Pharmacy Blog – Dr Vibore

Etoposide clearance appears to be increased by phenobarbital,phenytoin,and probably carbamazepine, and this may result inreduced efficacy.

Clinical evidence,mechanism, importance and management

The clearance of etoposide was found to be highly variable in children given etoposide 320 to 500 mg/m(See reference number 2) over 6 hrs on alternate days for a total of 3 doses. However,it was 77 % higher in 7 children taking antiepileptics (phenobarbital, phenytoin or both) than in 22 others not taking antiepileptics (See reference number 1). In a retrospective survey,long-term antiepileptic use (phenytoin, phenobarbital, carbamazepine, or a combination) was associated with worse event-free survival, and greater haematological and/or CNS relapse in children receiving chemotherapy for B-lineage acute lymphoblastic leukaemia. The authors considered that increased clearance of etoposide induced by antiepileptics was a likely factor in these findings (See reference number 2). Be alert for possible need to give larger doses of etoposide if these antiepileptics are used. More study is needed.

Rodman JH,Murry DJ, Madden T, Santana VM. Altered etoposide pharmacokinetics and timeto engraftment in pediatric patients undergoing autologous bone marrow transplantation. J Clin Oncol (1994) 12, 2390–7.

Relling MV,Pui C-H, Sandlund JT, Rivera GK, Hancock ML, Boyett JM, Schuetz EG, EvansWE. Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblasticleukaemia. Lancet (2000) 356, 285–90.

A patient with dendritic cell carcinoma who had been taking amiodarone for 18 months, and who had received 6 cycles of chemotherapy including cyclophosphamide over previous 12 months, was admitted to hospital with progressive shortness of breath 18 days after being given a single 4000-mg/m(See reference number 2) dose of cyclophosphamide. He was found to have interstitial pneumonitis and a lung biopsy indicated drug-induced pulmonary toxicity. The patient’s condition improved rapidly over following 10 days with discontinuation of amiodarone and treatment with prednisolone 60mg daily. Over previous year he had also received vincristine, etoposide and prednisone, cisplatin, cytarabine and dexamethasone as part of his chemotherapy.(See reference number 1) A patient with non-Hodgkin’s lymphoma who had been taking amiodarone 300mg twice daily for 4 years,developed acute respiratory distress 2 days after being given a single dose of cyclophosphamide. This was eventually fatal. Autopsy revealed lung damage consistent with effects of amiodarone and cyclophosphamide, with cyclophosphamide major cause. Other drugs used as part of chemotherapy regimen were rituximab, doxorubicin, vincristine and prednisone (See reference number 2).

The early onset of symptoms in patients described above suggests accelerated mechanisms of pulmonary toxicity. Both cyclophosphamide and amiodarone pulmonary toxicity appear to be enhanced by oxygen and combination of cyclophosphamide with amiodarone may enhance oxidative stress and therefore pulmonary toxicity

Although information seems to be limited to two case reports cited, potential for both cyclophosphamide and amiodarone to cause pulmonary toxicity is established. Be alert to possibility of enhanced pulmonary toxicity if these drugs are given together.

Bhagat R,Sporn TA, Long GD, Folz RJ. Amiodarone and cyclophosphamide: potential for enhanced lung toxicity. Bone Marrow Transplant (2001) 27, 1109–1111.

Gupta S,Mahipal A. Fatal pulmonary toxicity after a single dose of cyclophosphamide. Pharmacotherapy (2007) 27, 616–18.

Martin WJ,Rosenow EC. Amiodarone pulmonary toxicity. Recognition and pathogenesis(Part 1). Chest (1988) 93, 1067–75.

Martin WJ,Rosenow EC. Amiodarone pulmonary toxicity. Recognition and pathogenesis(Part 2). Chest (1988) 93, 1242–8.

There is some evidence to suggest that incidence of seriousbone marrow depression caused by cyclophosphamide can beincreased by allopurinol, but this was not confirmed in a controlled study. Allopurinol may prolong half-life of cyclophosphamide and increase levels of its cytotoxic metabolites.

A retrospective epidemiological survey of patients in four hospitals who, over a 4-year period, had been treated with cyclophosphamide, found that incidence of serious bone marrow depression was 57.7 % in 26 patients who had also received allopurinol,and 18.8 % in 32 patients who had not (See reference number 1). A pharmacokinetic study in 9 patients with malignant disease and 2 healthy subjects showed that while taking allopurinol 600mg daily concentration of cytotoxic metabolites of cyclophosphamide increased by an average of 37.5 % (range 1.5 to 110%) (See reference number 2). Another pharmacokinetic study reported that half-life of cyclophosphamide was more than twofold longer in 3 children also receiving allopurinol 300 mg/m(See reference number 2), when compared with that in children not given allopurinol (See reference number 3). However, another study found that although allopurinol pre-treatment increased half-life of cyclophosphamide, plasma alkylating activity and urinary metabolite and cyclophosphamide excretion were unchanged (See reference number 4). Moreover, a randomised controlled study,(See reference number 5) designed as a follow-up to survey cited above,(See reference number 1) failed to confirm that allopurinol increased toxicity of cyclophosphamide in 81 patients with Hodgkin’s or non-Hodgkin’s lymphoma. In this study,there was no difference in nadirs for white blood cells and platelets during 3 cycles of cyclophosphamide-containing chemotherapy in 44 patients receiving allopurinol and in 37 patients not receiving allopurinol.

Not understood. Cyclophosphamide itself is inactive, but it is converted by liver into cytotoxic metabolites (See reference number 4). Allopurinol or its metabolite oxypurinol may inhibit their renal excretion,or may alter hepatic metabolism (See reference number 2,3).

This interaction is not established with any certainty. The authors of randomised study consider that, if necessary, allopurinol can be used safely to prevent hyperuricaemia with chemotherapy regimens used for lymphomas (See reference number 5). However, other data introduce a note of caution. Be alert for increased cyclophosphamide toxicity if allopurinol is given.

Boston Collaborative Drug Surveillance Programme. Allopurinol and cytotoxic drugs. Interaction in relation to bone marrow depression. JAMA (1974) 227,1036–40.

Witten J,Frederiksen PL, Mouridsen HT. The pharmacokinetics of cyclophosphamide in manafter treatment with allopurinol. Acta Pharmacol Toxicol (Copenh) (1980) 46, 392–4.

Yule SM,Boddy AV, Cole M, Price L, Wyllie R, Tasso MJ, Pearson ADJ, Idle JR. Cyclophosphamide pharmacokinetics in children. Br J Clin Pharmacol (1996) 41, 13–19.

Bagley CM,Bostick FW, DeVita VT. Clinical pharmacology of cyclophosphamide. Cancer Res (1973) 33, 226–33.

Stolbach L,Begg C, Bennett JM, Silverstein M, Falkson G, Harris DT, Glick J. Evaluation ofbone marrow toxic reaction in patients treated with allopurinol. JAMA (1982) 247, 334–6.

Cisplatin can increase pulmonary toxicity of bleomycin by reducing its renal excretion

Thirty patients with carcinoma of cervix and 15 patients with germ cell tumours were given combination chemotherapy including bleomycin and cisplatin. Cisplatin was given by infusion on day 1,followed by bleomycin given intramuscularly every 12 hrs for 4 days or by continuous infusion over 72 hours. Nine of patients with normal renal function and no previous pulmonary disease developed serious pulmonary toxicity and 6 died from respiratory failure (See reference number 1).

In a study of 18 patients given cisplatin and bleomycin for treatment of disseminated testicular non-seminoma, 2 patients developed pneumonitis, and it was found that cisplatin-induced reduction in renal function was paralleled by an increase in bleomycin-induced pulmonary toxicity (See reference number 2). Similar results were found in a much larger study of 54 patients by same group (See reference number 3). A study in 2 children showed that total plasma clearance of bleomycin was halved (from 39 to 18 mL/minute/m(See reference number 2)) when they were also given cisplatin in cumulative doses exceeding 300 mg/m(See reference number 2). The renal clearance in one of children fell from 30 to 8.2 mL/minute/m(See reference number 2) although there was no evidence of severe bleomycin toxicity in either child (See reference number 4). Two cases of fatal bleomycin toxicity have been described in patients with cisplatin-induced renal impairment (See reference number 5,6).

A case report describes arterial thrombosis associated with pathological vascular changes in arteries of a man treated with cisplatin, bleomycin and etoposide (See reference number 7). Another man developed fatal thrombotic microangiopathy (characterised by microangiopathic haemolytic anaemia, thrombocytopenia, renal impairment), which was attributed to use of bleomycin and cisplatin (See reference number 8).

In an earlier study,digital ischaemia occurred in 41 % of patients treated with cisplatin, bleomycin and vinblastine compared with 21 % of patients treated with only cisplatin and vinblastine (See reference number 9).

Renal excretion accounts for almost half of total body clearance of bleomycin. Cisplatin is nephrotoxic and reduces glomerular filtration rate so that clearance of bleomycin is reduced. The accumulating bleomycin apparently causes pulmonary toxicity

Pulmonary toxicity with bleomycin is an established reaction with a potentially serious,sometimes fatal, outcome. Concurrent use should be very closely monitored and renal function checked. One of problems is that levels of creatinine may not accurately indicate extent of renal damage both during and after cisplatin treatment. The renal toxicity of cisplatin may also develop rapidly. Other toxic effects on vascular system can also occur.

Rabinowits M,Souhami L, Gil RA, Andrade CAV, Paiva HC. Increased pulmonary toxicitywith bleomycin and cisplatin chemotherapy combinations. Am J Clin Oncol (1990) 13, 132–8.

van Barneveld PWC,Sleijfer D Th, van der Mark Th W, Mulder NH, Donker AJM, Meijer S,Schraffordt Koops H, Sluiter HJ, Peset R. Influence of platinum-induced renal toxicity on bleomycin-induced pulmonary toxicity in patients with disseminated testicular carcinoma. Oncology (1984) 41, 4–7.

Sleijfer S,van der Mark TW, Schraffordt Koops H, Mulder NH. Enhanced effects of bleomycin on pulmonary function disturbances in patients with decreased renal function due to cisplatin. Eur J Cancer (1996) 32A, 550–2.

Yee GC,Crom WR, Champion JE, Brodeur GM, Evans WE. Cisplatin-induced changes in bleomycin elimination. Cancer Treat Rep (1983) 67, 587–9.

Bennett WM,Pastore L, Houghton DC. Fatal pulmonary bleomycin toxicity in cisplatin-induced acute renal failure. Cancer Treat Rep (1980) 64, 921–4.

Perry DJ,Weiss RB, Taylor HG. Enhanced bleomycin toxicity during acute renal failure. Cancer Treat Rep (1982) 66, 592–3.

Garstin IWH,Cooper GG, Hood JM. Arterial thrombosis after treatment with bleomycin andcisplatin. BMJ (1990) 300, 1018.

Fields SM,Lindley CM. Thrombotic microangiopathy associated with chemotherapy: case report and review of the literature. DICP Ann Pharmacother (1989) 23, 582–8.

Vogelzang NJ,Bosl GJ, Johnson K, Kennedy BJ. Raynaud’s phenomenon : a common toxicityafter combination chemotherapy for testicular cancer. Ann Intern Med (1981) 95, 288–92.

Five patients treated with bleomycin,exposed to oxygen concentrations of 35 to 42 % during and immediately following anaesthesia, developed a severe respiratory distress syndrome and died. Bleomycin-induced pneumonitis and lung fibrosis were diagnosed at post-mortem. Another group of 12 matched patients who underwent same procedures but with lower oxygen concentrations (22 to 25%) had an uneventful postoperative course (See reference number 1).

Another comparative study(See reference number 2) similarly demonstrated that adult respiratory distress syndrome (ARDS) in patients receiving bleomycin was reduced by a technique allowing use of lower oxygen concentrations of 22 to 30%. Bleomycin-induced pulmonary toxicity,apparently related to oxygen concentrations, has also been described in other case reports (See reference number 3-7). Studies in animals have also confirmed that severity of bleomycin-induced pulmonary toxicity is increased by oxygen (See reference number 8-10). However, in two other series of patients treated with bleomycin and undergoing surgery there was no obvious increase in pulmonary complications despite use of usual concentrations of oxygen (See reference number 11,12).

Not understood. One suggestion is that bleomycin-injured lung tissue is less able to scavenge free oxygen radicals,which may be present, and damage occurs as a result (See reference number 3).

An established,well-documented, serious and potentially fatal interaction. It is advised that any patient receiving bleomycin and undergoing general anaesthesia should have their inspired oxygen concentrations limited to less than 30%, and fluid replacement should be carefully monitored to minimise crystalloid load. This is clearly very effective because one author has treated 700 patients following these guidelines without a single case of pulmonary failure (See reference number 13). It has also been suggested that reduced oxygen levels should be continued during recovery period and at any time during hospitalisation (See reference number 3). If an oxygen concentration equal to or greater than 30 % has to be used, short-term use of prophylactic corticosteroids should be considered. Intravenous corticosteroids should be given at once if bleomycin toxicity is suspected (See reference number 3).

Goldiner PL,Carlon GC, Cvitkovic E, Schweizer O, Howland WS. Factors influencing postoperative morbidity and mortality in patients treated with bleomycin. BMJ (1978) 1, 1664–7.

El-Baz N,Ivankovich AD, Faber LP, Logas WG. The incidence of bleomycin lung toxicityafter anesthesia for pulmonary resection: a comparison between HFV and IPPV. Anesthesiology (1984) 61, A107.

Gilson AJ,Sahn SA. Reactivation of bleomycin lung toxicity following oxygen administration. A second response to corticosteroids. Chest (1985) 88, 304–6.

Cersosimo RJ,Matthews SJ, Hong WK. Bleomycin pneumonitis potentiated by oxygen administration. Drug Intell Clin Pharm (1985) 19, 921–3.

Hulbert JC,Grossman JE, Cummings KB. Risk factors of anesthesia and surgery in bleomycin-treated patients. J Urol (Baltimore) (1983) 130, 163–4.

Donohue JP,Rowland RG. Complications of retroperitoneal lymph node dissection. J Urol (Baltimore) (1981) 125, 338–40.

Ingrassia TS,Ryu JH, Trastek VF, Rosenow EC. Oxygen-exacerbated bleomycin pulmonarytoxicity. Mayo Clin Proc (1991) 66, 173–8.

Toledo CH,Ross WE, Hood I, Block ER. Potentiation of bleomycin toxicity by oxygen. Cancer Treat Rep (1982) 66, 359–62.

Berend N. The effect of bleomycin and oxygen on rat lung. Pathology (1984) 16,136–9.

Rinaldo J,Goldstein RH, Snider GL. Modification of oxygen toxicity after lung injury by bleomycin in hamsters. Am Rev Respir Dis (1982) 126, 1030–3.

Douglas MJ,Coppin CML. Bleomycin and subsequent anesthesia: a retrospective study atVancouver General Hospital. Can Anaesth Soc J (1980) 27, 449–52.

Mandelbaum I,Williams SD, Einhorn LH. Aggressive surgical management of testicular carcinoma metastatic to lungs and mediastinum. Ann Thorac Surg (1980) 30, 224–9.

Goldiner PL. Editorial comment. J Urol (Baltimore) (1983) 130,164.

Pyridoxine reduced neurotoxicity associated with altretamine, but also reduced its effectiveness.

Clinical evidence,mechanism, importance and management

In a large randomised study in women with advanced ovarian cancer neurotoxicity associated with altretamine and cisplatin chemotherapy was reduced by pyridoxine, but response duration was also reduced (See reference number 1). In this study,cisplatin was given on day 1 (37.5 or 75 mg/m(See reference number 2)) and altretamine 200 mg/m(See reference number 2) daily was given on days 8 to 21, and half patients also received pyridoxine 100mg three times daily on days 1 to 21. It is unclear how pyridoxine reduced activity of this regimen, but use of pyridoxine (vitamin B6) should probably be avoided in patients receiving altretamine.

1. Wiernik PH,Yeap B, Vogel SE, Kaplan BH, Comis RL, Falkson G, Davis TE, Fazzini E,Cheuvart B, Horton J. Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group. Cancer Invest (1992) 10, 1–9.

The antineoplastic drugs (also called cytotoxics or sometimes cytostatics) are used in treatment of malignant disease alone or in conjunction with radiotherapy, surgery or immunosuppressants. They also find application in treatment of a number of autoimmune disorders such as rheumatoid arthritis and psoriasis, and a few are used with other immunosuppressant drugs (ciclosporin, corticosteroids) to prevent transplant rejection. These other drugs are dealt with under section on immunosuppressants, .

Of all drugs discussed in this publication, antineoplastic drugs are amongst most toxic and have a low therapeutic index. This means that quite small increases in their levels can lead to development of serious and life-threatening toxicity. A list of antineoplastic drugs that are featured in this section appears in table 1 below,(below), grouped by their primary mechanism of action. This table also includes a number of hormone antagonists that are used in treatment of cancer.

Unlike most of other interaction monographs in this publication, some of information on antineoplastic drugs is derived from animal experiments and in vitro studies, so that confirmation of their clinical relevance is still needed. The reason for including these data is that anti-neoplastic drugs as a group do not lend themselves readily to kind of clinical studies that can be undertaken with many other drugs, and there would seem to be justification in this instance for including indirect evidence of this kind. The aim is not to make definite predictions, but to warn users of interaction possibilities.

1 Antineoplastics used in treatment of cancer

Alkylating agents,and drugs that appear to have an alkylating action

Carmustine,Lomustine, Streptozocin

Carboplatin,Cisplatin, Oxaliplatin

Altretamine,Busulfan, Chlorambucil, Chlormethine (Mechlorethamine), Cyclophosphamide, Dacarbazine, Estramustine, Ifosfamide, Melphalan, Temozolomide, Thiotepa

Methotrexate,Pemetrexed, Raltitrexed

Etoposide,Teniposide

Azathioprine,Cladribine, Fludarabine, Mercaptopurine, Tioguanine

Capecitabine,Carmofur, Cytarabine, Fluorouracil, Gemcitabine, Tegafur

Vinblastine,Vincristine, Vindesine, Vinorelbine

Docetaxel,Paclitaxel

Irinotecan,Topotecan, 9-Aminocamptothecin

Aclarubicin,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone

Bleomycin,Dactinomycin, Mitomycin, Plicamycin

Bicalutamide,Flutamide, Nilutamide

Fulvestrant,Tamoxifen, Toremifene

Aminoglutethimide,Anastrozole, Exemestane, Formestane, Letrozole

Amsacrine,Asparaginase (Colaspase, Crisantaspase, Pegaspargase), Bexarotene, Erlotinib, Hydroxycarbamide, Imatinib, Mitotane, Pentostatin, Procarbazine, Sorafenib, Thalidomide, Trastuzumab, Tretinoin

Table 1 Antineoplastics used in the treatment of cancer
Action	Drugs
Alkylating agents, and drugs that appear to have an alkylating action
Nitrosoureas	Carmustine, Lomustine, Streptozocin
Platinum derivatives	Carboplatin, Cisplatin, Oxaliplatin
Others	Altretamine, Busulfan, Chlorambucil, Chlormethine (Mechlorethamine), Cyclophosphamide, Dacarbazine, Estramustine, Ifosfamide, Melphalan, Temozolomide, Thiotepa
Antimetabolites
Folate antagonists	Methotrexate, Pemetrexed, Raltitrexed
Podophylotoxin derivatives	Etoposide, Teniposide
Purine analogues	Azathioprine, Cladribine, Fludarabine, Mercaptopurine, Tioguanine
Pyridmidine analogues	Capecitabine, Carmofur, Cytarabine, Fluorouracil, Gemcitabine, Tegafur
Mitotic inhibitors
Vinca alkaloids	Vinblastine, Vincristine, Vindesine, Vinorelbine
Taxanes	Docetaxel, Paclitaxel
Topoisomerase inhibitors	Irinotecan, Topotecan, 9-Aminocamptothecin
Cytotoxic antibiotics
Anthracyclines	Aclarubicin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitoxantrone
Others	Bleomycin, Dactinomycin, Mitomycin, Plicamycin
Anti-androgens	Bicalutamide, Flutamide, Nilutamide
Anti-oestrogens
Oestrogen-receptor antagonists	Fulvestrant, Tamoxifen, Toremifene
Aromatase inhibitors	Aminoglutethimide, Anastrozole, Exemestane, Formestane, Letrozole
Miscellaneous	Amsacrine, Asparaginase (Colaspase, Crisantaspase, Pegaspargase), Bexarotene, Erlotinib, Hydroxycarbamide, Imatinib, Mitotane, Pentostatin, Procarbazine, Sorafenib, Thalidomide, Trastuzumab, Tretinoin

A woman who had previously taken ergotamine tartrate successfully and uneventfully for 16 years was given doxycycline and dihydroergotamine 30 drops three times a day. Five days later her hands and feet became cold and reddened,and she was diagnosed as having a mild form of ergotism.(See reference number 1)

Other cases of ergotism,some of them more severe, have been described in two patients taking ergotamine tartrate and doxycycline,(See reference number 2,3) and in 3 patients taking tetracycline-containing preparations (See reference number 2,4,5).

Unknown. One suggestion is that these antibacterials may inhibit activity of liver enzymes concerned with metabolism and clearance of ergotamine, thereby prolonging its stay in body and enhancing its activity (See reference number 1). One of patients had a history of alcoholism(See reference number 2) and two of them were in their eighties,(See reference number 5) so impaired liver function may have played a part.

Information is very limited indeed. The incidence and general importance of this interaction is uncertain, but it would clearly be prudent to be on alert for signs of ergotism in any patient given ergot derivatives and a tetracycline. However, note that one of manufacturers of ergotamine(See reference number 6) actually recommends that concurrent use of tetracycline should be avoided. Impairment of liver function may possibly be a contributory factor in this interaction.

Amblard P,Reymond JL, Franco A, Beani JC, Carpentier P, Lemonnier D, Bessard G. Ergotisme. Forme mineure par association dihydroergotamine-chlorhydrate de doxycycline, étudecapillaroscopique. Nouv Presse Med (1978) 7, 4148–9.

Dupuy JC,Lardy P, Seaulau P, Kervoelen P, Paulet J. Spasmes artériels systémiques. Tartrated’ergotamine. Arch Mal Coeur (1979) 72, 86–91.

Van Gestel R,Noirhomme Ph. Ergotism aigu par association de tartrate d’ergotamine et dedoxycycline. Louvain Med (1984) 103, 207–208.

L’Yvonnet M,Boillot A, Jacquet AM, Barale F, Grandmottet P, Zurlinden B, Gillet JY. A propos d’un cas exceptionnel d’intoxication aigue par un dérivé de l’ergot de seigle. Gynecologie (1974) 25, 541–3.

Sibertin-Blanc M. Les dangers de l’ergotisme a propos de deux observations. Arch Med Ouest (1977) 9,265–6.

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

Ketoconazole and fluconazole increase AUC of eletriptan byabout sixfold and twofold, respectively. Almotriptan is less affected,and ketoconazole only raises its AUC by about 60%. Itraconazole is predicted to interact in same way as ketoconazole.

In a randomised,open label, crossover study, 16 healthy subjects were given ketoconazole 400mg daily on days 1 to 3, with a single 12.5mg dose of almotriptan on day 2. Ketoconazole increased AUC and maximum plasma levels of almotriptan by 57 % and 61%, respectively. The renal clearance of almotriptan was also reduced by approximately 16 % (See reference number 1).

A pharmacokinetic study by manufacturers of eletriptan found that ketoconazole 400 mg increased maximum serum levels of eletriptan 2.7-fold, AUC 5.9-fold and prolonged its half-life from 4.8 to

8.3 hours. Fluconazole caused a lesser 1.4-fold increase in maximum serum levels of eletriptan, and a twofold increase in its AUC (See reference number 2).

Ketoconazole is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4, by which eletriptan is metabolised. Fluconazole is a less potent inhibitor of CYP3A4,and therefore has a more modest effect. Almotriptan is also metabolised by CYP3A4, but as this is not only route of metabolism, and therefore inhibition of CYP3A4 by ketoconazole has a less dramatic effect on its levels.

Although studies are limited these interactions are established. In study with almotriptan and ketoconazole adverse events were not significantly altered, and so no almotriptan dosage adjustment is considered necessary when using this combination (See reference number 1). Ketoconazole dramatically raises eletriptan levels, and therefore manufacturers advise that concurrent use should be avoided.

Itraconazole, which is also a potent inhibitor of CYP3A4, has been predicted to interact in same way as ketoconazole (See reference number 2-4). In addition, US manufacturers recommend that eletriptan should not be given within 72 hrs of itraconazole and ketoconazole (See reference number 2). Fluconazole is a less potent inhibitor of CYP3A4 and therefore may be used with caution. Other triptans would be expected to have little or no interaction with azoles as they are not predominantly metabolised by CYP3A4 (see table 1 below,).

Fleishaker JC,Herman BD, Carel BJ, Azie NE. Interaction between ketoconazole and almotriptan in healthy volunteers. J Clin Pharmacol (2003) 43, 423–7.

Relpax (Eletriptan hydrobromide). Pfizer Inc. US Prescribing information,April 2007.

Relpax (Eletriptan hydrobromide). Pfizer Ltd. UK Summary of product characteristics,March2006.

Axert (Almotriptan malate). Ortho-McNeil Pharmaceutical Inc. US Prescribing Information,May 2007.

Table 1 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

Moclobemide markedly inhibits metabolism of rizatriptan,and approximately doubles bioavailability of sumatriptan.The manufacturers contraindicate these triptans with moclobemide and non-selective MAOIs. Moclobemide modestly inhibited metabolism of zolmitriptan but had no clinically significant effect on almotriptan or frovatriptan. Selegiline does not interact with sumatriptan or zolmitriptan, andwould not be expected to interact with any of other triptans. Non-selective MAOIs (e.g. phenelzine) are not expected to interact with eletriptan,frovatriptan, or naratriptan. Nevertheless, themanufacturer of frovatriptan contraindicates concurrent useof MAOIs, based on a theoretical increased risk of serotonin syndrome.

Clinical evidence,mechanism, importance and management

In a study in 12 healthy subjects, moclobemide 150mg twice daily for 8 days increased AUC of a single 12.5mg dose of almotriptan given on day 8 by 37%, decreased its clearance by 27 % and increased half-life by 24%, which was not considered clinically significant (See reference number 1). These findings are consistent with fact that less than half of a dose of almotriptan is metabolised by monoamine oxidase A,(See reference number 2) and it would seem therefore that concurrent use need not be avoided. There appears to be no direct clinical information about use of non-selective MAOIs but it seems unlikely that a clinically relevant interaction will occur.

The manufacturer of eletriptan notes that it is not a substrate for monoamine oxidase,and therefore no interaction with MAOIs is expected (See reference number 3,4). Because of this,they have not undertaken a formal interaction study (See reference number 3).

The manufacturer of frovatriptan notes that it is not a substrate for,or an inhibitor of, monoamine oxidase (See reference number 5,6). Nevertheless,they say that a potential risk of serotonin syndrome or hypertension cannot be excluded when it is used with MAOIs, so concomitant use is not recommended(See reference number 5)(but see also Antimigraine drugs,). A study in 9 healthy subjects given a single 2.5mg oral dose of frovatriptan following pre-treatment with moclobemide 150mg twice daily for 7 days did not find any pharmacokinetic changes, or any changes in vital signs and ECGs of subjects. Therefore no adverse interaction would be expected with concurrent use (See reference number 7).

In a double blind,randomised, crossover study, 12 healthy subjects were given moclobemide 150mg or a placebo three times daily for 4 days, with a single 10mg dose of rizatriptan on day 4. The moclobemide increased AUCs of rizatriptan and its active (but minor) metabolite by 2.2- and 5.3-fold,respectively, and increased their maximum serum levels by 1.4- and 2.6-fold,respectively. MAO-A is principal enzyme concerned with metabolism of rizatriptan. Moclobemide inhibits this enzyme and therefore raises rizatriptan levels. Despite these rises, concurrent use of these drugs was well tolerated and any adverse effects were mild and similar to those seen when rizatriptan was given with placebo. However, because of magnitude of rises, authors recommend avoiding combination (See reference number 9). The manufacturers of rizatriptan contraindicate its use both during, and 2 weeks after stopping an MAOI, stated reasons being that similar or greater rises in serum levels may be expected with irreversible non-selective MAOIs than with moclobemide (See reference number 10,11). In addition, US manufacturers(See reference number 11) note that no interaction would be expected with selective inhibitors of MAO-A (namely selegiline and rasagiline).

Three groups of 14 subjects were given a placebo,moclobemide 150mg three times daily, or selegiline 5mg twice daily for 8 days, with subcutaneous sumatriptan 6mg on day 8. No statistically significant differences in pulse rates or in blood pressures were seen between any of groups following injection of sumatriptan. However, sumatriptan AUC of moclobemide-treated group was approximately doubled (129% increase), its clearance was reduced by 56 % and its half-life increased by 52%. The pharmacokinetic changes seen in selegiline group were not consistent. There were no differences in adverse events experienced by any of three groups (See reference number 12). An in vitro study of metabolism of sumatriptan confirms that it is MAO-A enzyme, not MAO-B, that is major enzyme involved in metabolism of sumatriptan (See reference number 13).

A comprehensive search of literature and reports from proprietary manufacturers, identified published reports of 31 patients taking sumatriptan and MAOIs concurrently, but no adverse events were reported,(See reference number 14) and a patient taking moclobemide 300mg three times daily had no adverse effects when given oral sumatriptan 100mg on six occasions (See reference number 15).

However, a patient who had taken an overdose of moclobemide, together with sumatriptan, sertraline, and citalopram developed serotonin syndrome (See reference number 16).

The interaction between moclobemide and sumatriptan appears to be established. The same interaction seems likely to occur with any RIMA or non-selective MAOI, but not with selective MAO-B inhibitors like selegiline. However, increased sumatriptan bioavailability appears not to be clinically important because, in study cited, those subjects taking moclobemide did not experience any more adverse effects than those taking selegiline or placebo. Despite this UK manufacturers of sumatriptan quite clearly say that concurrent use of sumatriptan and MAOIs is contraindicated both during and for 2 weeks after stopping an MAOI (See reference number 17).

In a series of three-period,crossover, randomised studies, 12 healthy subjects were given selegiline 10mg daily or moclobemide 150mg twice daily for 7 days, with a single 10mg oral dose of zolmitriptan on day 7 (See reference number 18). It was found that AUC of zolmitriptan was increased by 26 % by moclobemide. A threefold increase in AUC of active metabolite also occurred (See reference number 19). It is likely that moclobemide inhibited metabolism of zolmitriptan via monoamine oxidase A. Despite these increases, because of good tolerability profile of zolmitriptan, no dosage reductions are thought to be needed if given with moclobemide, but a maximum intake of 5mg in 24 hrs is recommended by UK manufacturers (See reference number 19). However, US manufacturers contraindicate use of zolmitriptan both during and for 2 weeks after use of RIMAs (See reference number 20).

Selegiline on other hand had no effect on pharmacokinetics of zolmitriptan or its metabolites, apart from a small (7%) reduction in its renal clearance (See reference number 18). This finding was expected,since selegiline is specific for monoamine oxidase B (but note that this specificity is lost at higher doses). No special precautions would therefore seem to be necessary if selegiline is given with sumatriptan.

Fleishaker JC,Ryan KK, Jansat JM, Carel BJ, Bell DJA, Burke MT, Azie NE. Effect ofMAO-A inhibition on the pharmacokinetics of almotriptan, an antimigraine agent in humans.Br J Clin Pharmacol (2001) 51, 437–41.

Almogran (Almotriptan hydrogen malate). Organon Laboratories Ltd. UK Summary of product characteristics,April 2007.

Relpax (Eletriptan hydrobromide). Pfizer Ltd. UK Summary of product characteristics,March 2006.

Relpax (Eletriptan hydrobromide). Pfizer Inc. US Prescribing information,April 2007.

Migard (Frovatriptan succinate monohydrate). A. Menarini Pharma UK SRL. UK Summaryof product characteristics,February 2005.

Frova (Frovatriptan succinate). Endo Pharmaceuticals Inc. US Prescribing information,March 2007.

Buchan P,Ward C, Freestone S. Lack of interaction between frovatriptan and monoamine oxidase inhibitor. Cephalalgia (1999) 19, 364.

Naramig (Naratriptan hydrochloride). GlaxoSmithKline UK. UK Summary of product characteristics,November 2005.

van Haarst AD,van Gerven JMA, Cohen AF, De Smet M, Sterrett A, Birk KL, Fisher AL, De Puy ME, Goldberg MR, Musson DG. The effects of moclobemide on the pharmacokinetics of the 5-HT1B/1D agonist rizatriptan in healthy volunteers. Br J Clin Pharmacol (1999) 48, 190–96.

Maxalt (Rizatriptan benzoate). Merck Sharp & Dohme Ltd. UK Summary of product characteristics,April 2003.

Maxalt (Rizatriptan benzoate). Merck & Co.,Inc. US Prescribing information, April 2007.

Glaxo Pharmaceuticals UK Limited. A study to determine whether the pharmacokinetics,safety or tolerability of subcutaneously administered sumatriptan (6 mg) are altered by interaction with concurrent oral monoamine oxidase inhibitors. Data on file (Protocol C92–050),1993.

Dixon CM,Park GR, Tarbit MH. Characterization of the enzyme responsible for the metabolism of sumatriptan in human liver. Biochem Pharmacol (1994) 47, 1253–7.

Gardner DM,Lynd LD. Sumatriptan contraindications and the serotonin syndrome. Ann Pharmacother (1998) 32, 33–38.

Blier P,Bergeron R. The safety of concomitant use of sumatriptan and antidepressant treatments. J Clin Psychopharmacol (1995) 15, 106–9.

Höjer J,Personne M, Skagius A-S, Hansson O. Serotoninergt syndrom: flera allvarliga fallmed denna ofta förbisedda diagnos. Lakartidningen (2002) 99, 2054–5, 2058–60.

Imigran Radis (Sumatriptan succinate). GlaxoSmithKline UK. UK Summary of product characteristics,May 2006.

Rolan P. Potential drug interactions with the novel antimigraine compound zolmitriptan(Zomig(See reference number TM),311C90). Cephalalgia (1997) 17 (Suppl 18), 21–7.

Zomig (Zolmitriptan). AstraZeneca UK Ltd. UK Summary of product characteristics,September 2006.

Zomig (Zolmitriptan). AstraZeneca Pharmaceuticals LP. US Prescribing information,January 2007.