conversely, no effect on thyroid status was seen in 3 patients who had not had their thyroid gland removed (See reference number 1).

The authors postulated that imatinib might increase clearance of thyroid hormones thyroxine and tri-iodothyronine by induction of glucuronosyltransferases (UGTs) (See reference number 1)

The findings from this study appear to be established. TSH levels should be closely monitored in thyroidectomy patients taking levothyroxine if they are given imatinib, anticipate need to increase levothyroxine dose. The authors suggest that in thyroidectomy patients dose of levothyroxine should be doubled before starting imatinib (See reference number 1).

1. de Groot JWB,Zonnenberg BA, Plukker JTM, van Der Graaf WTA, Links TP. Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther (2005) 78, 433–8.

The phosphodiesterase type-5 inhibitors potentiate hypotensive effects of nitrates in a proportion of patients, which might result in potentially serious hypotension or even precipitatemyocardial infarction. Therefore, concurrent use of sildenafil,tadalafil or vardenafil with organic nitrates (glyceryl trinitrate(nitroglycerin), isosorbide dinitrate, isosorbide mononitrate, etc.)is contraindicated. The concurrent use of nicorandil and all phosphodiesterase type-5 inhibitors is also contraindicated.

Erectile dysfunction. Two double-blind, placebo-controlled studies in groups of 15 or 16 men with angina found that fall in blood pressure seen when taking nitrates and a single 50mg dose of sildenafil was about doubled. Those given sildenafil and isosorbide dinitrate 20mg twice daily had a mean blood pressure fall of 44/26 mmHg compared with 22/13 mmHg with placebo. Those who used 500 micrograms of sublingual glyceryl trinitrate one hour before sildenafil had a mean blood pressure fall of 36/21 mmHg compared with 26/11 mmHg with glyceryl trinitrate and placebo. Individual blood pressure falls as great as 84/52 mmHg were seen (See reference number 1). A postmarketing report from FDA in US for period late March to July 1998 briefly lists 69 fatalities after taking sildenafil. These were mostly in middle-aged and elderly men (average age 64), 12 of whom had also taken glyceryl trinitrate (nitroglycerin) or a nitrate medication, but it is not clear what part (if any) nitrates played in deaths (See reference number 2). In a limited and preliminary study it was reported that no blood pressure alteration was seen when a small dose of glyceryl trinitrate (amount not specified) was given as a dermal patch while subjects were taking 50mg of sildenafil. In addition, beneficial effects of glyceryl trinitrate on radial artery pressure waveform were approximately doubled, and persisted for up to 8 hrs (See reference number 3).

Pulmonary hypertension. In a study of combined use of intravenous sildenafil and inhaled nitric oxide in management of pulmonary hypertension in 15 infants, significant hypotension occurred, which, along with a decrease in oxygenation, was considered sufficiently detrimental for study to be stopped early (See reference number 4). Conversely,beneficial combined use has been described in one adult patient with severe hypoxemia caused by pulmonary hypotension (See reference number 5). Note that nitric oxide is not to be confused with anaesthetic nitrous oxide, which is not a nitric oxide donor and therefore poses no risk,(See reference number 6)see Mechanism below.

In a double-blind,randomised, placebo-controlled study, 51 patients with chronic stable angina were given tadalafil 5 mg, 10mg or a placebo, followed 2 hrs later by a single 400-microgram dose of sublingual glyceryl trinitrate. Although tadalafil caused little additional decrease in blood pressure to that seen with glyceryl trinitrate, a potentially clinically significant blood pressure reduction (standing systolic BP less than 85 mmHg) was seen in 13 and 11 of patients when given tadalafil 5 and 10 mg, respectively, compared with one patient in placebo group (See reference number 7,8). In a similar study in 45 patients taking long-term oral isosorbide mononitrate, tadalafil 5 or 10mg had minimal effects on decrease in blood pressure caused by this nitrate, but again, more patients had a standing systolic BP of less than 85 mmHg when receiving tadalafil 10mg than placebo (6 versus 0) (See reference number 7,8). Another similar study in 48 healthy subjects compared effects of tadalafil 10 mg, sildenafil 50 mg, and placebo, in combination with sublingual glyceryl trinitrate 400 micrograms. Again, it was found that presence of tadalafil had minimal effects on mean maximum decreases in blood pressure, but it was noted that 23 patients given tadalafil and 23 given sildenafil had a standing systolic blood pressure of 85 mmHg or less following use of nitrate, compared with 12 in placebo group (See reference number 8,9). In a further study, a haemodynamic interaction between tadalafil 20mg and sublingual glyceryl trinitrate was seen when glyceryl trinitrate was given 4, 8 and 24 hrs after tadalafil, and was not seen at 48 hrs and beyond. Note that no time points between 24 and 48 hrs were examined (See reference number 10).

An analysis of rates of serious cardiovascular adverse events (mortality, myocardial infarction, thrombotic strokes) in clinical studies involving tadalafil indicated that adverse events were no more frequent than in general population of men with erectile dysfunction (See reference number 8).

A single 400-microgram dose of sublingual glyceryl trinitrate (nitroglycerin) given to 18 healthy subjects 1 to 24 hrs after a single 10mg dose of vardenafil was found to be no different to placebo in causing changes in seated heart rate and blood pressure (See reference number 11,12). However, a single 20mg dose of vardenafil did potentiate blood pressure-lowering effects and increases in heart rate (about an 8 mmHg additional drop in systolic BP compared with placebo) seen with sublingual nitrates (400 micrograms) taken 1 and 4 hrs after vardenafil. These effects were not seen when nitrate was taken 24 hrs after vardenafil dose (See reference number 11,13).

Sexual stimulation causes endothelium of penis to release nitric oxide (NO), which in turn activates guanylate cyclase to increase production of cyclic guanosine monophosphate (cGMP). This relaxes blood vessel musculature of corpus cavernosum thus allowing it to fill with blood and cause an erection. The erection ends when guanosine mono-phosphate is removed by an enzyme (type 5 cGMP phosphodiesterase, or PDE5). Sildenafil, tadalafil and vardenafil inhibit this enzyme thereby increasing and prolonging effects of guanosine monophosphate. Because this vasodilation is usually fairly localised (these drugs are highly selective for PDE5) it normally only causes mild to moderate falls in blood pressure (on average about 10 mmHg) with mild headache or flushing. However,if other nitrates (e.g. glyceryl trinitrate) are taken concurrently, high levels of nitric oxide enter circulation, and this markedly increases systemic vasodilation and hence hypotensive effect.

The interaction between phosphodiesterase type-5 inhibitors and nitrates is established,clinically important, potentially serious and even possibly fatal. Sildenafil and organic nitrates of any form are contraindicated both for erectile dysfunction(See reference number 14,15) (within 24 hrs of each other(See reference number 6)) and for pulmonary hypertension(See reference number 16,17)because of risk of precipitating serious hypotension, or even myocardial infarction (See reference number 18). The ACC/AHA Expert consensus document provides a useful list of many of organic nitrates available, which include glyceryl trinitrate (nitroglycerin), isosorbide mononitrate, isosorbide dinitrate and illicit substances such as amyl ni

Similarly, manufacturers of vardenafil(See reference number 11,13) and tadalafil(See reference number 19,20) say that their combination with nitrates (taken either regularly and/or intermittently) is contraindicated. Nitrates should not be given for at least 48 hrs after last dose of tadalafil (See reference number 19,20).

It is not yet known whether nicorandil interacts with phosphodiesterase inhibitors to a clinically relevant extent or not,(See reference number 21)but because part of its vasodilatory actions are mediated by release of nitric oxide (like conventional nitrates), manufacturers of nicorandil contraindicate its use with all phosphodiesterase inhibitors (See reference number 22).

Webb DJ,Muirhead G, Wulff M, Sutton A, Levi R, Dinsmore WW. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina.J Am Coll Cardiol (2000) 36, 25–31.

FDA (US Food and Drug Administration) postmarketing information sildenafil citrate (Viagra): Postmarketing safety of sildenafil citrate (Viagra). Reports of death in Viagra users received from marketing (late March) through July 1998. August 27th 1998.

O’Rourke M,Jiang X-J. Sildenafil/nitrate interaction. Circulation (2000) 101, e90.

Stocker C,Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS. Intravenoussildenafil and inhaled nitric oxide: a randomised trial in infants after cardiac surgery. Intensive Care Med (2003) 29, 1996–2003.

Bigatello LM,Hess D, Dennehy KC, Medoff BD, Hurford WE. Sildenafil can increase theresponse to inhaled nitric oxide. Anesthesiology (2000) 92, 1827–9.

ACC/AHA Expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol (1999) 33,273–82.

Kloner RA,Emmick J, Bedding A, Humen D. Pharmacodynamic interactions betweentadalafil and nitrates. Int J Impot Res (2002) 14 (Suppl 3) S29.

Kloner RA,Mitchell M, Emmick J. Cardiovascular effect of tadalafil. Am J Cardiol (2003) 92 (Suppl) 37M–46M.

Kloner RA,Mitchell MI, Bedding A, Emmick J. Pharmacodynamic interactions betweentadalafil and nitrates compared with sildenafil. J Urol (Baltimore) (2002) 167 (Suppl) 176–7.

Kloner RA,Hutter AM, Emmick JT, Mitchell MI, Denne J, Jackson G. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol (2003) 42, 1855–60.

Levitra (Vardenafil hydrochloride trihydrate). Bayer plc. UK Summary of product characteristics,November 2006.

Mazzu AL,Nicholls AJ, Zinny M. Vardenafil, a new selective PDE-5 inhibitor, interacts minimally with nitroglycerin in healthy middle-aged male subjects. Int J Impot Res (2001) 13 (Suppl 5) S64.

Levitra (Vardenafil hydrochloride). Bayer Pharmaceuticals Corporation. US prescribing information,March 2007.

Viagra (Sildenafil citrate). Pfizer Ltd. UK Summary of product characteristics,June 2006.

Viagra (Sildenafil citrate). Pfizer Inc. US Prescribing information,October 2006.

Revatio (Sildenafil citrate). Pfizer Ltd. UK Summary of product characteristics,March 2007.

Revatio (Sildenafil citrate). Pfizer Inc. US Prescribing information,July 2006.

Viagra (Sildenafil). Pfizer Inc. Dear Doctor letter,May 1998.

Cialis (Tadalafil). Eli Lilly and Company Ltd. UK Summary of product characteristics,July2006.

Cialis (Tadalafil). Eli Lilly and Company Ltd. US Prescribing information,January 2007.

Aventis Pharma,Personnal communication, February 2000.

Ikorel (Nicorandil). Sanofi-Aventis. UK Summary of product characteristics,June 2004.

Apart from a brief and unconfirmed report alleging that cimetidine reduced response to ferrous sulfate in three patients,there appears to be no other evidence that H2-receptor antagonists reduce absorption of iron to a clinically relevant extent

Clinical evidence,mechanism, importance and management

A brief report describes 3 patients taking cimetidine 1g and ferrous sulfate 600mg daily whose ulcers healed after 2 months,but their anaemia and altered iron metabolism persisted. When cimetidine was reduced to 400mg daily, but with same dose of iron, blood picture resolved satisfactorily within a month (See reference number 1). The author of report attributed this response to cimetidine-induced rise in gastric pH, which reduced absorption of iron. However, this suggested mechanism was subsequently disputed, as medicinal iron is already in most absorbable form, Fe(See reference number 2+), and so does not need an acidic environment to aid absorption (See reference number 2). A study in patients with iron deficiency, or iron-deficiency anaemia, found that concurrent use of famotidine, nizatidine, or ranitidine, did not affect their response to 2.4 g of iron succinyl-protein complex (equivalent to 60mg of iron twice daily) (See reference number 3). No special precautions would seem necessary on concurrent use.

In a series of 3 studies,healthy subjects were given a 300mg tablet of cimetidine with either a 300mg tablet of ferrous sulfate or 300mg of ferrous sulfate in solution. The reductions in AUC and maximum serum levels of cimetidine were small (less than 16%). In third experiment they were given famotidine 40mg with a 300mg tablet of ferrous sulfate. Again, AUC and maximum serum level reductions were also very small (10% or less). These small reductions are almost certainly due to formation of a weak complex between iron and these H2-receptor antagonists (See reference number 4). An in vitro study with ranitidine found that,while it also binds with iron, it forms a very weak complex, and is less likely to bind than cimetidine or famotidine (See reference number 4). It was concluded that no clinically relevant interaction occurs between ferrous sulfate and any of these H2-receptor antagonists (See reference number 4).

Esposito R. Cimetidine and iron-deficiency anaemia. Lancet (1977) ii,1132.

Rosner F. Cimetidine and iron absorption. Lancet (1978) i,95.

Bianchi FM,Cavassini GB, Leo P. Iron protein succinylate in the treatment of iron deficiency: Potential interaction with H2-receptor antagonists. Int J Clin Pharmacol Ther Toxicol (1993) 31, 209–17.

Partlow ES,Campbell NRC, Chan SC, Pap KM, Granberg K, Hasinoff BB. Ferrous sulfatedoes not reduce serum levels of famotidine or cimetidine after concurrent ingestion. Clin Pharmacol Ther (1996) 59, 389–93.

Ginseng does not appear to affect metabolism of alprazolamor dextromethorphan

Clinical evidence,mechanism, importance and management

A study in 12 healthy subjects found that Siberian ginseng, 485mg twice daily for 14 days, did not affect pharmacokinetics of a single 2mg dose of alprazolam or metabolism of a single 30mg dose of dextromethorphan. This suggests that Siberian ginseng is unlikely to affect metabolism of other drugs that are substrates of cytochrome P450 isoenzymes CYP2D6 or CYP3A4 (See reference number 1). For a list of drugs that are substrates of these enzymes,see table 1 below,, and table 2 below,, respectively.

1. Donovan JL,DeVane CL, Chavin KD, Taylor RM, Markowitz JS. Siberian ginseng (Eleutheroccus [sic] senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers. Drug Metab Dispos (2003) 31, 519–22.

Table 1 Drugs affecting or metabcytochrome P450 isoenzymes		olised by the CY	P2 family of
Isoenzyme	Inhibitors	Inducers	Substrates
CYP2B6	Thiotepa	Phenobarbital Phenytoin	Cyclophosphamide Ifosfamide
CYP2C8	Gemfibrozil Rifampicin Trimethoprim		Pioglitazone Repaglinide Rosiglitazone
CYP2C9	Amiodarone Azoles Fluconazole Miconazole Voriconazole Fluvastatin SSRIs Fluoxetine Fluvoxamine Sulfinpyrazone Ticlopidine Zafirlukast	Aprepitant Rifampicin	Irbesartan Losartan Nateglinide NSAIDs Celecoxib Diclofenac Etoricoxib Valdecoxib Phenytoin Statins Fluvastatin Rosuvastatin Sulphonylureas Glibenclamide Gliclazide Glimepiride Glipizide Tolbutamide* S-Warfarin*

Table 2 Drugs affecting or metabolised by isoenzyme CYP3A4		the cytochrome P450
Inhibitors	Aprepitant Azoles Itraconazole Ketoconazole Voriconazole Cimetidine Delavirdine Diltiazem Grapefruit juice Imatinib	Macrolides Clarithromycin Erythromycin Troleandomycin Nefazodone Nicardipine Protease inhibitors SSRIs Fluoxetine Verapamil

Several case reports describe acute life-threatening colchicinetoxicity caused by addition of erythromycin or clarithromycin, and one retrospective study found that 9 of 88 patients whohad received combination of colchicine and clarithromycindied.

A 29-year-old woman with familial Mediterranean fever and amyloidosis,who was taking long-term colchicine 1mg daily, developed acute and life-threatening colchicine toxicity (fever, diarrhoea, myalgia, pancytopenia and later alopecia) 16 days after starting to take erythromycin 2g daily. This patient had both cholestasis and renal impairment,factors that would be expected to reduce colchicine clearance and therefore predispose her to colchicine toxicity (See reference number 1). Colchicine levels rose from below

12.6 nanograms/mL to 22 nanograms/mL after addition of erythromycin (See reference number 1). In another patient,who had been taking colchicine 1.5mg daily for 6 years,similar signs of acute colchicine toxicity developed 4 days after starting a 7-day course of clarithromycin 1 g daily, amoxicillin and omeprazole for H. pylori associated gastritis. The colchicine dose was reduced to 500 micrograms daily and then,after recovery, gradually increased slowly back to 1.5mg daily (See reference number 2).

In another case,a 67-year-old man on CAPD taking colchicine 500 micrograms twice daily was admitted with symptoms of colchicine toxicity (including pancytopenia) 4 days after starting a course of clarithromycin 500mg twice daily for an upper respiratory tract infection. All drugs were stopped and supportive treatment given,but he later died from multi-organ failure (See reference number 3).

These case reports led to a retrospective study of patients who had received combination of colchicine and clarithromycin as inpatients. Of 116 patients given drugs, 88 had received them concurrently and 28 received them sequentially. Nine of concurrent group died (compared with only 1 of sequential group), and of nine, five had pancytopenia, and six had renal impairment. In 88 patients receiving drugs concurrently, longer overlapping therapy increased relative risk of death 2.16-fold, presence of renal impairment increased risk 9.1-fold, and development of pancytopenia increased risk 23.4-fold (See reference number 4).

Two further cases of fatal agranulocytosis,presumed to result from use of colchicine with clarithromycin, have been reported,(See reference number 5)and 2 other cases describe colchicine toxicity during clarithromycin use in patients with renal impairment (See reference number 6).

Erythromycin and clarithromycin may inhibit hepatic metabolism of colchicine via cytochrome P450 isoenzyme CYP3A4, and/or might increase its bioavailability via effects on P-glycoprotein (See reference number 2,4). These effects would be more marked in patients with renal impairment.

Information on this interaction is limited, but it appears that macrolide antibacterials can provoke acute colchicine toxicity, at very least in predisposed individuals. If any patient is given colchicine and a macrolide (except probably azithromycin, which is not a notable CYP3A4 inhibitor), be aware of potential for toxicity, especially in patients with pre-existing renal impairment.

Caraco Y,Putterman C, Rahamimov R, Ben-Chetrit E. Acute colchicine intoxication – possiblerole of erythromycin administration. J Rheumatol (1992) 19, 494–6.

Rollot F,Pajot O, Chauvelot-Moachon L, Nazal EM, Kélaïdi C, Blanche P. Acute colchicineintoxication during clarithromycin administration. Ann Pharmacother (2004) 38, 2074–7.

Dogukan A,Oymak FS, Taskapan H, Güven M, Tokgoz B, Utas C. Acute fatal colchicine intoxication in a patient on continuous ambulatory peritoneal dialysis (CAPD). Possible role ofclarithromycin administration. Clin Nephrol (2001) 55, 181–2.

Hung IFN,Wu AKL, Cheng VCC, Tang BSF, To KW, Yeung CK, Woo PCY, Lau SKP, Cheung BMY, Yuen KY. Fatal interaction between clarithromycin and colchicine in patients withrenal insufficiency: a retrospective study. Clin Infect Dis (2005) 41, 291–300.

Cheng VCC,Ho PL, Yuen KY. Two probable cases of serious drug interaction between clarithromycin and colchicine. South Med J (2005) 98, 811–13.

Akdag I,Ersoy A, Kahvecioglu S, Gullulu M, Dilek K. Acute colchicine intoxication duringclarithromycin administration in patients with chronic renal failure. J Nephrol (2006) 19, 515–

17.