Itraconazole, terbinafina y Cisapride, en el ojo del huracan.  

Data-Medicos 
Dermagic/Express No. 3-(100) 
30 Mayo 2.001.30 May 2.001. 

EDITORIAL ESPANOL
=================
Hola amigos DERMAGICOS, de nuevo con ustedes, en esta ocasion con un tema bien caliente que le esta recorriendo el mundo dermatologico hoy en dia. Las famosas medicinas ITACONAZOLE (SPORANOX-JANSSEN) Y TERBINAFINA (NOVARTIS-LAMISIL), lanzadas al mercado como las nuevas promesas y grandes esperanzas para los tratamientos antimicoticos hoy dia TIENEN LOS DIAS CONTADOS. 

La FDA recientemente lanzo a la red un aviso publico del cuidado que hay que tener con estas dos drogas por sus efectos desvastadores sobre el higado y ademas de ello sobre el corazon al estar involucradas una de ellas (itraconazole) en la produccion de insuficiencia cardiaca congestiva. 

LOS HECHOS:

EL ITRACONAZOLE:  (Janssen-Cilag Pharmaceutica)

Lanzado al mercado en 1.992, como un nuevo antifungico del grupo de los azoles, la DROGA que SUPERABA EN EFECTIVIDAD y menos efectos HEPATOTOXICOS que el KETOCONAZOLE (años 80) del mismo laboratorio JANSSEN PHARMACEUTICA. Ha sido utilizado en el mundo por unas 50 millones de personas. Desde su aprobacion en septiembre de ese año comenzaron a reportarse efectos adversos entre los que destacan: 

1.) Colestasis severa
2.) Daño hepatico y muerte. 
3.) sincopes durante uso simultaneo con terbinafina. 
4.) Sincope y arritmias cardiacas uso simultaneo con terfenadina
5. )Incremento de riesgo de taquicardia ventricular uso con terfenadina.
6.) Colitis Pseudomembranosa
7.) Retardo del sangramiento menstrual por uso con anticonceptivos.
8.) Hipocalemia. 
9.) Reaccion del suero-like. 
10.) Toxicidad severa uso con vincristina y muerte. 
11.) Disturbios del ciclo menstrual uso con anticonceptivos.
12.) Erupcion purpurica. 
13.) Hepatitis aguda
14.) Muerte asociada a uso con vinorelbine tartrato. 
15.) Anormalidades de la enzimas hepaticas. 
16.) Erupcion medicamentosa confirmada por test. 
17.) Insuficiencia cardiaca congestiva y muerte. 

La gota que rebaso el vaso: 
-------------------------------------------

Desde su aprovacion en Septiembre de 1.992 hasta Abril del 2.001

Durante este perido la FDA recibio 94 casos que recibiendo SPORANOX desarrollaron insuficiencia cardiaca congestiva. En 58 de los 94 casos la FDA cree que el SPORANOX contribuyo o fue el causal de la ICC. En 28 de estos 58 casos Sporanox fue administrado para el tratamiento de infeccion micotica ungueal. De estos 58 pacientes,28 fueron hospitalizados. 13 murieron.

Resultados de recientes estudios sobre el Sporanox revelaron un potencial efecto de la droga de producir un efecto inotropico negatico en el musculo cardiaco, el cual es observado despues de inyectar intravenosamente en perros anestesiados y voluntarios humanos sanos. Es estos estudios el efecto adverso sobre el musculo cardiaco se resolvio una vez la droga fue descontinuada.

Para Marzo del 2.001 La FDA recibio y reviso 24 casos de FALLA HEPATICA, posiblemente asociadas al Sporanox, incluyendo 11 muertes.Aproximadamente la mitad de estos casos (50%) estaba recibiendo Itraconazole para infeciones micoticas ungueales y otras infecciones dermatologicas.


LA TERBINAFINA: (Novartis Pharmaceutical)

Lanzada al mercado en Mayo de 1.996 como UN ANTIFUNGICO perteneciente al grupo de las alilaminas por el laboratorio NOVARTIS PHARMACEUTICAL, rapidamente ocupo un lugar importante como terapia antimicotica, siendo utilizado por mas de 7 millones de personas en el mundo y con un reporte de efectos adversos del 47%, entre ellos destacan: 

1.) Fulminate daño hepatico ocasionando muerte y o transplante hepatico. 
2.) Hepatitis aguda. 
3.) Colestasis con reduccion de los ductos biliares. 
4.) Pustulosis exantematosa aguda. 
5.) trastornos persistentes del gusto. 
6.) Precipitacion de psoriasis de novo y empeoramiento de psoriasis pre-existente. 
7.) Precipitacion de Psoriasis pustulosa 
8.) Eritema multiforme severo. 
9.) Glosopirosis. 
10.) Trombocitopenia. 
11.) Agranulocitosis. 
12.) Trastornos oculares (vision verdosa) 
13.) Reacciones de Hipersensibilidad. 
14.) Inflamacion de las Parotidas. 
15.) Eritema fijo medicamentoso 
16.) deterioro de la funcion renal. 
17.) Lupus eritematoso. 

La gota que rebaso el vaso: 
--------------------------------------- 
Para abril del 2.0001 la FDA americana, reviso 16 posibles casos de falla y daño hepatic asociado al uso de LAMISIL, incluyendo 11 muertes y 2 transplantes de Higado. 


EL CISAPRIDE:  (Janssen-Cilag Pharmaceutica)
---------------------- 
Otra droga del laboratorio Janssen Pharmaceutica, lanzada al mercado en 1.993 para el tratamiento del reflujo gastrico con grandes espectativas. Para el 31 de diciembre de 1.999 se habian reportado 341 casos de arritmias cardiacas asociadas al uso de esta droga, incluyendo 80 muertes. Para enero del año 2.000 Janssen hace un esfuerzo para informar sobre los riesgos del manejo de la droga. 

La Agencia de Control de Medicinas del Reino Unido decide suspender la la licensia para la venta y comercializacion del CISAPRIDE en JULIO del  2.000, producto para tratar desordenes gastricos y digestivos en niños y adultos, despues del reporte de 5 MUERTES, en el REINO UNIDO Y 125 MUERTES REPORTADAS EN EL MUNDO, asociadas al uso de esta droga.

Para el 12 de Abril de 2.001 
Janssen Pharmaceutica decide retirar del mercado la droga para evitar mayores problemas. 

EL FUTURO DE TERBINAFINA E ITRACONAZOLE :
------------------------------------------------------------------------ 
La danza de los millones comenzo a moverse, Janssen -Cilag esta distribuyendo cartas a todos los paises advirtiendo los potenciales peligros del USO DEL ITRACONAZOLE, alegando que ha sido usada en mas de 50 millones de personas, y que tuvo 8 años previos de estudio. Probablemente NOVARTIS con LA TERBINAFINA haga lo mismo, pero la evidencia del efecto desvastador sobre el HIGADO de estas DOS DROGAS ES practicamente IMPREDECIBLE E IMBATIBLE, Y el efecto inotropico NEGATIVO sobre el musculo cardiaco producido por el ITRACONAZOLE tambien es un hecho indiscutible. Quiza por un tiempo permanezcan en el mercado, pero si siguen presentandose casos de FALLA HEPATICA e INSUFICIENCIA CARDIACA seguidas de MUERTE, muy probablemente pronto SERAN retiradas del mercado, como ha ocurrido con el FAMOSO CISAPRIDE(PREPULSID). Ese es el futuro que les espera a estas medicinas. 

Una posible solucion seria hacerle firmar al paciente una autorizacion para su uso como se hace con el isotretinoin de ROCHE. 

LA AUTORIZACION PODRIA DECIR: 

" Estoy consciente que con estas drogas puedo curarme, pero tambien morir"... 

En las referencias los hechos: 

Saludos a todos. 

Dr. Jose Lapenta R.


EDITORIAL ENGLISH
==================
Hello DERMAGIC'S friends , again with you, in this occasion with a very hot topic that it's traveling around the dermatologic world today in day. The famous medicines ITRACONAZOLE(SPORANOX-JANSSEN) AND TERBINAFINE(NOVARTIS-LAMISIL), rushed to the market as the new promises and big hopes for the fungus treatments nowadays HAVE THE COUNTED DAYS. 

The FDA recently throws to the net a warning I publish of the care that it is necessary to have with these Two drugs for its disastrous effects on the liver and besides its negative effects on the heart when being involved one of them (itraconazole) in the production of real risk of developing congestive heart failure (CHF). 

THE FACTS:

THE ITRACONAZOLE: (Janssen-Cilag Pharmaceutica)

Thrown to the market in 1.992, as a new antifungal of the group of the "azoles", the DRUG that OVERCAME IN EFFECTIVENESS and less HEPATOTOXIC effects than the KETOCONAZOLE (eighties) of the same laboratory JANSSEN-CILAG PHARMACEUTICA. It has been used in the world by some 50 million people. From its approval in September of that year began to be reported adverse effects among those that highlight: 

1.) Severe cholestasis.
2.) [Liver damage and death. 
3.) [Syncopes during simultaneous uses of terfenadine and itraconazole]. 
4.) Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine. 
5. )Itraconazole prevents terfenadine metabolism and increases risk of torsades of pointes ventricular tachycardia. 
6.) Pseudomembranous colitis. 
7.) Delay of withdrawal bleeding during concomitant uses of oral contraceptives and itraconazole. 
8.) Hypokalemia. 
9.) Serum sickness-like reaction. 
10.) Severe vincristine toxicity in combination with itraconazole. 
11.) [Pill cycle disturbance.
12.) Purpuric drug eruption. 
13.) Acute hepatitis. 
14.) Interaction between itraconazole and vinorelbine tartrate leading to death. 
15.) Abnormalities in liver enzymes. 
16.) Drug eruption confirmed by challenge test. 
17.) Congestive heart failure and death (CHF) 

The drop that I surpass the glass: 
------------------------------------- 
From its approval in September 1992 and April 2001. 

During this period, FDA received 94 cases in which patients receiving Sporanox® developed CHF (congestive heart failure). In 58 of the 94 cases, FDA believes Sporanox® contributed to or may have been the cause of CHF. In 26 of these 58 cases, Sporanox® was being administered to treat fungal nail infections. Of these 58 patients, 28 were hospitalized. Death was reported in 13 cases.

Results of recent studies of Sporanox® revealed a potential for the drug to weaken the force of the heart muscle's contractions. This so-called "negative inotropic effect" was observed when intravenous Sporanox® was injected into anesthetized dogs and healthy human volunteers. In these studies, the adverse effect on the heart muscle resolved once the drug was stopped. 

As of March 2001, FDA has received and reviewed 24 cases of liver failure possibly associated with Sporanox®, including 11 deaths. Approximately half of the liver failure cases received Sporanox® for fungal nail infections or other dermatological infections. 


THE TERBINAFINE: (Novartis Pharmaceutical)
-------------------------------
Rushed to the market in May of 1.996 as an ANTIFUNGAL belonging to the group of the allylamines for the laboratory NOVARTIS PHARMACEUTICAL, quickly I occupy an important place as antifungal therapy, being used for but of 7 million people in the world and with a report of adverse effects of 47%, among them they highlight: 

1.) Fulminant Hepatic Failure and death. 
2.) [Acute hepatitis associated with terbinafine]. 
3.) Cholestasis with reduction of interlobular bile ducts. 
4.) Acute generalized exanthematous pustulosis.
5.) Persistent impairment of taste. 
6.) Severe pustular psoriasis.
7.) Severe erythema anulare centrifugum-like psoriatic drug eruption.
8.) Serious interaction between warfarin.
9.) Fixed drug eruption.
10.) Glossopyrosis.
11.) Thrombocytopenia.
12.) Agranulocytosis.
13.) The development of green vision.
14.) Parotid swelling.
15.) Hypersensitivity reaction.
16.) Lupus erythematosus.
17.) Renal impairment.


The drop that I surpass the glass: 
------------------------------------------------- 
As of April 2001, FDA has received and reviewed 16 possible Lamisil®-associated cases of liver failure, including 11 deaths and two liver transplantations.


THE CISAPRIDE: (Janssen-Cilag Pharmaceutica)
  ------------------------- 
Another drug of the laboratory Janssen Pharmaceutica, thrown to the market in 1.993 for the treatment of the gastric reflux with big hopes. For December 31 1.999, 341 cases of heart arrhythmias had been reported, including 80 deaths. For January of year 2.000 Janssen makes an effort to inform on the risk of the handling of the drug.

For JULY 2.000, The product licence for cisapride (Prepulsid), a drug used to treat gastric and digestive disorders in adults and children, has been suspended by the Medicines Control Agency after five (5) DEATHS in the United Kingdom and 125 DEATHS WORLDWIDE  that are thought to be associated with the drug.

For April 12- 2.001  Janssen Pharmaceutica decides to retire of the market the drug to avoid bigger problems. 

THE FUTURE OF TERBINAFINE AND ITRACONAZOLE: 
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The dance of the millions began to move, Janssen -Cilag are distributing letters to all the countries noticing the potential dangers of the USE OF THE ITRACONAZOLE, alleging that it has been used in but of 50 million people, and that he was 8 previous years of study old. Probably NOVARTIS with THE TERBINAFINE makes the same thing, but the evidence of the big "bad " effects on the LIVER of these TWO DRUGS it is practically without prediction AND UNBEATABLE, AND the NEGATIVE inotropic effect on the heart muscle taken place by the ITRACONAZOLE is also an unquestionable fact. 

They maybe for a while remain in the market, but if they continue being presented cases of HEPATIC FAILURE and CONGESTIVE HEART FAILURE followed by DEATH, they will very probably soon be retired of the market, like it has happened with the FAMOUS CISAPRIDE (PROPULSID). That is the future that waits to these medicines. 

A possible serious solution could be to make him sign the patient an authorization for their use like the isotretinoin of ROCHE. 

THE AUTHORIZATION COULD SAY: 

" I am conscious that with these drugs I can be treated, but also to die"... 

In the references the facts 

greetings to all 

Dr Jose Lapenta R. 


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TERBINAFINE (Novartis Pharmaceuticals) LAMISIL
============================================================
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1.)Terbinafine and Fulminant Hepatic Failure
2.) [Acute hepatitis associated with terbinafine].
3.) [Hepatitis attributed to the use of terbinafine].
4.) Hepatitis associated with terbinafine therapy: three case reports and a review of the literature.
5.) Terbinafine-associated hepatic injury.
6.) Terbinafine-induced prolonged cholestasis with reduction of interlobular bile ducts.
7.) Terbinafine hepatotoxicity: case report and review of the literature.
8.) Acute generalized exanthematous pustulosis associated with oral terbinafine.
9.) Acute generalized exanthematous pustulosis induced by terbinafine.
10.) Persistent impairment of taste associated with terbinafine.
11.) Oral terbinafine and erythema multiforme.
12.) Terbinafine and erythema multiforme.
13.) [Severe erythema multiforme during terbinafine therapy].
14.) Terbinafine therapy may be associated with the development of psoriasis de novo or its exacerbation: four case reports and a review of drug-induced psoriasis.
15.) Severe pustular psoriasis provoked by oral terbinafine.
16.) Severe erythema anulare centrifugum-like psoriatic drug eruption induced by terbinafine.
17.) Serious interaction between warfarin and oral terbinafine.
18.) Terbinafine and fixed drug eruption.
19.)[Glossopyrosis and terbinafine].
20.) Thrombocytopenia associated with oral terbinafine.
21.) [Agranulocytosis during a treatment with terbinafine].
22.) Terbinafine-induced neutropenia.
23.) The development of green vision in association with terbinafine therapy.
24.) Parotid swelling and terbinafine.
25.) [Parotiditis and terbinafin].
26.) Hypersensitivity reaction to terbinafine.
27.) [Terbinafine and lupus erythematosus (1st published case)].
28.) Persistent impairment of taste resulting from terbinafine.
29.) [Ageusia caused by terbinafine].
30.) Renal impairment associated with oral terbinafine.
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ITRACONAZOLE (Janssen-Cilag Pharmaceutica) SPORANOX, TRISPORAL
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31.) Severe cholestasis related to intraconazole for the treatment of onychomycosis.
32.) [Liver damage during administration of itraconazole (Trisporal)].
33.) [Syncopes during simultaneous use of terfenadine and itraconazole].
34.) Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine.
35.)Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia.
36.) Interaction of itraconazole and digoxin.
37.) Severe cholestasis related to intraconazole for the treatment of onychomycosis.
38.) Potential interaction between itraconazole and clarithromycin.
39.) Drug interactions with itraconazole, fluconazole, and terbinafine and their management.
40.) Pseudomembranous colitis after itraconazole therapy.
41.) Signalling possible drug-drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole.
42.) [Itraconazole-induced hypokalemia in a patient with pulmonary aspergilloma].
43.) Serum sickness-like reaction to itraconazole.
44.) Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole.
45.) Severe vincristine toxicity in combination with itraconazole.
46.) [Pill cycle disturbance in simultaneous use of itraconazole and oral contraceptives].
47.) Purpuric drug eruption secondary to itraconazole.
48.) Itraconazole-induced acute hepatitis.
49.) [Liver damage during administration of itraconazole (Trisporal)].
50.) Hepatic injury associated with itraconazole.
51.) Possible drug interaction between itraconazole and vinorelbine tartrate leading to death after one dose of chemotherapy.
52.) Abnormalities in liver enzymes during simultaneous therapy with itraconazole and amphotericin B in leukaemic patients.
53.) Itraconazole-induced drug eruption confirmed by challenge test.
54.) ITRACONAZOLE AND TERBINAFINE FDA HEALTH ADVISORY
55.) FDA PUBLIC HEALTH ADVISORY ABOUT SPORANOX AND LAMISIL 
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CISAPRIRIDE (Janssen -Cilag Pharmaceutica) PROPULSID, PREPULSID
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56.) [Cisapride and risk of cardiac complications].
57.) FDA, Janssen bolster cardiac risk warnings for cisapride.
58.) [The proarrhythmogenic activity of non-anti-arrhythmia drugs. Is treatment with antihistamines and cisapride safe]?
59.) News/ UK licence for cisapride suspended 
60.) (In)Efficacy of cisapride 
61.) Should cisapride have been "blacklisted"?
62.) Effects of cisapride on QT interval in infants: A prospective study 
63.) [Long QT interval and malignant ventricular arrhythmia during treatment with cisapride. Report of a clinical case].
64.) Cisapride and Fatal Arrhythmia
65.) Media: 301-827-6242/ FDA UPDATES WARNINGS FOR CISAPRIDE
66.) New Safety Recommendations for Use of Cisapride (Propulsid)
67.)JANSSEN PHARMACEUTICA STOPS MARKETING CISAPRIDE IN THE US
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TERBINAFINE (Novartis-Pharmaceutical) LAMISIL
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1.)Terbinafine and Fulminant Hepatic Failure
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The New England Journal of Medicine -- April 22, 1999 -- Vol. 340, No. 16 

To the Editor: 

Terbinafine is an antifungal agent that is widely prescribed for common skin infections. (1) We describe a patient who had taken terbinafine and in whom fulminant hepatic failure developed, requiring orthotopic liver transplantation. 

A 48-year-old woman took 250 mg of terbinafine daily for five days for a fungal nail infection. Over the next four weeks, fulminant hepatic failure developed. The patient had been taking dothiepin (75 mg per day), which is a tricyclic antidepressant, and propranolol (40 mg twice daily) for more than 18 months. She had no risk factors for liver disease, a minimal intake of alcohol (<40 g per week), and no history of ingestion of acetaminophen or other analgesics. Serum acetaminophen levels were undetectable. Autoantibody screening and screening for serologic hepatitis A, B, and C viruses were negative; abdominal ultrasonography revealed a normal-sized liver with no evidence of splenomegaly or ascites. The patient's condition deteriorated; encephalopathy increased, requiring ventilation and intensive care. She subsequently underwent uncomplicated orthotopic liver transplantation. She remains well 18 months after transplantation. 

Histologic examination of the explanted liver revealed panacinar submassive necrosis and nearly complete disappearance of hepatocytes, with no evidence of chronic liver disease. These findings are compatible with a drug-related cause of disease. 

In our patient, a presumed idiosyncratic (type B) drug reaction to terbinafine may have been an important factor in the development of fulminant hepatic failure. The two other prescribed medications that she was taking have a low reported potential for hepatotoxicity, and she had been taking them for many months. Minor abnormalities in the results of liver-function tests have been reported in up to 4 percent of patients during oral treatment with terbinafine, (2) with two reports of predominantly cholestatic, reversible, terbinafine-associated hepatic injury. (3,4,5) 


Kosh Agarwal, M.R.C.P. 
Derek M. Manas, F.C.S.(S.A.) 
Mark Hudson, F.R.C.P. 
Freeman Hospital 
Newcastle upon Tyne NE7 7DN, United Kingdom

References 

1. Gupta AK, Scher RK. Oral antifungal agents for onychomycosis. Lancet 1998;351:541-2.
Return to Text 

2. van der Schroeff JG, Cirkel PK, Crijns MB, et al. A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J Dermatol 1992;126:Suppl 39:36-9. 
Return to Text 

3. van't Wout JW, Herrmann WA, de Vries R, Stricker BH. Terbinafine-associated hepatic injury. J Hepatol 1994;21:115-7.
Return to Text 

4. Lazaros GA, Papatheodoridis GV, Delladetsima JK, Tassopoulos NC. Terbinafine-induced cholestatic liver disease. J Hepatol 1996;24:753-6.
Return to Text 

5. Fernandes NF, Geller SA, Fong TL. Terbinafine hepatotoxicity: case report and review of the literature. Am J Gastroenterol 1998;93:459-60.
Return to Text 

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2.) [Acute hepatitis associated with terbinafine].
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Gastroenterol Hepatol 1997 Nov;20(9):456-8 

[Article in Spanish]

Vivas S, Rodriguez M, Palacio MA, Cadenas F, Lomo J, Rodrigo L.

Servicio de Aparato Digestivo, Hospital Central de Asturias, Oviedo.

Oral terbinafine is a recently introduced antifungal drug with slight side effects that rarely includes liver involvement. A case of toxic hepatitis secondary to terbinafine administration in a patient with no previous history of liver disease and in whom other possible causes of liver damage and histologic study were performed is reported. A mixed lesion was presented with predominance of cholestasis. The initial worsening following discontinuation of the drug is of note as are the prolonged course of the enzymatic alterations which normalized at one year. The precise mechanism by which terbinafine produced liver damage is unknown and is probably due to an idiosyncratic type reaction.

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3.) [Hepatitis attributed to the use of terbinafine].
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Ned Tijdschr Geneeskd 1996 Mar 23;140(12):669-72 

[Article in Dutch]

Boldewijn OY, Ottervanger JP, Mostart CM, Janssens AR, Calame J, Jonkers GJ.

Afd. Inwendige Geneeskunde, Rijnlandziekenhuis, Leiderdorp.

A 71-year-old woman was admitted to our hospital with jaundice after she had been using terbinafine for a few weeks. The liver function tests showed a mixed cholestatic-hepatocellular pattern. A liver biopsy revealed large amounts of intracellular bile pigment. Causes of the liver disorder other than the use of the aforementioned antimycotic drug were excluded. Ten months after cessation of the drug the patient had recovered completely. The Netherlands Inspectorate for Health Care received 20 reports of liver enzyme elevations due to terbinafine in 1991-1994.

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4.) Hepatitis associated with terbinafine therapy: three case reports and a review of the literature.
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Clin Exp Dermatol 1998 Mar;23(2):64-7 

Gupta AK, del Rosso JQ, Lynde CW, Brown GH, Shear NH.

Department of Medicine, Sunnybrook Health Science Center, Ontario, Canada. [email protected]

Terbinafine is an allylamine antifungal agent first launched in the USA in May 1996 with an estimated 7.5 million individuals worldwide having used the drug. Given orally it is effective for the treatment of dermatophyte infections and is prescribed predominantly for the superficial mycoses. Adverse effects have been reported in 46.7% of patients receiving the oral drug (compared with 29.2% receiving placebo, the attributable risk to terbinafine being 17.5%). Thus, oral terbinafine is associated with the rare development of symptomatic idiosyncratic hepatobiliary dysfunction (1:45,000-1:54,000) and we now describe three patients who developed this disorder whilst taking the medication. The hepatitis produced has the features of both hepatocellular necrosis (with elevations of hepatic enzyme concentrations) and cholestatic injury (with elevations of alkaline phosphatase and cholesterol levels), the latency period between the start of medication and the development of liver injury being approximately 4-6 weeks. The US terbinafine product monograph recommends that serum hepatic enzymes should be assessed in individuals receiving terbinafine for more than 6 weeks, as a result of which some physicians monitor these values at baseline and at 4-6 weeks.

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5.) Terbinafine-associated hepatic injury.
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J Hepatol 1994 Jul;21(1):115-7 

van 't Wout JW, Herrmann WA, de Vries RA, Stricker BH.

Department of Internal Medicine and Dermatology, Bronovo Hospital, The Hague, The Netherlands.

We describe two cases of terbinafine-associated hepatic injury, in which a mixed cholestatic-hepatocellular type of hepatitis was present. In both cases extrahepatic cholestasis and viral hepatitis were excluded and involvement of other drugs was unlikely. In the first patient all abnormalities have disappeared, but in the second patient alkaline phosphatase, aminotransferase and gamma-glutamyl transferase levels have remained elevated (follow up 3 months after cessation of treatment with terbinafine). Most likely, the terbinafine-associated hepatic injury in these patients was caused by an idiosyncratic rather than a direct hepatotoxic reaction.

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6.) Terbinafine-induced prolonged cholestasis with reduction of interlobular bile ducts.
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Dig Dis Sci 1997 Jul;42(7):1486-8 
Mallat A, Zafrani ES, Metreau JM, Dhumeaux D.

Service d'Hepatologie et de Gastroenterologie, Hopital Henri Mondor, Creteil, France.

The antifungal drug terbinafine has infrequently been incriminated in the occurrence of acute liver injury. We report a case of prolonged cholestasis that occurred in a 75-year-old woman, following terbinafine administration. Jaundice followed by pruritus appeared after four weeks of therapy and was associated with mixed hepatocellular and cholestatic liver tests abnormalities. Following drug withdrawal, serum bilirubin returned to normal values within three months, but anicteric cholestasis persisted for over six months. A liver biopsy performed after six months showed centrilobular cholestasis, discrete portal fibrosis, and a reduction in the number of interlobular biliary ducts. Terbinafine should be added to the list of drugs that can cause reduction in interlobular bile ducts.

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7.) Terbinafine hepatotoxicity: case report and review of the literature.
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Am J Gastroenterol 1998 Mar;93(3):459-60 

Fernandes NF, Geller SA, Fong TL.

Center for Liver Diseases and Transplantation and Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.

We report a patient who developed significant liver dysfunction following therapy with terbinafine. At the end of a 3 1/2-wk course of terbinafine, he developed progressive jaundice and pruritus. His serum bilirubin peaked at 30.9 mg/dl 3 wk after discontinuing terbinafine. A liver biopsy revealed mild to moderate mixed cellular infiltrate in the portal tracts, and hepatocellular and canicular cholestasis. His liver tests normalized 100 days after stopping terbinafine.

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8.) Acute generalized exanthematous pustulosis associated with oral terbinafine.
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Australas J Dermatol 2000 Feb;41(1):42-5
Hall AP, Tate B.

Department of Dermatology, Western Hospital, Footscray, Victoria, Australia.

A case history of acute generalized exanthematous pustulosis (AGEP) following oral terbinafine is reported. A 64-year-old woman presented with a rapidly spreading micropustular eruption 3 days after completing a 28-day course of oral terbinafine. There was a positive family history of psoriasis but no personal history. The clinical presentation and histopathology were consistent with AGEP. There was nearly complete resolution of the pustular eruption within 3.5 weeks following cessation of oral terbinafine and treatment with topical and systemic corticosteroids. The patient has remained free of any recurrence 18 months later. A summary of drugs known to be associated with AGEP is presented. Prompt recognition of AGEP is stressed in order to avoid confusion with acute generalized pustular psoriasis or a systemic infection. The most important aspect of management is the immediate withdrawal of the suspect drug.

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9.) Acute generalized exanthematous pustulosis induced by terbinafine.
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Arch Dermatol 1996 Oct;132(10):1253-4 

Dupin N, Gorin I, Djien V, Helal H, Zylberberg L, Leibowitch M, Escande JP.

Publication Types: 
Letter 
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10.) Persistent impairment of taste associated with terbinafine.
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Br Dent J 2000 Mar 25;188(6):295-6 

Duxbury AJ, Oliver RJ, Pemberton MN.

University Dental Hospital of Manchester.

A second case of persistent taste disturbance associated with terbinafine is described. Taste disturbance associated with this drug is reviewed and a table is provided listing the more common drugs associated with taste disturbance.

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11.) Oral terbinafine and erythema multiforme.
============================================================
Clin Exp Dermatol 1995 May;20(3):247-8 

Todd P, Halpern S, Munro DD.

Department of Dermatology, St Bartholomew's Hospital, West Smithfield, London, UK.

Two patients developed classical erythema multiforme while taking oral terbinafine. A case of Stevens-Johnson syndrome occurring after terbinafine therapy has recently been described, but there have been no published reports of an association with erythema multiforme until now.

============================================================
12.) Terbinafine and erythema multiforme.
============================================================
Br J Dermatol 1994 Oct;131(4):587-8 

McGregor JM, Rustin MH.

Publication Types: 
Letter 

============================================================
13.) [Severe erythema multiforme during terbinafine therapy].
============================================================
Therapie 1995 Nov-Dec;50(6):594-5 Related Articles, Books 

[Article in French]

Tramaloni S, Castanet J, Chichmanian RM, Lacour JP, Ortonne JP.

Publication Types: 
Letter 

============================================================
14.) Terbinafine therapy may be associated with the development of psoriasis de novo or its exacerbation: four case reports and a review of drug-induced psoriasis.
============================================================
J Am Acad Dermatol 1997 May;36(5 Pt 2):858-62 

Gupta AK, Sibbald RG, Knowles SR, Lynde CW, Shear NH.

Department of Medicine, Sunnybrook Health Science Center, Toronto, Canada.

Adverse effects may occur in 10.4% of patients receiving terbinafine therapy, with cutaneous reactions in 2.7%. We describe the development of psoriasis in four patients who took oral terbinafine. Two patients had plaque-type psoriasis that flared 12 and 17 days, respectively, after starting terbinafine. Another patient developed pustular-type psoriasis de novo after 27 days of terbinafine therapy. The fourth patient was a psoriatic with stable plaque disease who experienced a pustular flare after taking terbinafine for 21 days. We are aware of only one report in the literature in which a patient developed pustular psoriasis de novo after 5 days of terbinafine therapy. In all patients the psoriasis cleared or lessened after discontinuation of terbinafine and institution of antipsoriatic therapy.

============================================================
15.) Severe pustular psoriasis provoked by oral terbinafine.
============================================================
Br J Dermatol 1998 Jul;139(1):168 

Wilson NJ, Evans S.

Publication Types: 
Letter 

============================================================
16.) Severe erythema anulare centrifugum-like psoriatic drug eruption induced by terbinafine.
============================================================
Arch Dermatol 1995 Aug;131(8):960-1 

Wach F, Stolz W, Hein R, Landthaler M.

Publication Types: 
Letter 

============================================================
17.) Serious interaction between warfarin and oral terbinafine.
============================================================
BMJ 1998 Feb 7;316(7129):440 


Comment in: 
BMJ. 1998 Jul 18;317(7152):205-6 
BMJ. 1998 Jul 18;317(7152):205; discussion 205 

Warwick JA, Corrall RJ.

Department of Pharmacy, Bristol Royal Infirmary.

============================================================
18.) Terbinafine and fixed drug eruption.
============================================================
Br J Dermatol 1995 Nov;133(5):815-6 Related Articles, Books 

Munn SE, Russell Jones R.

Publication Types: 
Letter 

============================================================
19.)[Glossopyrosis and terbinafine].
============================================================
Dtsch Med Wochenschr 1999 Oct 8;124(40):1186 

[Article in German]

Haneke E.

Hautklinik, Klinikum Wuppertal GmbH.

============================================================
20.) Thrombocytopenia associated with oral terbinafine.
============================================================
Int J Dermatol 1998 Aug;37(8):634 

Grunwald MH.

Publication Types: 
Letter 

============================================================
21.) [Agranulocytosis during a treatment with terbinafine].
============================================================
Rev Med Interne 1997;18(3):258-9 

Barete S, Bissuel F, Longuet P, Pocidalo MA, Leport C, Vilde JL.

Publication Types: 
Letter 

============================================================
22.) Terbinafine-induced neutropenia.
============================================================
Br J Dermatol 1999 Jun;140(6):1196-997 

Shapiro M, Li LJ, Miller J.

Publication Types: 
Letter 
Review 
Review of reported cases 

============================================================
23.) The development of green vision in association with terbinafine therapy.
============================================================
Arch Dermatol 1996 Jul;132(7):845-6 

Gupta AK, Gonder JR, Shear NH, Dilworth GR.

Publication Types: 
Letter 

============================================================
24.) Parotid swelling and terbinafine.
============================================================
BMJ 1998 Feb 7;316(7129):440-1 


Torrens JK, McWhinney PH.

============================================================
25.) [Parotiditis and terbinafin].
============================================================
Ann Dermatol Venereol 1999 Nov;126(11):887 

[Article in French]

Schmutz J, Barbaud A, Trechot P.

Service de Dermatologie, Hopital Fournier, 54000 Nancy.

============================================================
26.) Hypersensitivity reaction to terbinafine.
============================================================
J Am Acad Dermatol 1997 Jun;36(6 Pt 1):1018-9 

Gupta AK, Kopstein JB, Shear NH.

Division of Dermatology, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.

============================================================
27.) [Terbinafine and lupus erythematosus (1st published case)].
============================================================
Ann Dermatol Venereol 1999 May;126(5):463 

[Article in French]

Publication Types: 
News 

============================================================
28.) Persistent impairment of taste resulting from terbinafine.
============================================================
Br J Dermatol 1998 Oct;139(4):747-8 

Bong JL, Lucke TW, Evans CD.

Publication Types: 
Letter 
============================================================
29.) [Ageusia caused by terbinafine].
============================================================
Med Clin (Barc) 1995 Sep 9;105(7):276 

[Article in Spanish]

Martinez Yelamos S, Ballabriga Planas J, Peres Serra J, Prat Rojo J.

Publication Types: 
Letter 

============================================================
30.) Renal impairment associated with oral terbinafine.
============================================================
Br J Dermatol 1996 Feb;134(2):374-5 

Lee MS, Lau AK, Crosland G, Caterson R.

Publication Types: 
Letter 
============================================================
============================================================
ITRACONAZOLE (Janssen-Cilag Pharmaceutica) SPORANOX, TRISPORAL
============================================================
============================================================
31.) Severe cholestasis related to intraconazole for the treatment of onychomycosis.
============================================================
Am J Gastroenterol 1999 Dec;94(12):3632-3 

Talwalkar JA, Soetikno RE, Carr-Locke DL, Berg CL.

Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

We describe a case of prolonged cholestasis temporally associated with the use of itraconazole for onychomycosis. Peak bilirubin level of 32.0 mg/dl was documented approximately 2 months after discontinuation of the patient's itraconazole therapy, with symptoms of cholestasis persisting more than 1 month after the peak in bilirubin. Physicians should be aware of the potential for severe cholestasis associated with itraconazole usage.

============================================================
32.) [Liver damage during administration of itraconazole (Trisporal)].
============================================================
Ned Tijdschr Geneeskd 1993 Jan 2;137(1):38-41 

Comment in: 
Ned Tijdschr Geneeskd. 1993 Jan 9;137(2):97-8 

[Article in Dutch]

Lavrijsen AP, Balmus KJ, Nugteren-Huying WM, Roldaan AC, van 't Wout JW, Stricker BH.

Academisch Ziekenhuis, afd. Dermatologie, Leiden.

Three case histories are described of patients, two women aged 62 and 57 and a man aged 75 years, who developed symptomatic hepatic injury five to six weeks after starting itraconazole treatment. In two of them the biochemical pattern of liver injury was cholestatic. Other causes of hepatic injury were excluded. Monitoring serum liver enzymes is advisable in patients treated with itraconazole for one month or longer.

============================================================
33.) [Syncopes during simultaneous use of terfenadine and itraconazole].
============================================================
Ned Tijdschr Geneeskd 1997 May 10;141(19):950-3 Related Articles, Books 

Comment in: 
Ned Tijdschr Geneeskd. 1997 Sep 6;141(36):1752-3 
Ned Tijdschr Geneeskd. 1997 Sep 6;141(36):1753-4 

[Article in Dutch]

Romkes JH, Froger CL, Wever EF, Westerhof PW.

Academisch Ziekenhuis, afd. Cardiologie, Utrecht.

A 36-year-old female was given terfenadine 120 mg/day for hay fever, and itraconazole 100 mg twice daily for mycosis. Nine days after starting these drugs, she had several episodes of syncope. The ECG showed a long QT interval and torsades de pointes. The drugs were withdrawn and the patient temporarily received an infusion of isoprenaline, after which the QT interval returned to normal and no further episodes of torsades de pointes occurred. No other causes than the two drugs were found to explain these episodes.

============================================================
34.) Syncope and cardiac arrhythmia due to an interaction between itraconazole and terfenadine.
============================================================
Am J Med 1993 Oct;95(4):445-6 

Crane JK, Shih HT.

University of Texas Health Sciences Center at Houston.

============================================================
35.)Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia.
============================================================
Eur J Clin Pharmacol 1993;45(2):191-3 

Pohjola-Sintonen S, Viitasalo M, Toivonen L, Neuvonen P.

First Department of Medicine, Helsinki University Central Hospital, Finland.

Terfenadine, a nonsedating H1-selective antihistamine, is widely used in many countries. We report pharmacokinetic results in a patient who developed a prolonged QT-interval in ECG and symptomatic torsades de pointes ventricular tachycardia as a consequence of the interaction of itraconazole and terfenadine. Both drugs were taken in the recommended doses: terfenadine 60 mg b.d. and itraconazole 100 mg b.d. Terfenadine metabolism was delayed by itraconazole, leading to an increased level of unmetabolised terfenadine. Seven weeks after the cessation of itraconazole treatment, terfenadine was rapidly metabolized to its active metabolite and did not prolong the QT-interval when given as a single provocation dose (120 mg). The findings suggest that intraconazole in therapeutic doses inhibits terfenadine metabolism. It is also possible that unmetabolised terfenadine alone, without an increased level of its active metabolite, may cause torsades de pointes. The concomitant use of terfenadine and itraconazole (and ketoconazole) should be avoided.

============================================================
36.) Interaction of itraconazole and digoxin.
============================================================
Clin Infect Dis 1993 Mar;16(3):400-3 

Comment in: 
Clin Infect Dis. 1994 Feb;18(2):259-60 

Sachs MK, Blanchard LM, Green PJ.

Division of Infectious Diseases, Jefferson Medical College, Philadelphia, Pennsylvania.

A 69-year-old man who had been taking digoxin for 2.5 years developed an elevated serum concentration of digoxin in association with digoxin toxicity (characterized by nausea and vomiting) 9 days after the addition of itraconazole to his regimen for the treatment of sternal osteomyelitis. Coadministration of itraconazole resulted in a statistically significant increase in the half-life of digoxin that necessitated a reduction of the digoxin dose by almost 60%. We thus recommend that patients receiving itraconazole and digoxin concomitantly have serum levels of digoxin monitored frequently. In addition, these patients should be carefully questioned about nonspecific gastrointestinal symptoms, which may indicate early digoxin toxicity.

============================================================
37.) Severe cholestasis related to intraconazole for the treatment of onychomycosis.
============================================================
Am J Gastroenterol 1999 Dec;94(12):3632-3 

Talwalkar JA, Soetikno RE, Carr-Locke DL, Berg CL.

Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

We describe a case of prolonged cholestasis temporally associated with the use of itraconazole for onychomycosis. Peak bilirubin level of 32.0 mg/dl was documented approximately 2 months after discontinuation of the patient's itraconazole therapy, with symptoms of cholestasis persisting more than 1 month after the peak in bilirubin. Physicians should be aware of the potential for severe cholestasis associated with itraconazole usage.

============================================================
38.) Potential interaction between itraconazole and clarithromycin.
============================================================
Pharmacotherapy 1999 Dec;19(12):1439-44 

Auclair B, Berning SE, Huitt GA, Peloquin CA.

Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, University of Colorado, Denver 80206, USA.

Three patients negative for human immunodeficiency virus infection were admitted for pulmonary Mycobacterium avium complex (MAC) and aspergillosis infections. They were treated with different drug combinations, but all regimens included clarithromycin for MAC and itraconazole for aspergillosis. All patients experienced an increase in clarithromycin concentrations and clarithromycin: 14-OH-clarithromycin ratio compared with expected range values. They had no clinical side effects. The time course suggested a possible interaction between clarithromycin and itraconazole, presumably through itraconazole's effects on cytochrome P450 3A4 activity. A bidirectional interaction cannot be ruled out. The data suggest that, when necessary, these two drugs can be administered together safely. Further investigation is necessary to determine the extent and clinical consequences of coadministration in humans.

============================================================
39.) Drug interactions with itraconazole, fluconazole, and terbinafine and their management.
============================================================
J Am Acad Dermatol 1999 Aug;41(2 Pt 1):237-49 
Erratum in: 
J Am Acad Dermatol 2000 Jan;42(1 Pt 1):148 

Gupta AK, Katz HI, Shear NH.

Division of Dermatology, Department of Medicine, University of Toronto,London, Ontario, N6K 1L6, Canada. [email protected]

A drug interaction develops when the effect of a drug is increased or decreased or when a new effect is produced by the prior, concurrent, or subsequent administration of the other. Before prescribing a drug, it is important to obtain a thorough drug history of the prescription and nonprescription medications taken by the patient. The nonprescription medications may include items such as nutritional supplements and herbal medications. The risk of side effects is an inevitable consequence of drug use. The frequency of adverse reactions is increased in those patients receiving multiple medications. Drug interactions reported in animal or in vitro studies may not necessarily develop in humans. When drug interactions are observed with a particular agent, it cannot be automatically assumed that all closely related drugs will necessarily produce the same interaction. However, caution is advised until sufficient experience accrues. The prescriber should not overestimate or underestimate the potential for a given drug interaction on the basis of personal experience alone. Drug interactions will not necessarily occur in every patient who is given a particular combination of drugs known to produce an interaction. For a clinically significant drug interaction to be manifest, several other factors may be relevant other than just using the two drugs. In many instances drug interactions can be predicted and therefore avoided if the pharmacodynamic effects, the pharmacokinetic properties, and the mechanisms of action of the 2 drugs in question are known. In the case of contraindicated drugs, it may be possible to use an alternative agent.

============================================================
40.) Pseudomembranous colitis after itraconazole therapy.
============================================================
Am J Gastroenterol 1999 Jul;94(7):1971-3 

Nguyen AJ, Nelson DB, Thurn JR.

Department of Medicine VA Medical Center and University of Minnesota, Minneapolis, 55417, USA.

A 53-yr-old man was admitted with new onset of abdominal pain and nonbloody diarrhea 1 month after exposure to the antifungal agent itraconazole. Flexible sigmoidoscopy demonstrated the presence of pseudomembranes, and subsequent evaluation excluded other causes of diarrhea. Disruption of the resident fungal flora of the colon by itraconazole is proposed as the mechanism by which this patient developed pseudomembranous colitis. This association has not previously been reported.

============================================================
41.) Signalling possible drug-drug interactions in a spontaneous reporting system: delay of withdrawal bleeding during concomitant use of oral contraceptives and itraconazole.
============================================================
Br J Clin Pharmacol 1999 Jun;47(6):689-93 

Van Puijenbroek EP, Egberts AC, Meyboom RH, Leufkens HG.

Netherlands Pharmacovigilance Foundation LAREB, 's-Hertogenbosch, the Netherlands.

AIMS: In spontaneous adverse drug reaction reporting systems, there is a growing need for methods facilitating the automated detection of signals concerning possible adverse drug reactions. In addition, special attention is needed for the detection of adverse drug reactions resulting from possible drug-drug interactions. We describe a method for detecting possible drug-drug interactions using logistic regression analysis to calculate ADR reporting odds ratios. METHODS: To illustrate this method, we analysed the adverse drug reaction 'delayed withdrawal bleeding' resulting from a possible interaction between itraconazole and oral contraceptives in reports received by the Netherlands Pharmacovigilance Foundation LAREB between 1991 and 1998. RESULTS: In total 5,503 reports were included in the study. The odds ratio, adjusted for year of reporting, age and source of the reports, for a delayed withdrawal bleeding in women who used both drugs concomitantly compared with women who used neither oral contraceptives, nor itraconazole, was 85 (95% CI: 32-230). CONCLUSIONS: Since spontaneous reporting systems can only generate signals concerning possible relationships, this association needs to be analysed by other methods in more detail in order to determine the real strength of the relationship. This approach might be a promising tool for the development of procedures for automated detection of possible drug-drug interactions in spontaneous reporting systems.

============================================================
42.) [Itraconazole-induced hypokalemia in a patient with pulmonary aspergilloma].
============================================================
Nihon Kokyuki Gakkai Zasshi 1999 Jan;37(1):36-40 

[Article in Japanese]

Sasaki E, Maesaki S, Kawamura S, Kakeya H, Ohno H, Hirakata Y, Tomono K, Ohzono Y, Tashiro T, Kohno S.

Second Department of Internal Medicine Nagasaki University School of Medicine.

An 80-year-old man was admitted to the hospital with a diagnosis of pulmonary aspergilloma. A new azole antifungal agent, D 0870, was administered to the patient for 7 days orally, and itraconazole (400 mg/day) was started on March 5, 1997. After 1 month of chemotherapy, facial and pretibial edema were observed and the patient's serum potassium concentration decreased to 2.5 mEq/l. A chest radiograph disclosed cardiomegaly with cardiac effusion and right pleural effusion on admission. The serum potassium concentration rose after the cessation of itraconazole therapy. The serum ITCZ concentration remained high for 2 weeks after admission. Although reports of hypopotassemia induced by ITCZ are rare, we concluded that blood concentrations should be monitored more carefully when treating pulmonary aspergilloma patients with high-dose regimens of ITCZ.

============================================================
43.) Serum sickness-like reaction to itraconazole.
============================================================
Ann Pharmacother 1998 Nov;32(11):1249 

Park H, Knowles S, Shear NH.

Publication Types: 
Letter 
============================================================
44.) Plasma concentration of itraconazole in patients receiving chemotherapy for hematological malignancies: the effect of famotidine on the absorption of itraconazole.
============================================================
Hematol Oncol 1998 Mar;16(1):33-7 

Kanda Y, Kami M, Matsuyama T, Mitani K, Chiba S, Yazaki Y, Hirai H.

Department of Cell Therapy and Transplantation Medicine, Faculty of Medicine, University of Tokyo, Japan.

Fungal infection is a serious complication in immunocompromised patients, especially those with neutropenia. Itraconazole (ITZ) is expected to be an effective prophylactic agent for fungal infection because it has more activity against Aspergillus species than fluconazole and it is less toxic than amphotericin-B. However, ITZ is available only as an oral capsule, the absorption of which is thought to depend on the presence of acid in the stomach. In this study, the effect of famotidine, an H2-blocker, on the absorption of ITZ was investigated. Patients undergoing chemotherapy for hematological malignancies were enrolled. To minimize the effect of famotidine, the time of ITZ intake was different from that of famotidine intake. The plasma concentrations of ITZ with or without taking famotidine were determined just before and 4 h after ITZ intake. Mean trough and peak concentrations of ITZ without famotidine were 332 ng/ml and 476 ng/ml, respectively. When famotidine was co-administered, the concentrations decreased to 204 ng/ml and 315 ng/ml, respectively. Statistical analyses revealed significant differences between trough concentrations in the presence and absence of famotidine (p = 0.008). There was also a clear tendency toward higher peak concentrations in the plasma concentrations with famotidine (p = 0.06). These findings suggest that famotidine decreases the plasma concentration of ITZ in patients undergoing chemotherapy. Close monitoring of the plasma concentration of ITZ and dose adjustment are required for efficient prophylaxis.

============================================================
45.) Severe vincristine toxicity in combination with itraconazole.
============================================================
Clin Lab Haematol 1998 Apr;20(2):123-4 

Gillies J, Hung KA, Fitzsimons E, Soutar R.

Department of Haematology, Monklands District General Hospital, Airdrie, UK.

We report two patients with acute lymphoblastic leukaemia (ALL) who were entered into the current MRC adult ALL trial (UKALL XII) in whom unusually severe vincristine induced neurotoxicity developed. This appeared to be the result of an interaction with itraconazole suspension.

============================================================
46.) [Pill cycle disturbance in simultaneous use of itraconazole and oral contraceptives].
============================================================
Ned Tijdschr Geneeskd 1998 Jan 17;142(3):146-9 

[Article in Dutch]

van Puijenbroek EP, Feenstra J, Meyboom RH.

Stichting Landelijke Registratie Evaluatie Bijwerkingen, Hertogenbosch.

Since the introduction of itraconazole in the Netherlands, the Netherlands Pharmacovigilance Foundation LAREB and the Inspectorate for Health Care received 15 reports of pill cycle disturbances and one of pregnancy occurring during simultaneous use of itraconazole and oral contraceptives. Twelve women used oral contraceptives containing ethinylestradiol and desogestrel. In these women, the withdrawal bleeding was either delayed or did not occur at all; one of these women reported a transiently positive pregnancy test after previous breakthrough bleedings. Three women who used a contraceptive containing ethinylestradiol and levonorgestrel had a breakthrough bleeding. One woman who used an oral contraceptive containing ethinylestradiol and cyproterone acetate became pregnant during the concomitant use of itraconazole. The possible mechanism involved remains to be explained. Although an influence of itraconazole on the reliability of oral contraceptives is uncertain, additional contraceptive measurements might be considered.

============================================================
47.) Purpuric drug eruption secondary to itraconazole.
============================================================
J Am Acad Dermatol 1997 Dec;37(6):994-5 

Kramer KE, Yaar M, Andersen W.

Department of Dermatology, Boston University School of Medicine, MA, USA.

============================================================
48.) Itraconazole-induced acute hepatitis.
============================================================
Br J Dermatol 1993 Oct;129(4):500-1 

Hann SK, Kim JB, Im S, Han KH, Park YK.

Publication Types: 
Letter 
============================================================
49.) [Liver damage during administration of itraconazole (Trisporal)].
============================================================
Ned Tijdschr Geneeskd 1993 Jan 9;137(2):97-8 Related Articles, Books 

Comment on: 
Ned Tijdschr Geneeskd. 1993 Jan 2;137(1):38-41 


[Article in Dutch]

Jacobs AE.

Publication Types: 
Comment 
Letter 
============================================================
50.) Hepatic injury associated with itraconazole.
============================================================
Lancet 1992 Jul 25;340(8813):251-2 

Lavrijsen AP, Balmus KJ, Nugteren-Huying WM, Roldaan AC, van't Wout JW, Stricker BH.

Publication Types: 
Letter 
============================================================
51.) Possible drug interaction between itraconazole and vinorelbine tartrate leading to death after one dose of chemotherapy.
============================================================
Ann Intern Med 2001 Mar 6;134(5):427 

Bosque E.

Publication Types: 
Letter 
============================================================
52.) Abnormalities in liver enzymes during simultaneous therapy with itraconazole and amphotericin B in leukaemic patients.
============================================================
J Antimicrob Chemother 2000 Jun;45(6):928-9 

Persat F, Schwartzbrod PE, Troncy J, Timour Q, Maul A, Piens MA, Picot S.

Publication Types: 
Clinical trial 
Letter 
============================================================
53.) Itraconazole-induced drug eruption confirmed by challenge test.
============================================================
Acta Derm Venereol 2000 Jan-Feb;80(1):72 

Goto Y, Kono T, Teramae K, Ishii M.

Publication Types: 
Letter 
============================================================
54.) ITRACONAZOLE AND TERBINAFINE FDA HEALTH ADVISORY
============================================================
FDA Issues Health Advisory Regarding the Safety of Sporanox® 
Products and Lamisil® Tablets to Treat Fungal Nail Infections


The Food and Drug Administration (FDA) today issued a Public Health Advisory to announce significant safety-related updates to the labeling of Sporanox® (itraconazole) products and Lamisil® (terbinafine hydrochloride) tablets. Sporanox® and Lamisil® are used to treat nail (onychomycosis), skin and other systemic fungal infections. The following may be used to answer questions. 

The purpose of today's FDA Public Health Advisory is to alert healthcare professionals to serious risks associated with the use of Sporanox® and Lamisil®. 

FDA believes there is a small but real risk of developing congestive heart failure (CHF) associated with the use of Sporanox®. Both Sporanox® and Lamisil® have been associated with serious liver problems resulting in liver failure and death. However, there is insufficient data to allow FDA to make any kind of statement about the comparative safety of Sporanox® and Lamisil®. 

Results of recent studies of Sporanox® revealed a potential for the drug to weaken the force of the heart muscle's contractions. This so-called "negative inotropic effect" was observed when intravenous Sporanox® was injected into anesthetized dogs and healthy human volunteers. In these studies, the adverse effect on the heart muscle resolved once the drug was stopped. 

Since becoming aware of the study findings, FDA analyzed US and international post-marketing adverse event reports involving Sporanox that were received between its approval in September 1992 and April 2001. 

During this period, FDA received 94 cases in which patients receiving Sporanox® developed CHF. In 58 of the 94 cases, FDA believes Sporanox® contributed to or may have been the cause of CHF. In 26 of these 58 cases, Sporanox® was being administered to treat fungal nail infections. Of these 58 patients, 28 were hospitalized. Death was reported in 13 cases. However, the causal relationship between the 13 deaths and Sporanox® is very unclear because of confounding factors. For example, 10 of the 13 patients who died had serious underlying conditions. 

In response to the study findings and the analysis of the post-marketing adverse event reports, FDA has added additional information to the current "black box" warning in the Sporanox® labeling. The warning now states that Sporanox® should not be administered for the treatment of fungal nail infections in patients with evidence of cardiac dysfunction, such as CHF, or a history of CHF. The Sporanox® "black box" warning also includes important information about heart-related adverse events caused by drug interactions. 

If signs and symptoms of CHF occur during treatment of fungal nail infections, the revised labeling recommends that Sporanox® should be discontinued. If signs and symptoms of CHF occur during treatment for more serious fungal infections involving other parts of the body, the revised labeling recommends that continued use of Sporanox® should be reassessed by the physician.

The advisory also alerts healthcare professionals to rare cases of serious liver problems including liver failure and death associated with the use of Sporanox® products and Lamisil® tablets. While adverse liver effects were already included in the labeling for both products, FDA decided to include this information in the advisory because some cases involved patients who had neither pre-existing liver disease nor a serious underlying medical condition. 

FDA's concerns do not apply to the topically applied versions of Lamisil® such as cream and solution.

As of April 2001, FDA has received and reviewed 16 possible Lamisil®-associated cases of liver failure, including 11 deaths and two liver transplantations.

As of March 2001, FDA has received and reviewed 24 cases of liver failure possibly associated with Sporanox®, including 11 deaths. Approximately half of the liver failure cases received Sporanox® for fungal nail infections or other dermatological infections. 

Given the possible serious risks associated with Sporanox® products and Lamisil® tablets, the new labeling for both products now recommends that healthcare professionals should obtain nail specimens for laboratory testing prior to prescribing the medications for fungal nail infections, to confirm the diagnosis. 

In conjunction with FDA's advisory, the manufacturer of Sporanox® (Janssen Pharmaceutica Products, L.P. of Titusville, NJ and Ortho Biotech Products, L.P. of Raritan, NJ) and Lamisil® (Novartis Pharmaceuticals of East Hanover, NJ) are notifying healthcare professionals of the labeling changes by issuing "Dear Healthcare Professional" letters. 

FDA encourages healthcare professionals and patients to report adverse events associated with the use of Sporanox® and Lamisil® to FDA's MEDWATCH Program. Reports may be submitted to MEDWATCH by phone at 1-800-FDA-1088, by fax at 1-800-FDA-1078, by mail at MEDWATCH, HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20852-9787, or on the MEDWATCH web site at www.fda.gov/medwatch.

============================================================
55.) FDA PUBLIC HEALTH ADVISORY ABOUT SPORANOX AND LAMISIL II
============================================================
THE SAFETY OF SPORANOX® CAPSULES AND LAMISIL® TABLETS FOR THE TREATMENT OF ONYCHOMYCOSIS
The Food and Drug Administration (FDA) is issuing a public health advisory concerning Sporanox® (itraconazole) Capsules and Lamisil® (terbinafine hydrochloride) Tablets for the treatment of onychomycosis. It is important for physicians to be aware of the association of congestive heart failure and hepatic adverse events with the administration of these therapies. Prior to prescribing systemic antifungal drug therapy for the treatment of onychomycosis, healthcare professionals should consider this new safety information.

Sporanox® Capsules and Lamisil® Tablets, synthetic antifungal agents, are approved in the United States for the treatment of onychomycosis [Sporanox® Capsules, Oral Solution, and Injection are also approved for the treatment of serious systemic fungal infections (e.g., esophageal candidiasis, aspergillosis, blastomycosis, and histoplasmosis).]

CARDIAC RISKS

FDA believes that there is a small but real risk of developing congestive heart failure associated with Sporanox® therapy. Recent studies conducted in dogs and healthy human volunteers revealed negative inotropic effects with intravenous (IV) itraconazole. In these studies, once the drug was stopped the negative inotropic effects resolved. The mechanism for these cardiac effects has not been determined.

Since becoming aware of these findings, FDA reviewed spontaneous post-marketing reports received between September 1992 and April 2001 for congestive heart failure (CHF) in association with itraconazole use. During this period, FDA received 94 U.S. and international spontaneous reports of CHF in which itraconazole was listed as a suspect drug. In 58 of the 94 cases, FDA believes itraconazole contributed to or may have been the cause of CHF. In 26 of the 58 cases, itraconazole was being administered for the treatment of onychomycosis. Of these 58 cases, 28 were hospitalized. Death was reported in 13 cases. However, the causal relationship between the 13 deaths and itraconazole is unclear because of confounding factors, including 10 of the 13 patients who had serious underlying conditions.

Because of the low but possible risk of cardiac toxicity, Sporanox® should NOT be administered for the treatment of onychomycosis in patients with ventricular dysfunction such as CHF or a history of CHF. If signs or symptoms of CHF occur during treatment for onychomycosis, Sporanox® should be discontinued.

If signs or symptoms of CHF occur during treatment for more serious systemic fungal infections, continued Sporanox® use should be reassessed as to the appropriate risk benefit analysis in relationship to any other therapeutic options.

HEPATIC RISKS

Both Sporanox® and Lamisil® have been associated with serious hepatic toxicity, including liver failure and death, including some cases involving patients who had neither pre-existing liver disease nor a serious underlying medical condition.

As of April 2001, the FDA is aware of 16 cases of liver failure in association with Lamisil® Tablet use (including 11 deaths and two liver transplantations). These patients received Lamisil® Tablets for the treatment of various dermatologic conditions, including onychomycosis.

FDA's concerns about hepatic risks associated with the use of Lamisil® do not apply to topically applied formulations of terbinafine, such as Lamisil® Solution and Lamisil® AT Cream.

As of March 2001, the FDA is aware of 24 cases of liver failure associated with Sporanox® use (including 11 deaths). These patients received Sporanox® for the treatment of either onychomycosis or systemic fungal infections.

Given the possible risks associated with both drugs, FDA wants healthcare providers to be aware of this new safety information for the two most commonly prescribed systemic onychomycosis drug therapies. Because of these risks, the new labeling for both Sporanox® and Lamisil® recommends that healthcare providers obtain nail specimens for laboratory testing prior to prescribing the medications for onychomycosis to confirm the diagnosis. However, there is insufficient data to allow FDA to make any kind of statement about the comparative safety of Sporanox® and Lamisil®.

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CISAPRIRIDE (Janssen-Cilag Pharmaceutica) PROPULSID, PREPULSID
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56.) [Cisapride and risk of cardiac complications].
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Minerva Pediatr 1999 Sep-Oct;51(9-10):309-11 

[Article in Italian]

Cataldo F.

Clinica Pediatrica R, P. O. Aiuto Materno, Palermo.

Cisapride is a prokinetic agent thought to be without severe side effects. Recently, rare cisapride-induced cardiotoxic effects (QT interval prolongation, ventricular arrhythmias) have been reported, raising questions about its safety. Some risk factors have been reported: overdosage of cisapride, association with some drugs inhibiting hepatic metabolism via the cytochrome P450 3A4 enzymatic system (such as azole antifungals, macrolide antibiotics, non sedating antihistamines), other pharmacological agents increasing the parasympathetic tone by raising the effect of cisapride (such as ranitidine and cimetidine), electrolyte abnormalities (such as low serum levels of calcium, potassium and magnesium in the blood), liver dysfunctions, congenital long QT syndrome, and infants born before 36 weeks' gestation, for three months after birth. Physicians, prescribing cisapride should pay attention to these risk factors, to avoid the possibility of a rare cardiac adverse effect.

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57.) FDA, Janssen bolster cardiac risk warnings for cisapride.
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Am J Health Syst Pharm 2000 Mar 1;57(5):414 

Miller JL.

Publication Types: 
News 
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58.) [The proarrhythmogenic activity of non-anti-arrhythmia drugs. Is treatment with antihistamines and cisapride safe]?
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Vutr Boles 1999;31(2-3):5-9 

[Article in Bulgarian]

Pelov R, Tankova L, Krushkov I.

The non-antiarrhythmic drugs, which possess antiarrhythmic properties could induce dangerous, potentially fatal arrhythmias--extrasystoles, ventricular tachycardia, sudden cardiac arrest. The arrhythmogenic properties are due to block of the potassium channels of the cells and are realized by prolongation of the QT interval on ECG. Accelerating mechanisms are the bradycardia and the hypokalemia. Such drugs are the H1 blockers--astemisol (hismanal) and terfenadine, the prokinetic cisaprid (prepulsid, propulsid, coordinax) and the macrolides. These preparations should be carefully prescribed and not combined with each other, as well as, with antiarrhythmics and blockers of the cytochrome oxidase system (antifungal antibiotics, metronidazole, cyprofloxacin, antidepressants). During their use the patients have to be followed up for changes in QT, bradycardia, arrhythmia, hypokalemia.

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59.) News/ UK licence for cisapride suspended 
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Drugs: gastrointestinal system 
BMJ 2000;321:259 ( 29 July )

Annabel Ferriman, BMJ 

The product licence for cisapride (Prepulsid), a drug used to treat gastric and digestive disorders in adults and children, has been suspended by the Medicines Control Agency after five deaths in the United Kingdom and 125 deaths worldwide that are thought to be associated with the drug. 

When the Committee on Safety of Medicines recently reviewed the drug, which is made by Janssen-Cilag, it found rare but serious disturbances in heart rhythm associated with it. 

Since 1988, when cisapride was licensed in the United Kingdom, the yellow card schemeunder which doctors report adverse drug reactionshas received 60 reports of serious cardiovascular reactions, five of which were fatal. 

Worldwide there have been 386 reports of serious ventricular arrhythmias (125 of which were fatal) suspected to be due to cisapride and 50 reports of sudden unexplained death. Risk factors predisposing a patient taking cisapride to heart rhythm disturbances, such as interacting medicines, could be identified in many but not all cases. 

In February the US Food and Drug Administration warned doctors that the drug should be used only as a last resort, for patients with the worst cases of gastro-oesophageal reflux disease when other treatments have failed (5 February, p 336). In July Janssen-Cilag suspended marketing of the drug in the United States, but cisapride is still available there through a limited access programme for patients who can show it is of "unique benefit." 

Last week the Department of Health told patients to stop taking the drug and see their doctors over the next few weeks to discuss their treatment. "Stopping cisapride does not carry any risk," the advice said. 

Concern about cardiac arrhythmias has recently led to a Europe-wide review of the risks and benefits of cisapride, which will consider what indications for the drug, if any, are justified. The suspension of UK licences will be reassessed once the review has been completed in 2001. 

Professor Alasdair Breckenridge, chairman of the Committee on Safety of Medicines, said: "We have concluded that at the present time the balance of risks and benefits for cisapride is not favourable. There are several alternatives to cisapride available." 

Health minister Lord Philip Hunt said: "The independent scientific advice of the Committee on Safety of Medicines means that measures short of suspending cisapride marketing authorisations are not adequate to protect UK public health, which is of course our priority." 

Marketing of cisapride has also been suspended in Germany and Canada. 

A spokesman for Janssen-Cilag UK said that serious cardiovascular adverse effects occurred principally in cases where the drug had been used "with contraindicated medicines or in patients with contraindi-cated comorbidities." 

"Janssen-Cilag continues to believe that Prepulsid can be used with an acceptable benefit to risk ratio in appropriate patients." 

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60.) (In)Efficacy of cisapride 
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J Pediatr 2000 Aug;137(2):288-90 

To the Editor:

In the study by Cohen et al,1 cisapride was no better than placebo for relief of symptoms in children with uncomplicated gastroesophageal reflux (GER); 95 infants with uncomplicated reflux were included in a 2-week, randomized, double-blind, placebo-controlled trial.1 The treatment period was rather short,2 and the dropout rate was high (38%),1 which likely reflects the fact that infants with uncomplicated reflux were included. Thus the studied infants had a low-grade disease, making parents less faithful to treatment. The European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other international ad hoc working groups recommend a step-wise approach to the treatment of GER in infants (Table).3-5 Unnecessary medication should be avoided. Therefore cisapride should be considered after failure of parental reassurance and dietary treatment.3-5 Esophageal pH monitoring may be performed as an end point in clinical studies, but there is general consensus that it is not recommended to do any procedure in infants with uncomplicated reflux.3

Although cisapride, in the study by Cohen et al, did not do better than placebo on symptoms in infants with uncomplicated reflux, there was a significant improvement on reflux parameters as measured with pH monitoring.1 The latter is again in line with all other published trials of cisapride in which some of the end point parameters improved significantly during treatment.6 This observation contrasts with the absence of evidence of efficacy of other prokinetics, such as metoclopramide or domperidone.6 Moreover, it is also obvious that the safety profile of cisapride is better than that of bethanechol, metoclopramide, and domperidone, or other therapeutic alternatives in GER (disease).6,7 In the few comparative studies that have been published, cisapride consistently seems the best.

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61.) Should cisapride have been "blacklisted"?
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Arch Dis Child Fetal Neonatal Ed 2000;82:F3-F4 ( January )

Markiewicz M, Vanden Plas Y.

Imperial College School of Medicine at Chelsea & Westminster Hospital, 369 Falham Road, London SW10 9NH.


The recent decision by the Committee on the Safety of Medicine effectively to "blacklist" cisapride for use in neonates has led to considerable debate. The following is intended as a contribution to that debate. 

Indications for the use of cisapride 

In mild gastro-eosophageal reflux disease (GORD) parental reassurance and dietary manipulation is the most appropriate course of action. In moderate or severe GORD, when medication is thought to be necessary, cisapride is considered to be the most appropriate drug.1 Although it is recognised that cisapride does not consistently show an improvement in all the parameters measured, it consistently shows improvement in at least some of them, most of the time.2 Lack of similar data for the efficacy of domperidone, metoclopramide, and erythromycin precludes their use as first line agents for GORD.3 Published findings on the efficacy of cisapride in the treatment of motility related gastrointestinal disorders in premature infants is not entirely clear.2 3 The impending studies of cisapride in the USA should clarify the issue. Cisapride is useful in several other conditions, such as chronic respiratory disease caused by GORD, oesophagitis, functional dyspepsia and postoperative ileus.2 3 

Risks associated with cisapride 

Cisapride is known to prolong the QTc interval.3-5 At therapeutic doses in children, however, there is no direct association between serum concentrations and QTc prolongation. Even in overdose situations the drug has a remarkable safety profile.3-6 

Events which also predispose towards prolongation of the QTc interval must be avoidedthat is, concurrent administration of macrolide antibiotics and azole antifungals, as well as hypokalaemia and hypomagnesaemia. In these situations there is a real risk that QTc prolongation may have an adverse clinical outcome such as torsade des pointes or a clinically significant degree of heart block.3 

Safety data 

Cisapride has been used in 140 million patient treatments of which 18% (25.2 million) were in the age group 0-1 years7 and 9% (12.6 million) in the age group 1-20 years. There was not a single report of a death in a previously healthy child taking an appropriate dose of cisapride.3 The single most worrying feature of cisapride is its potential to prolong the QT interval. However, the fact that there is no agreed method for measuring the normal QTc interval, nor is there an agreed normal range in neonates and premature infants, makes any comment on QTc prolongation rather suspect. Although normal ranges in infants have been published,8 those in premature infants are unknown. A review of published findings suggests that a QTc beyond 0.5 seconds is prolonged,8 implying that cisapride should be withheld in these cases. All reported cases of the arrhythmia torsade de pointes were associated either with concomitant administration of a macrolide antibiotic, or a cisapride overdose, or both.3 5 

From post-marketing experience it can be concluded that cisapride can be used safely at a maximal dose of 0.8 mg/kg/day. It is this dose that we feel should be recommended. 

Safety data for fundoplication for intractable GORD showed the "accepted" risk of death was 0.07% in the group of "normal" children and 0.8% in the group of children who were neurologically impaired.9 The equivalent figures of risk of death from the use of cisapride in the normal population are significantly lower than that1 in 250 000 being a conservative estimate. 

Pharmacokinetic data 

In adults a dose of 10 mg four times a day gives a plasma concentration of 48-76 ng/ml.10 (According to company data on a larger cohort of patients, plasma concentrations range from 14.1192 ng/ml). In 66 premature infants a similar profile (7.1-170 ng/ml) was achieved with a dose of 0.2 mg/kg three to four times a day (unpublished observations). In spite of the immaturity of the drug metabolising capacity and the renal function, the plasma concentrations of cisapride in premature infants appeared very similar to those in term infants, children, and adults.11 

In 41 infants ranging from 351 weeks a similar dose produced plasma concentrations not dissimilar to those of the premature infants, albeit with a lower mean: 42.6 (36.6) ng/ml (range 0155 ng/ml).12 Thus at the appropriate dose, plasma cisapride concentrations in premature and term infants, as well as in children, were within the therapeutic and safe range observed in adults. (Company data suggest that plasma concentrations in older children follow a similar pattern.) 


All premature infants (36 weeks of gestation or less) should have an ECG before starting treatment with cisapride; this should be repeated three days later. This recommendation is based on the fact that premature infants treated with cisapride are thought to be specifically at risk of QTc prolongation. Furthermore, it is very important to ensure that electrolyte status is normal. 

For term infants we do not feel it necessary to check an ECG before starting treatment with cisapride unless there are indications of congenital problems (prolonged QT). 

Concomitant administration of macrolide antibiotics such as erythromycin, clarithromycin, and troleandromycin, as well as azole antifungal agents are contraindicated. 

Cisapride is safe, but can potentially be associated with serious side effects if used inappropriately. We suggest that the Committee on the Safety of Medicine re-evaluate their guidance on cisapride use in infants and children, as has already been suggested.12 Trials shortly to begin in the USA should be used to finalise data on the drug's efficacy and safety. An appropriate license for use in children should be obtained in the UK as soon as possible. 

Cisapride should not be used in the dose range >0.8 mg/kg/day except under strict specialist guidance. Safety monitoring with an ECG 2 to 3 days after starting treatment should be mandatory. Cisapride should not be used in conjunction with macrolide antibiotics and azole antifungals. Hypokalaemia and hypomagnesaemia must be corrected before treatment is started and electrolytes should be checked during treatment. Further information is required about the excretion in breast milk of other pro-arrhythmic drugs such as antihistamines and antidepressants in case drugs given to breast feeding mothers may affect their infants. Premature infants should also have an ECG checked routinely before treatment with cisapride as well as three days after starting treatment. 

Acknowledgments 

We thank the following who contributed to the discussions that formed the basis for our report: Abrahamson S Biswas, I Balfour-Lynn, A Bedford Russell, M Brueton, I Costello, S Craig S, M Elsawi, J Fell, J Hawdon, I Kovar, N Madden, S Mitton, B Planer, R Rivers, E Smith S Spielberg, P Sullivan, M Thomson, J Till, R Tubman, O C Ward. 

Dr Spielberg is employed by Celag Johnson as their chief clinical pharmacologist and attended as a representative for the company. The meeting was not sponsored and all participants attended at their own expense. 

M MARKIEWICZ
Imperial College School of Medicine at Chelsea & Westminster Hospital, 369 Falham Road, London SW10 9NH

Y VANDEN PLAS
AZ-VUB, Department of Paediatrics, Laarbeeklaan 101, 1090 Brussels, Belgium

1. Vandenplas Y, Ashkenazi A, Belli D, Boige N, et al. A proposition for the diagnosis and treatment of gastro-oesophageal reflux disease in children: a report from a working group on gastro-oesophageal reflux disease. Working Group of the European Society of Paediatric Gastro-enterology and Nutrition (ESPGAN). Eur J Pediatr 1993;152:704-711[Medline]. 
2. Vandenplas Y. Clinical use of cisapride and its risk-benefit in paediatric patients. Eur J Gastroenterol Hepatol 1998;10:871-881[Medline]. 
3. Vandenplas Y, Belli DC, Benatar A, et al. The role of cisapride in the treatment of pediatric gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1999;28:518-528[Medline]. 
4. Bedford TA, Rowbotham DJ. Cisapride. Drug interactions of clinical significance. Drug Safety. 1996;15:167-175[Medline]. 
5. Shulman RJ, Boyle JT, Colletti RB, et al. The use of cisapride in children. J Pediatr Gastroenterol Nutr 1999;28:529-533[Medline]. 
6. Volmer PA. Cisapride toxicosis in dogs. Vet Hum Toxicol 1996;38:118-120[Medline]. 
7. Ward RM, Lemons JA, Molteni RA. Cisapride: a survey of the frequency of use and adverse trials in premature newborns. Pediatrics 1999;103:469-472[Medline]. 
8. Schwartz PJ, Montemerlo M, Facchini M, et al. The QT interval throughout the first 6 months of life: A prospective study. Circulation 1982;66:496-501[Abstract]. 
9. Fonkalsrud EW, Ashcraft KW, Coran AG, Ellis DG, Grosfeld JL, Tunell WP, Weber TR. Surgical treatment of gastroesophageal reflux in children: a combined hospital study of 7467 patients. Pediatrics 1998;101(3 Pt 1):419-422[Abstract/Full Text]. 
10. Holloway RH, Downton J, Mitchell B, Dent J. Effect of cisapride on postprandial gastro-oesophageal reflux. Gut 1989;30:1187-1193[Abstract]. 
11. Feenstra A, Benatar A, De Craene T, Vandenplas Y. Cisapride plasma levels and effects on QTc interval and heart rate. J Pediatr Gastroenterol Nutr 1999;28:553(A). 
12. Lander A. The risks and benefits of cisapride in premature neonates, infants, and children. Arch Dis Child 1998;79:469-470[Full Text] 

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62.) Effects of cisapride on QT interval in infants: A prospective study 
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J Pediatr 2000 Aug;137(2):287-8

Guala A, Pastore G, Licardi G, Noe G, Zolezzi F.

To the Editor:

Cisapride, a gastrointestinal prokinetic agent, is being used with increasing frequency in infants with gastroesophageal reflux disease (GERD). The drug is generally well tolerated; however, in anecdotal reports there has been an association with cardiac arrhythmias as a result of QT prolongation.1,2 Risk factors included preterm and newborn age, heart disease, electrolyte abnormalities, and genetic syndromes with prolonged QTc. In addition, overdosage or concomitant use of drugs that are metabolized through P 450 cytochrome (ie, macrolide antibiotics, phenothiazines, azole antifungals) increase the serum level of cisapride.

In 2 recent prospective studies,3,4 children with reflux or feeding intolerance and other concomitant diagnosis were treated with cisapride at a dose of 0.6 to 1.2 mg/kg/d. Cisapride significantly lengthened QTc in 23 out of 136 children, but other factors that might contribute to a long QT were present. As recently suggested by Grifka,5 a prospective study evaluating cardiac functions before and during cisapride assumption would be useful to address this clinical question.5

A prospective study between January and December 1998 was conducted to evaluate the cardiac effects of cisapride on 31 infants with GERD. All the infants (mean age 5.1 months, range 1.5 to 20 months) born at term and had Apgar scores >7, and they were otherwise healthy. In all cases the diagnosis of GERD was ascertained by upper gastrointestinal tract contrast x-ray films or by prolonged monitoring of distal esophageal pH. Cisapride was prescribed at 0.8 mg/kg/d (range 0.67 to 0.85 mg/kg/d), divided in 4 doses. No child was taking any other medication know to increase the cisapride serum level.

Electrocardiography (ECG) was performed on all the infants with the same device (Cardioline, Digital ECG, Delta Plus) at a paper speed of 25 mm/s. Heart rate and PR, QRS, QT, and QTc intervals were measured and averaged from 3 cardiac cycles. The QT interval was corrected to the patient's heart rate by Bazett's method. Measurements were done by the same investigator. Baseline ECG was performed before cisapride was started. ECG was repeated 5 days later, at least 2 hours after the first daily dose was administered, because the cisapride level peaks 1 to 2 hours after oral administration, and the steady-state is reached after 2 to 3 days.6 The variables are expressed as mean ± SD. A paired t test was used to compare continuous variables. Heart rate, PR, QRS, and QT intervals in baseline ECG and in ECG after therapy were in the normal range. The QTc interval, measured before therapy was started, was 328 ± 37 ms (range 210 to 440 ms). The corresponding figures during cisapride therapy were 306 ± 42 ms (range 200 to 440 ms) (P > .05).

A recent Medical Position Statement of the European Society of Paediatric Gastroenterology, Hepatology, and Nutrition7 stated that children with no known risk factors for cisapride need “no special safety procedures regarding potential cardiac adverse events.” The Medical Position Statement of the North American Society for Pediatric Gastroenterology and Nutrition8 “does not recommend that every patient on cisapride should receive an ECG; however, the clinician must rely on his or her judgment about the need for an ECG.” Our study confirms that in the absence of any known or suspected risk factors for cisapride, infants do not have any cardiac side effects during cisapride therapy.

As suggested by Lander,9 we continue to perform a baseline ECG and an ECG control after 5 days of cisapride. The first ECG is focused to recognize patients with genetic syndrome of prolonged QTc,10 and the second ECG is used to identify patients who are idiosyncratic to cisapride (ie, heterozygotes for congenital long-QT syndrome). To assess the frequency of cardiac adverse events in patients during cisapride therapy, a large-scale surveillance study is required.

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63.) [Long QT interval and malignant ventricular arrhythmia during treatment with cisapride. Report of a clinical case].
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Ital Heart J 2000 Aug;1(8 Suppl):1055-8 

[Article in Italian]

Massari FM, Trevano FQ, Diehl L, Romano S.

Divisione di Cardiologia, Ospedale Maggiore IRCCS, Milano.

Cisapride is largely used in the treatment of secondary symptoms due to gastroesophageal reflux, as a prokinetic drug that increases and coordinates gastrointestinal motility and gastroesophageal sphincteric tone. Potential proarrhythmic effects of the drug have been demonstrated in several clinical studies and reported by the drug manufacturers. These effects are increased in the presence of risk factors such as renal insufficiency, electrolytic disorders, coronary artery disease and positive history for arrhythmias including atrial fibrillation and bradyarrhythmia. Therefore in such cases a careful cardiac evaluation, both clinical and electrocardiographic, is recommended. This is still not routinely performed. The following case report shows an example in which diagnosis of increased QT interval due to cisapride was missed. This caused hospitalization for malignant ventricular arrhythmias and recurrent syncope.

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64.) Cisapride and Fatal Arrhythmia
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The New England Journal of Medicine -- July 25, 1996 -- Vol. 335, No. 4 

To the Editor: 

From September 1993, the month in which the marketing of cisapride (Propulsid, Janssen Pharmaceutica, Titusville, N.J.) began, to April 1996, the Food and Drug Administration's MedWatch reporting program (telephone number, 1-800-FDA-1088) received reports of 34 patients in whom torsade de pointes developed and 23 in whom prolonged QT intervals developed while using this drug. Four were reported to have died, and 16 responded to resuscitation after cardiopulmonary arrest. Arrhythmia was often preceded by syncopal episodes. Seven of the patients were children, and one was an adolescent. 

Thirty-two of the 57 patients (56 percent) were also taking medications of the imidazole class (ketoconazole, fluconazole, itraconazole, and metronidazole) or macrolide antibiotics (erythromycin and clarithromycin), which have been found to inhibit the cytochrome P-450 3A4 enzyme system that affects cisapride metabolism and results in increased serum cisapride levels. (1,2) 

There were temporal associations between the onset of arrhythmia and the initiation of cisapride, an increase in the dose, or the addition of an imidazole antifungal agent or macrolide antibiotic. For most patients, arrhythmia stopped after the discontinuation of cisapride or the imidazole or macrolide antibiotic (or both). In 9 of the 15 patients tested, serum cisapride levels were higher than the mean maximal levels found in clinical studies, although 2 patients with normal serum levels had recently undergone hemodialysis. Torsade de pointes and prolongation of the QT interval recurred in two patients who were rechallenged with cisapride and one rechallenged with ketoconazole. Other factors that may have increased the risk of arrhythmia in the 57 patients included histories of coronary disease and arrhythmia (predominantly atrial fibrillation) in 22 (39 percent), renal insufficiency or renal failure in 14 (25 percent), electrolyte imbalance in 11 (19 percent), and long-term use of medications associated with arrhythmia or prolonged QT intervals (such as amiodarone and phenothiazines) in 7 (12 percent). 

The development of torsade de pointes and prolonged QT intervals in cisapride users appears to be associated with conditions that affect the metabolism of the drug. These include the concomitant use of medications that are metabolized by the cytochrome P-450 3A4 isozyme, the presence of renal insufficiency, and the administration of high doses of cisapride. (3) Also, because there is some evidence that cisapride may be arrhythmogenic, (4,5) users with histories of arrhythmia and cardiac disease may have an increased risk, beyond that conferred by their disease, of prolonged QT intervals and torsade de pointes. 

As stated by the manufacturer in two letters (1,2) addressed to physicians in the United States in 1995 and in a boxed warning recently added to the cisapride product-information label, physicians should avoid prescribing cisapride to patients who are taking ketoconazole, fluconazole, itraconazole, miconazole, erythromycin, clarithromycin, or troleandomycin. In addition, caution should be exercised when prescribing cisapride to patients who are taking medications known to prolong the QT interval and to those with renal insufficiency, a history of arrhythmia, and cardiac disease. 


Diane K. Wysowski, Ph.D. 
Janos Bacsanyi, M.D. 
Food and Drug Administration 
Rockville, MD 20857

References 

1. Klausner MA, Janssen Pharmaceutica Research Foundation. Dear Doctor letters. February 3, 1995, October 14, 1995.
Return to Text 

2. Ahmad SR, Wolfe SM. Cisapride and torsades de pointes. Lancet 1995;345:508. 
Return to Text 

3. Bran S, Murray WA, Hirsch IB, Palmer JP. Long QT syndrome during high-dose cisapride. Arch Intern Med 1995;155:765-8.
Return to Text 

4. Olsson S, Edwards IR. Tachycardia during cisapride treatment. BMJ 1992;305:748-9.
Return to Text 

5. Kaumann AJ. Do human atrial 5-HT4 receptors mediate arrhythmias? Trends Pharmacol Sci 1994;15:451-5.
Return to Text 

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65.) Media: 301-827-6242
January 24, 2000 Broadcast Media: 301-827-3434
Media: 800-INFO-FDA
FDA UPDATES WARNINGS FOR CISAPRIDE
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The Food and Drug Administration (FDA) is advising health care professionals and patients of important new information, including recommendations for performing diagnostic tests, that should be considered prior to any use of the drug cisapride (Propulsid). Cisapride is a treatment for severe nighttime heartburn in patients with gastroesophageal reflux disease (GERD) who do not adequately respond to other therapies. The new measures are being recommended to help physicians avoid giving cisapride to patients at known risk of rare-- but serious--cardiac events associated with the drug.
As part of an ongoing risk management effort, FDA is also announcing a public advisory committee meeting to be held on April 12, where the safety of the drug and additional methods to reduce the occurrence of adverse events will be discussed.

Meantime, patients who already take the drug are encouraged to ask their doctors about having the recommended tests performed and whether they should pursue other treatment options.

Today's actions are prompted by continuing reports of heart rhythm disorders and deaths associated mostly with the use of the drug in people who are either taking certain other medications or who have certain underlying conditions that are known risk factors. A recent analysis of 270 adverse event reports (including 70 fatalities) revealed that approximately 85% of these cases occurred in patients with these identifiable risks.

The new risk management measures are being announced in conjunction with a "Dear Healthcare Professionals" letter issued today by the drug's sponsor, Janssen Pharmaceutica of Titusville, NJ, that summarizes the updates being made to the warnings and precautions sections of the drug's label. The changes include recommending that physicians perform an electrocardiogram and certain blood tests prior to prescribing the drug.

The revised labels also list the contraindicated drugs and underlying conditions which put patients at increased risk. Cisapride should not be used by patients taking some of the following types of medications: anti-allergy, anti-angina, anti-arrhythmics (irregular heart rhythm), antibiotics, anti-depressants, anti-fungals, anti-nausea, anti-psychotics and protease inhibitors (anti-HIV infection).

It is also advised that patients with any of the following conditions not take the drug: history of irregular heartbeats, abnormal electrocardiogram (ECG or EKG), heart disease, kidney disease, lung disease, low blood levels of potassium, calcium or magnesium, eating disorder (such as bulimia or anorexia), dehydration or persistent vomiting.

Cisapride was approved by FDA in tablet form in 1993, and in suspension form in 1995. Unlike drugs that reduce stomach acid, cisapride works by a prokinetic mechanism that moves the harmful acids through the digestive tract thus preventing its painful reflux into the esophagus. A previous warning regarding cardiac risks was issued in June 1998 (see FDA Talk Paper T98-39).

Healthcare providers are encouraged to report any adverse events related to cisapride to Janssen Pharmaceutica (800-526-7736) or the FDA. Reports may be submitted to FDA by telephone (800-FDA-1088), fax (800-FDA-0178), online at www.fda.gov/medwatch/ or by mail to:

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66.) New Safety Recommendations for Use of Cisapride (Propulsid)
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Source: Harvard Heart Letter
April 2000 

Heart Lines

This month the Food and Drug Administration will hold a public advisory committee meeting to further discuss the safety of cisapride (Propulsid) and how to reduce the chances that someone will experience a severe adverse event from this drug.

The FDA first approved cisapride in tablet form in 1993 and then in liquid form in 1995. It is used to treat severe nighttime heartburn, usually due to gastroesophageal reflux disease (a condition where the band of muscle that prevents stomach acid from leaking back into the esophagus relaxes spontaneously, creating a painful heartburn-like sensation). Many drugs used to treat this condition suppress production of stomach acids. Cisapride works a little differently, moving the harmful acids through the digestive tract thereby preventing their painful reflux into the esophagus. Because this drug can be risky, it is generally reserved for use in patients who have not responded well to lifestyle changes or other medications used to manage gastroesophageal reflux disease.

In June 1998, several reports of serious adverse reactions in patients taking cisapride prompted the FDA to issue a warning about the drug. The medical problems included heart-rhythm disorders and death (most often occurring in people with certain health problems or who were taking other medications). Although it could not find a direct link between the reported problems and cisapride, the FDA did strengthen the precautions for use of this drug. A more recent analysis of 270 adverse event reports (including 70 deaths) suggests that roughly 85% of these cases were patients with these identifiable risks.

In January 2000, the FDA bolstered its efforts to reduce the likelihood of complications from cisapride by recommending that physicians consider performing an electrocardiogram and certain blood tests before prescribing it. New labeling lists drugs and underlying conditions that put patients at increased risk. Cisapride should not be used by patients taking some of the following types of medications: anti-allergy, anti-angina, anti-arrhythmics (to treat an irregular heart rhythm), antibiotics, antidepressants, anti-fungals, anti-nausea, antipsychotics, and protease inhibitors (to treat HIV infection). Also, patients with any of the following conditions should not take the drug: history of irregular heartbeats; abnormal electrocardiogram; heart disease; kidney disease; lung disease; low potassium, calcium, or magnesium levels; an eating disorder (such as bulimia or anorexia); dehydration or persistent vomiting.

If you are taking Propulsid (cisapride), then most likely your doctor is aware of the potential problems, but it may be worth having a conversation about it. If you are not on this medication but your doctor recommends it, be sure that he or she knows your complete medical history and is aware of all other medications you take. And ask about what, if any, medical tests you might need before you start taking this drug.

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67.)JANSSEN PHARMACEUTICA STOPS MARKETING CISAPRIDE IN THE US
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Janssen Pharmaceutica Inc., of Titusville, N.J., has announced that it has decided to stop marketing cisapride (Propulsid) in the United States as of July 14, 2000. The effective date of the voluntary action is intended to provide adequate time for patients and physicians to make alternative treatment decisions.
Cisapride is a prescription drug treatment approved only for severe nighttime heartburn experienced by adult patients with gastroesophageal reflux disease (GERD) that does not adequately respond to other therapies.

As of December 31, 1999, use of cisapride has been associated with 341 reports of heart rhythm abnormalities including 80 reports of deaths. Most of these adverse events occurred in patients who were taking other medications or suffering from underlying conditions known to increase risk of cardiac arrhythmia associated with cisapride.

Patients who are currently prescribed cisapride are urged to promptly contact their health care providers to discuss alternative treatments.

Physicians who are treating patients with severely debilitating conditions for whom they believe the benefits of the cisapride may still outweigh its risks are encouraged to contact Janssen at 1-800-JANSSEN. The company will continue to make the drug available to patients who meet specific clinical eligibility criteria for a limited-access protocol.

Since the drug’s approval in 1993, Cisapride’s labeling has been revised several times (most recently in January 2000, see FDA Talk Paper T00-6) to inform health care professionals and patients about the drug’s risks. Despite these risk management efforts, the firm decided in consultation with the Food and Drug Administration that continued general US prescription access to the drug poses unacceptable risks.

A public advisory committee meeting, previously scheduled for April 12 to discuss ways to reduce the occurrence of adverse events associated with cisapride, has been cancelled.

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DATA-MEDICOS/DERMAGIC-EXPRESS No 3-(100)  27/05/2.001 DR. JOSE LAPENTA R. 
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