Pharmacy Blog – Dr Vibore

The azole antifungals are predicted to raise levels of ergot derivatives, which may lead to ergotism. Concurrent use is contraindicated. Methysergide is also contraindicated with cimetidine andNNRTIs such as delavirdine. Caution is also advised with other CYP3A4 inhibitors,including grapefruit juice and quinupristin/dalfopristin.

Clinical evidence,mechanism, importance and management

The ergot alkaloids are mainly metabolised by cytochrome P450 isoenzyme CYP3A4. The manufacturers of ergotamine dihydroergotamine and methysergide therefore logically predict that their levels will be raised by CYP3A4 inhibitors and advise against their concurrent use. They specifically contraindicate macrolides,, and protease inhibitors, , which are potent CYP3A4 inhibitors(See reference number 1-3) and which have been shown to interact with these ergot derivatives in a number of cases. They also contraindicate azole antifungals and NNRTIs (delavirdine, efavirenz).(See reference number 1,4) Although there appear to be no studies or case reports, given way other potent CYP3A4 inhibitors interact, this seems prudent. Note that, of azoles, ketoconazole, itraconazole are most potent CYP3A4 inhibitors, and would therefore be expected to interact to greatest extent. The US manufacturers of ergotamine and dihydroergotamine specifically contraindicate these azoles,but advise caution with fluconazole and clotrimazole, which are less potent CYP3A4 inhibitors.(See reference number 2,3)The manufacturers of ergotamine also advise caution with use of less potent CYP3A4 inhibitors including grapefruit juice,(See reference number 2)quinupristin/dalfopristin and cimetidine.(See reference number 1) The manufacturers of dihydroergotamine(See reference number 3) and methysergide(See reference number 4) give a similar list.

Given rarity of cases of an adverse effect with potent CYP3A4 inhibitors any clinically significant interaction with these drugs would be expected to be extremely rare indeed, but concurrent use should be well monitored so any adverse effect can be identified swiftly and appropriate treatment given.

Cafergot Suppositories (Ergotamine tartrate and caffeine). Alliance Pharmaceuticals. UK Summary of product characteristics,January 2007.

Cafergot Suppositories (Ergotamine tartrate and caffeine). Novartis. US Prescribing information,March 2003.

Migranal (Dihydroergotamine mesylate). Valeant Pharmaceuticals International. US Prescribing information,March 2006.

Deseril (Methysergide). Alliance Pharmaceuticals. UK Summary of product characteristics,December 2006.

The drugs dealt with in this section are ergot derivatives and triptans (or more properly serotonin 5-HT1 agonists), whose main use is in treatment of migraine. table 1 below, (below) lists some of drugs commonly used in migraine. Drugs such as propranolol, which are more commonly used in other conditions, are discussed elsewhere in publication.

The main problem with use of ergot derivatives is that of ergotism. Drug interactions may result in additive effects or cause raised levels of ergot derivatives, which may result in symptoms of ergot poisoning. This may include severe circulatory problems e.g. the extremities may become numb,cold to the touch, tingle, and muscle pain may result. In extreme cases there may be no palpable pulse. Ultimately gangrene may develop,and amputation may be required. Chest pain can also occur,and in some cases myocardial infarction has been reported. Since ergotamine and dihydroergotamine are metabolised in liver by CYP3A4, drugs which inhibit this isoenzyme, particularly potent inhibitors, such as protease inhibitors, , should generally be avoided due to risk of precipitating ergotism.

Although triptans would be expected to share a number of pharmacodynamic drug interactions, due to their differing metabolic pathways they will not all necessarily share same pharmacokinetic interactions. For example, sumatriptan, which is metabolised mainly by monoamine oxidase A, is unlikely to interact with macrolide antibacterials, which are inhibitors of cytochrome P450 isoenzyme CYP3A4. However,eletriptan, which is metabolised by CYP3A4 and possibly CYP2D6 could potentially interact (see Triptans + Macrolides interaction, for full details). Frovatriptan and zolmitriptan are substrates for CYP1A2,and are affected by CYP1A2 inhibitors such as fluvoxamine, but zolmitriptan also inhibits CYP1A2 and may therefore be expected to have additional interactions. The picture with zolmitriptan becomes more complicated since it is also metabolised by monoamine oxidase A. Naratriptan appears unlikely to undergo significant pharmacokinetic interactions since half dose is excreted unchanged and rest metabolised by a variety of isoenzymes. A summary of metabolic pathways of triptans can be found in table 2 below,(below).

Early in development of triptans it was theorised that they might possibly add to increased levels of serotonin caused by other serotonergic drugs, leading to excess serotonergic activity and increasing risk of the serotonin syndrome, . Therefore sumatriptan was contraindicated in patients taking SSRIs,MAOIs, and lithium, but note, there is little evidence that this occurs in practice. However,there is also a pharmacokinetic interaction between some triptans and MAOIs, see or SSRIs, .

Flunarizine,Pizotifen

Atenolol,Metoprolol, Nadolol, Propranolol, Timolol

Codergocrine,Ergotamine, Dihydroergotamine, Methysergide

Almotriptan,Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan

2 Interactions between drug metabolising enzymes and triptans†

†Other isoenzymes have been implicated, but not at clinically relevant concentrations of triptans

Table 1 Antimigraine drugs
Group	Drugs
Antihistamines	Flunarizine, Pizotifen
Beta blockers	Atenolol, Metoprolol, Nadolol, Propranolol, Timolol
Ergot derivatives	Codergocrine, Ergotamine, Dihydroergotamine, Methysergide
Triptans (Serotonin (5-HT1) agonists)	Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan

Table 2 Interactions between drug metabolising enzymes and the triptans†
	MAO-A	CYP1A2	CYP2C9	CYP2C19	CYP2D6	CYP3A4
Almotriptan	Substrate				Substrate	Substrate
Eletriptan						Substrate
Frovatriptan		Substrate			Possible substrate
Naratriptan		Substrate (minor)	Substrate (minor)	Substrate (minor)	Substrate (minor)	Substrate (minor)
Rizatriptan	Substrate	Substrate (minor)
Sumatriptan	Substrate
Zolmitriptan	Substrate	Substrate				Substrate

Nelfinavir markedly increases terfenadine levels, which is expected to increase risk of QT prolongation and torsade de pointesarrhythmias. Other protease inhibitors are predicted to interactsimilarly with both terfenadine and astemizole,and concurrentuse is contraindicated. Ritonavir modestly increases cetirizinelevels,and in vitro data suggests that saquinavir will have a similar effect, but this is not considered to be clinically relevant. Basedon in vitro data,ritonavir is predicted to markedly raise fexofenadine levels, but this may not be of any clinical relevance.

Clinical evidence,mechanism, importance and management

Protease inhibitors are inhibitors of cytochrome P450 isoenzyme CYP3A4, by which astemizole is metabolised. On basis of interaction of astemizole with other CYP3A4 inhibitors, such as azoles, , concurrent use of astemizole with any protease inhibitor is contraindicated (See reference number 1). This seems a sensible precaution.

In a study in 16 healthy subjects concurrent use of cetirizine 10mg daily and ritonavir 600mg twice daily for 4 days (after reaching steady-state ritonavir levels), increased AUC of cetirizine by 42 % with a slight 9 % increase in maximum plasma levels. It was suggested that ritonavir may have decreased renal excretion of cetirizine. The increase in cetirizine levels was not considered to be clinically relevant. Ritonavir pharmacokinetics were minimally affected by cetirizine (See reference number 2).

An in vitro study showed that ritonavir markedly reduced transport of fexofenadine, thought to be via inhibition of P-glycoprotein (See reference number 3). This would be predicted to markedly increase bioavailability of fexofenadine, as occurs with verapamil, see Calcium-channel blockers + Antihistamines interaction,

. However, similar marked increases in fexofenadine levels that occurred with erythromycin, and ketoconazole, did not increase adverse effects and were not associated with any prolongation of QT interval. This suggests that a clinically relevant interaction between ritonavir and fexofenadine is not expected.

Nelfinavir 750mg every 8 hrs for 5 days raised levels of a single 60mg dose of terfenadine from less than 5 nanograms/mL to a range of 5 to 15 nanograms/mL. The pharmacokinetics of nelfinavir were unaffected.(See reference number 4) This rise in terfenadine levels is predicted to prolong QT interval, and to increase risk of torsade de pointes arrhythmias. In an in vitro study, saquinavir was a potent inhibitor of metabolism of terfenadine.(See reference number 5) Note that saquinavir is least potent CYP3A4 inhibitor of protease inhibitors. On basis of in vitro study, and what is known about interactions with other inhibitors of CYP3A4 such as azoles, , all protease inhibitors are predicted to raise terfenadine levels and consequently concurrent use is contraindicated.(See reference number 6) Because of seriousness of this reaction, and fact that it is not possible to predict which individuals will be affected, this seems a sensible precaution.

Hismanal (Astemizole). Janssen-Cilag Ltd. UK Summary of product characteristics,June1998.

Peytavin G,Gautran C, Otoul C, Cremieux AC, Moulaert B, Delatour F, Melac M, Strolin-Benedetti M, Farinotti R. Evaluation of pharmacokinetic interaction between cetirizine andritonavir, an HIV-1 protease inhibitor, in healthy male volunteers. Eur J Clin Pharmacol (2005) 61, 267–73.

Perloff MD,von Moltke LL, Greenblatt DJ. Fexofenadine transport in caco-2 cells: inhibitionwith verapamil and ritonavir. J Clin Pharmacol (2002) 42, 1269–74.

Kerr B,Yuep G, Daniels R, Quart B, Kravcik S, Sahai J, Anderson R. Strategic approach tonelfinavir mesylate (NFV) drug interactions involving CYP3A metabolism. 6(See reference number th) European Conference on Clinical Aspects and Treatment of HIV-infection, Hamburg, October 11–15(See reference number th) 1997. Abstracts.

Fitzsimmons ME,Collins JM. Selective biotransformation of the human immunodeficiency virus protease inhibitor saquinavir by human small-intestinal cytochrome P4503A4. Drug Metab Dispos (1997) 25, 256–6.

Histafen (Terfenadine). Approved Prescription Services Ltd. UK Summary of product characteristics,December 1999.

Rifampicin increases oral clearance of fexofenadine, but theclinical significance of this is unclear.

Clinical evidence,mechanism, importance and management

A single 60mg dose of fexofenadine was given to 24 healthy subjects 2 days before and on last day of a 6-day course of rifampicin 600mg daily. The oral clearance of fexofenadine was increased 1.3-to 5.3-fold,with no effect on renal clearance or half-life. This was thought to be due to effect of rifampicin on P-glycoprotein, which is involved in uptake of fexofenadine.(See reference number 1) The clinical significance of this interaction is unclear, but until more is known it would seem prudent to monitor efficacy of fexofenadine if it is given in combination with rifampicin.

1. Hamman MA,Bruce MA, Haehner-Daniels BD, Hall SD. The effect of rifampin administration on the disposition of fexofenadine. Clin Pharmacol Ther (2001) 69, 114–21.

A study in 6 healthy subjects found that oral aminophylline200 mg every 6 hrs for 3 doses did not affect pharmacokinetics of a single 400mg dose of sodium valproate

1. Kulkarni C,Vaz J, David J, Joseph T. Aminophylline alters pharmacokinetics of carbamazepine but not that of sodium valproate — a single dose pharmacokinetic study in humanvolunteers. Indian J Physiol Pharmacol (1995) 39, 122–6.

Antihistamines (histamine H1-antagonists) vary in their interaction profiles by sedative potential,route of metabolism, and cardiotoxicity (QT interval prolongation) .

The older antihistamines (e.g. chlorphenamine,diphenhydramine and hydroxyzine) are also referred to as sedating antihistamines or first-generation antihistamines. As former name suggests they have potential to cause additive sedative effects with other sedating drugs. This type of interaction is discussed elsewhere,see CNS depressants + CNS depressants interaction. The sedating antihistamines also tend to have antimuscarinic (also called anticholinergic) adverse effects and so therefore may interact additively with other antimuscarinic-type drugs. This is also discussed elsewhere,see Antimuscarinics + Antimuscarinics interaction.

The newer (non-sedating antihistamines or second-generation antihistamines) have a low potential to cause sedative effects. This appears to be because they are substrates for P-glycoprotein, an efflux transporter found in many organs, which would have effect of actively ejecting any drug molecules that crossed blood-brain barrier. Nevertheless, sedation may occur on rare occasions and patients should be advised to be alert to possibility of drowsiness if they have not taken drug before. Any drowsiness is likely to become apparent after first few doses, and would indicate that additive sedative effects with other sedating drugs might be expected. The antihistamines are listed,by sedative potential, in table 1 below,(below).

Some of sedating antihistamines, such as diphenhydramine, are inhibitors of cytochrome P450 isoenzyme CYP2D6. None of non-sedating antihistamines are known to inhibit cytochrome P450 isoenzymes, but some are substrates for CYP3A4 including astemizole, desloratadine, ebastine, loratadine, mizolastine, and terfenadine, see table 2 below,. This has important consequences for potential cardiotoxicity of astemizole and terfenadine, see (c) below. Loratadine and desloratadine are also substrates for CYP2D6,and mizolastine is also metabolised by glucuronidation. Cetirizine,levocetirizine and fexofenadine are minimally metabolised. Where pharmacokinetic interactions occur with fexofenadine,these appear to be mediated via drug transporters such as P-glycoprotein and/or organic anion transport polypeptide (OATP). For more information see Drug transporter proteins,.

Important drug interactions occur with non-sedating antihistamines astemizole and terfenadine

mines can block potassium channels, lengthening QT interval and increasing risk of potentially fatal cardiac arrhythmias (torsade de pointes). Therefore, dangerous interactions may result when other drugs reduce metabolism of astemizole or terfenadine, usually by inhibition of cytochrome P450 isoenzyme CYP3A4. Such drugs include macrolides’, and azoles, . Adverse interactions are also predicted when astemizole or terfenadine are used with drugs that prolong QT interval, see Antihistamines + Drugs that prolong QT interval. Due to these potentially fatal interactions, astemizole has been withdrawn from many countries, while terfenadine has been withdrawn in US and reclassified as a prescription-only medicine in UK. Apart from possibly ebastine, loratadine and mizolastine, where information is inconclusive, none of other non-sedating antihistamines have been clearly shown to be associated with QT prolongation (see ‘table 2 below,). Therefore,even when pharmacokinetic interactions result in increased levels, these are unlikely to be clinically important in terms of cardiotoxicity.

Acrivastine,Astemizole,* Cetirizine, Desloratadine, Ebastine,* Fexofenadine, Levocetirizine, Loratadine, Mizolastine,* Rupatadine, Terfenadine*

Azatadine,Brompheniramine, Buclizine, Chlorphenamine, Cinnarizine, Clemastine, Cyclizine, Cyproheptadine, Dexchlorpheniramine, Flunarizine, Meclozine, Mepyramine, Mequitazine, Pheniramine, Tripelennamine, Triprolidine

Alimemazine,Bromazine, Carbinoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine, Trimeprazine

Antazoline,Azelastine, Emedastine, Epinastine, Levocabastine, Olopatadine

(See reference number *)Important QT prolongation known to occur (astemizole,terfenadine), or may possibly occur (ebastine, mizolastine), see table 2 below,p. 583

Drug blocks HERG† potassium channel in vitro

Yes. See Azoles,p. 584

Yes. See Azoles,p. 584,or Macrolides, p. 589

Yes. See Azoles,p. 584,or Macrolides, p. 589

Yes,in one study10

Yes. See Azoles,p. 584,or Nefazodone, p. 592

Yes. See Azoles,p. 584,or Macrolides, p. 589

Yes. See Azoles,p. 584

Yes. See Azoles,p. 584,Macrolides, p. 589,or Nefazodone, p. 592

Yes. See Azoles,p. 584,or Macrolides, p. 589

Blocking HERG channels results in prolongation of QT interval

Zhou Z,Vorperian VR, Gong Q, Zhang S, January CT. Block of HERG potassium channels by antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol (1999) 10,836–43.

Craft TM. Torsade de pointes after astemizole overdose. BMJ (1986) 292,660.

Snook J,Boothman-Burrell D, Watkins J, Colin-Jones D. Torsade de pointes ventricular tachycardia associated with astemizole overdose. Br J Clin Pract (1988) 42,257–9.

Simons FER,Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-induced torsade de pointes. Lancet (1988) ii,624.

Bishop RO,Gaudry PL. Prolonged Q-T interval following astemizole overdose. Arch Emerg Med (1989) 6,63–5.

Hasan RA,Zureikat GY, Nolan BM. Torsade de pointes associated with astemizole overdose treated with magnesium sulfate. Pediatr Emerg Care (1993) 9,23–5.

Gowardman J. QT prolongation on standard dose of astemizole. N Z Med J (1996) 109,38.

Vorperian VR,Zhou Z, Mohammad S, Hoon TJ, Studenik C, January CT. Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole. J Am Coll Cardiol (1996) 28,1556–61.

Ko CM,Ducic I, Fan J, Shuba YM, Morad M. Suppression of mammalian K+ channel family by ebastine. J Pharmacol Exp Ther (1997) 281,233–44.

Crumb WJ. Loratadine blockade of K+ channels in human heart: comparison with terfenadine under physiological conditions. J Pharmacol Exp Ther (2000) 292,261–4.

Kuchar DL,Walker BD, Thorburn CW. Ventricular tachycardia following ingestion of a commonly used antihistamine,Med J Aust (2002) 176, 429–30.

Sager PT,Veltri EP. Ventricular tachycardia following ingestion of a commonly used antihistamine. Med J Aust (2003) 178,245–6.

Kuchar DL,Walker BD, Thorburn CW. In reply. Med J Aust (2003) 178,246.

Taglialatela M,Pannaccione A, Castaldo P, Giorgio G, Annunziato L. Inhibition of HERG1 K(+) channels by novel second-generation antihistamine mizolastine. Br J Pharmacol (2000) 131,1081–8.

Woosley RL,Chen Y, Freiman JP, Gillis RA. Mechanism of cardiotoxic actions of terfenadine. JAMA (1993) 269,1532–6.

MacConnell TJ,Stanners AJ. Torsades de pointes complicating treatment with terfenadine. Br Med J (1991) 302,1469.

June RA,Nasr I. Torsades de pointes with terfenadine ingestion. Am J Emerg Med (1997) 15,542–3.

Renard S,Ostorero M, Yvorra S, Zerrouk Z, Bargas E, Bertocchio P, Pracchia S, Ebagosti A. Torsades de pointes caused by cetirizine overdose. Arch Mal Coeur Vaiss (2005) 98; 157–61.

Pinto YM,van Gelder IC, Heeringa M, Crijns HJ. QT lengthening and life-threatening arrhythmias associated with fexofenadine. Lancet (1999),353, 980.

Scherer CR,Lerche C, Decher N, Dennis AT, Maier P, Ficker E, Busch AE, Wollnik B, Steinmeyer K. The antihistamine fexofenadine does not affect Ikr currents in a case report of drug-induced cardiac arrhythmia. Br J Pharmacol (2002) 137,892–900.

Table 1 Systemic antihistamines (classified by sedative potential) and topical antihistamines
Sedative potential	Antihistamine
Non-sedative	Acrivastine, Astemizole,* Cetirizine, Desloratadine, Ebastine,* Fexofenadine, Levocetirizine, Loratadine, Mizolastine,* Rupatadine, Terfenadine*
Sedating	Azatadine, Brompheniramine, Buclizine, Chlorphenamine, Cinnarizine, Clemastine, Cyclizine, Cyproheptadine, Dexchlorpheniramine, Flunarizine, Meclozine, Mepyramine, Mequitazine, Pheniramine, Tripelennamine, Triprolidine
Significantly sedating	Alimemazine, Bromazine, Carbinoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine, Trimeprazine
Topical use (mainly)	Antazoline, Azelastine, Emedastine, Epinastine, Levocabastine, Olopatadine

Table 2 Metabolism and cardiac effects o		f non-sedating antihistamines
Drug	Drug blocks the HERG† potassium channel in vitro	QTc interval prolongation shown in pharmacological studies with drug alone	QTc interval prolongation shown in pharmacological studies with CYP3A4 inhibitors	Case reports of torsade de pointes with drug alone	Case reports of torsade de pointes with CYP3A4 inhibitors
Metabolised by CYP3A4
Astemizole	Yes1	Yes2	Yes. See Azoles, p. 584	Several2-8	Yes. See Azoles, p. 584, or Macrolides, p. 589
Desloratadine	No	No	No	No	No
Ebastine	Yes9	Uncertain	Yes. See Azoles, p. 584, or Macrolides, p. 589	No	No
Loratadine	Yes, in one study10	No	Yes. See Azoles, p. 584, or Nefazodone, p. 592	Possible case11-13	Yes. See Azoles, p. 584, or Macrolides, p. 589
Mizolastine	Yes14	Uncertain	Yes. See Azoles, p. 584	No	No
Terfenadine	Yes10,15	Yes	Yes. See Azoles, p. 584, Macrolides, p. 589, or Nefazodone, p. 592	A few16,17	Yes. See Azoles, p. 584, or Macrolides, p. 589
Not metabolised by CYP3A4
Cetirizine	No	No	No	Possible case18	No
Fexofenadine	No	No	No	Possible case19,20	No
Levocetirizine	No	No	No	No	No

Table 3 Metabolism and cardiac effects o		f non-sedating antihistamines
Drug	Drug blocks the HERG† potassium channel in vitro	QTc interval prolongation shown in pharmacological studies with drug alone	QTc interval prolongation shown in pharmacological studies with CYP3A4 inhibitors	Case reports of torsade de pointes with drug alone	Case reports of torsade de pointes with CYP3A4 inhibitors
Metabolised by CYP3A4
Astemizole	Yes1	Yes2	Yes. See Azoles, p. 584	Several2-8	Yes. See Azoles, p. 584, or Macrolides, p. 589
Desloratadine	No	No	No	No	No
Ebastine	Yes9	Uncertain	Yes. See Azoles, p. 584, or Macrolides, p. 589	No	No
Loratadine	Yes, in one study10	No	Yes. See Azoles, p. 584, or Nefazodone, p. 592	Possible case11-13	Yes. See Azoles, p. 584, or Macrolides, p. 589
Mizolastine	Yes14	Uncertain	Yes. See Azoles, p. 584	No	No
Terfenadine	Yes10,15	Yes	Yes. See Azoles, p. 584, Macrolides, p. 589, or Nefazodone, p. 592	A few16,17	Yes. See Azoles, p. 584, or Macrolides, p. 589
Not metabolised by CYP3A4
Cetirizine	No	No	No	Possible case18	No
Fexofenadine	No	No	No	Possible case19,20	No
Levocetirizine	No	No	No	No	No

Table 4 Metabolism and cardiac effects o		f non-sedating antihistamines
Drug	Drug blocks the HERG† potassium channel in vitro	QTc interval prolongation shown in pharmacological studies with drug alone	QTc interval prolongation shown in pharmacological studies with CYP3A4 inhibitors	Case reports of torsade de pointes with drug alone	Case reports of torsade de pointes with CYP3A4 inhibitors
Metabolised by CYP3A4
Astemizole	Yes1	Yes2	Yes. See Azoles, p. 584	Several2-8	Yes. See Azoles, p. 584, or Macrolides, p. 589
Desloratadine	No	No	No	No	No
Ebastine	Yes9	Uncertain	Yes. See Azoles, p. 584, or Macrolides, p. 589	No	No
Loratadine	Yes, in one study10	No	Yes. See Azoles, p. 584, or Nefazodone, p. 592	Possible case11-13	Yes. See Azoles, p. 584, or Macrolides, p. 589
Mizolastine	Yes14	Uncertain	Yes. See Azoles, p. 584	No	No
Terfenadine	Yes10,15	Yes	Yes. See Azoles, p. 584, Macrolides, p. 589, or Nefazodone, p. 592	A few16,17	Yes. See Azoles, p. 584, or Macrolides, p. 589
Not metabolised by CYP3A4
Cetirizine	No	No	No	Possible case18	No
Fexofenadine	No	No	No	Possible case19,20	No
Levocetirizine	No	No	No	No	No