EDITORIAL ESPANOL:

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Hola amigos de la red,, DERMAGIC de nuevo con ustedes, La Dra Clara Jaramillo (Colombia), me pide un artículo sobre VERRUGA VULGAR Y BLEOMICINA, aproveche la oportunidad para hacer una corta revisión del tema. Al final una monografía del producto. Definitivamente una alternativa terapéutica para el tratamiento de esta patología que a veces se hace recalcitrante. 

Bienvenidas a DERMAGIC Drs. Nelly Vigil (Valencia), Altanisia Ramunno (Maracay), Venezuela.

En el attach una lámina ilustrativa del tema: verrugas periungueales

Próxima edición: ENCONTRADOS EN LA RED.

Saludos,,,

Dr. José Lapenta R.,,,

 EDITORIAL ENGLISH:

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Hello friends of the net, DERMAGIC again with you, The Dra Clara Jaramillo (Colombia), requests me a topic published in VENEZUELAN DERMATOLOGY on WART AND BLEOMICINA, besides I make it a short revision of the topic. At the end a monograph of the product bleomycin. Definitively an alternative for the treatment of this pathology that sometimes are recalcitrant.

NEXT EDITION: FOUND IN THE NET...!!!

In the attach an illustrative sheet of the topic: periungual warts. 

Greetings,,,

Dr. José Lapenta R. 

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DERMAGIC/EXPRESS(58)

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VERRUGA VULGAR Y BLEOMICINA /VERRUCA VULGARIS AND BLEOMYCIN

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1.) Solución salina hipertonica vs. bleomicina intralesional en el

tratamiento de verrugas vulgares / Ensayo terapeutico.

2.) Dermatography with bleomycin as a new treatment for verrucae vulgaris.

3.) Bleomycin: revival of an old drug.

4.) Bleomycin sulfate in the treatment of mosaic plantar verrucae: a follow-up study.

5.) Histologic, pharmacologic, and immunocytochemical effects of injection of bleomycin into viral warts [see comments]

6.) Intralesional injection of bleomycin sulphate into resistant warts in renal transplant recipients versus non-transplant warty patients.

7.) Therapeutic evaluation for intralesional injection of bleomycin sulfate in 143 resistant warts.

8.) Reduced dose of bleomycin in the treatment of recalcitrant warts.

9.) The treatment of resistant warts with intralesional bleomycin: a controlled clinical trial.

10.) Bleomycin in the treatment of recalcitrant warts.

11.) The common wart: intralesional treatment with bleomycin sulfate.

12.) Bleomycin-lidocaine mixture reduces pain of intralesional injection in the treatment of recalcitrant verrucae.

13.) Intralesional bleomycin sulfate therapy for warts. A novel bifurcated needle puncture technique.

14.) Intradermal bleomycin injections into normal human skin. A histopathologic and immunopathologic study.

15.) Onychodystrophy induced by intralesional injection of bleomycin for periungual 

wart.

16.) Nail dystrophy following intralesional injections of bleomycin for a periungual wart.

17.) Raynaud's phenomenon and intralesional bleomycin [letter]

18.) Intralesional bleomycin and Raynaud's phenomenon [see comments]

19.) BLEOMYCIN (Systemic), The Product

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1.) SOLUCION SALINA HIPERTONICA Vs. BLEOMICINA INTRALESIONAL EN EL

TRATAMIENTO DE VERRUGAS VULGARES / ENSAYO TERAPÉUTICO

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Dr. Ricardo Pérez Alfonzo

Dr. Eduardo Weiss

Dr. Jaime Piquero Martín

Dra. Marcela Fundamínski de Weiss

Pérez Alfonzo R, Weiss E, Piquero Martin J,

Fundarnisky de Weiss M: Solución Salina Hipertónica

VS. Bleomicina intralesional en el tratamiento de

Verrugas Vulgares. Dermatología Venezolana 3Q: i7~

178, 1992

RESUMEN

Se realizo un estudio doble ciego con 37 pacientes, con verrugas vulgares en diversas localizaciones, tratando un grupo con solucion salina hipertónica al 23,4% y otro grupo con sulfato de bleornicina al 0,1%. No se

encontraron diferencias estadfsticamente significativas, entre estas dos sustancias al comparar sus porcentajes de curación.

SUMMARY

A donble-blind srudy of 37 patenrs, with warts in differents locations was made. One group was treated with saline hipertonic solution <23,4%) and the otner group with bleomycin -sulfate (0,1%). We found no statistical difierence between the two groups.

Palabras Clave: Verrugas vulgares. Solución salina hipertónica. Bleomicina.

INTRODUCCION

las verrugas vulgares (V.V.), son tumores benignos, epidérmicos, causados por la inteccion de un papova-virus.

Múltiples tratamientos han sido empleados para la erradicación de las V.V., pero es importante puntualizar que la terapéutica a usar, nunca deberá producir más problemas que la verruga por sí misma, ya que es bien conocido el fenómeno de regresión espontánea descrito por Massing y Epstein,1 al estudiar la historia natural de niños con V.V.

Los tratamientos empleados para la erradicación de V.V. van desde excisión quirúrgica; curetaje; cauteri-zación con ácidos o cáusticos, hiper-termia o con corriente de alta fre-cuencia; crioterapia con nieve carbó-nica o nitrógeno líquido; radioterapia; fUación con formalina o glutaraldehí-do; vesiculación con cantaridina; uso de queratolíticos; citostáticos como podofilina; 54luorouracilo, bleomici-na; vitamina A; dinitroclorobenceno, hasta incluso hipnosis.

Cualquiera sea el método usado, siempre existirá una inexplicable rata de fallas o de recurrencias. Además la terapéutica a emplear, deberá sopesar la posibilidad de efectos secundarios en ocasiones peligro-sos, sobre todo en niños con V.V. múltiples;

La bleomicina es el nombre genérico para un grupo de antibióticos glicopeptídicos-ulfurosos citotóxicos producidos por el Streptomyces venicillus. La bleomicina ha despertado mucho interés como droga antineoplásica, ya que aparentemente carece de un franco efecto inmunosupresor. Las reacciones tóxicas más frecuentemente encontradas como son cutáneas y pulmonares, ocurren con dosis totales mayores a 150 mg o 300 mg, respectivamente. Los primeros reportes de la utilidad de la bleomicina en el tratamiento de "tumores benignos virales tipo ADN" son presentados por Mishima y Ma-tunaka en 1972, encontrando una completa regresión en un caso de condiloma acuminado y dos casos de V.V., posterior a la inyección endovenosa de la misma. Fujita, es el primero en usar la bleomicina en solución salina al 0,1%, intralesional, en el tratamiento de V.V. obteniendo una curación del 100%.2 A partir de entonces, diferentes autores han encontrado diversas ratas de cura-ción, variando éstas desde un 63%, en los estudios de Bremmer;2 50% para Abbott;3 84% reportado por Hudson;4 hasta un 85,8% encontra-do por Rassi et al.~ Sin embargo, estudios recientes realizados por Munkvad et al,6 no encontraron dife-rencias significativas entre el grupo tratado con bleomicina y el grupo placebo.

Se cree que la bleomicina, no sólo actúa por inhibición de la síntesis de ADN del papova virus que causa la V.V., sino que también pre-senta una afinidad por la piel, así cuando el antibiótico es localmente inyectado, su capacidad destructiva aumenta por la formación de micro-trombosis.7

Por otro lado, la solución salina hipertónica en concentraciones del 18%, 20%, 23,4% y 25% ha sido usada por algunos autores en las técnicas de fleboesclerosis,6-10 pro-duciendo irritación moderada y lenta de la íntima vascular con inflama-ción, edema y oclusión del lumen por reemplazo con tejido cicatricial.10 La extravasación de estas soluciones hipertónicas produce invariablemente un edema importante con posterior necrosis de la zona afectada.

El fin de este estudio, ha sido investigar el efecto clínico de la aplicación intralesional de la solución salina hipertónica y compararlo con la solución de sulfato de bleomicina en el tratamiento de V.V.

PACIENTES Y MÉTODOS

Se realizó un estudio doble ciego con 37 pacientes de ambos se-xos, con edades comprendidas entre 9 y 61 años.

Los pacientes incluidos en la investigación, fueron distribuidos en dos grupos: uno de los grupos fue tratado con solución salina hipertóni-ca al 23,4% y el otro con sulfato de bleomicina al 0,1%.

Durante el desarrollo del estudio, tanto los investigadores como los pacientes desconocieron el trata-miento empleado en cada caso. Cada modalidad terapéutica fue iden-tificada por un código que sólo fue revelado en el momento de finaliza-da la investigación.

Las soluciones a emplear fueron preparadas bajo condiciones de es-terilidad. La solución de bleomicina fue reconstruida a partir de ampollas de BlenoxaneR (laboratorios Bristol), disolviendo 15 mg de sulfato de bleomicina en 15 cc de solución sali-na normal. La solución salina hiper-tónica fue preparada a una concen-tración de 23,4% en agua destilada.

Las soluciones a emplear fueron conservadas en nevera por un tiempo no mayor de 3 meses.

La bleomicina y la solución sali-na hipertónica fueron administradas intralesionales, con inyectadoras descartables de 1 ml, con aguja # 27. Las dosis variaron entre 0,2 cc a

0,6 cc, de acuerdo al tamaño de cada lesión; siempre se aplicó anes-tesia local infiltrativa con xilocaina al 1%, sin epinefrina.

Se realizó control fotográfico de

las lesiones, pre-tratamiento, al día 14 y 30 de iniciado el tratamiento, valorándose en cada una de estas visitas la evolución y la tolerancia al mismo.

Las soluciones fueron reaplicadas, también intralesional, a los 14. días y a los 30 días de la primera aplicación, cuando así se consideró necesario, si en este lapso de tiem-PO no se observó curación, se tomó al paciente como un fracaso.

En los casos necesarios, siempre en forma doble ciego, se realizó en los controles sucesivos curetaje con cureta roma de las lesiones tra-tadas.

Los resultados fueron analizados estadísticamente, mediante la comparación de dos porcentajes y el chi2.

RESULTADOS

De los 37 pacientes que se incluyeron en la investigación completa. ron el estudio 31, de los cuales 15 correspondieron al grupo de solución salina hipertónica al 23,4% y 16 al grupo tratado con bleomicina al 0,1%.

Del grupo tratado con solución salina hipertónica al 23,4% curaron 11 pacientes, lo que representa un

73%; del grupo tratado con bleomid-na al 0,1% curaron 15 pacientes, lo que representa un 93% (ver Cuadros N0 1 y 2>. Al comparar estadística-mente estos resultados, no encontra-mos diferencia significativa entre es-tos métodos.

CUADRO N0 1

% DE CURACIÓN CON SOLUCIÓN SALINA HIPERTÓNICA AL 23,4%

Y BLEOMICINA AL 0,1% INTRALESIONAL,

EN EL TRATAMIENTO DE VERRUGAS VULGARES

casos Casos % de

Tratados Curados Curación

Solución Salina 15 11 73

Hipertónica 23,4%

Sulfato Bleomicina 16 15 93

CUADRO N~ 2

CASOS CURADOS Y NO CURADOS CON SOLUCIÓN SALINA

HIPERTÓNICA AL 23,4% Y BLEOMICINA AL 0,1% INTRALESIONAL EN EL TRATAMIENTO DE VERRUGAS VULGARES

Casos Casos Total de

Curados No curados Casos

Solución Salina 11 4 15

Hipertónica 23,4%

Sulfato Bleomicina 15 1 16

Total 26 5 31

DISCUSIÓN

La efectividad en el tratamiento de las V.V. con solución salina hiper-tónica al

23,4% es comprable esta-

Es importante recalcar la ocurren- disticamente con la curación obteni

rrencia de necrosis en los dos gru- da por el sulfato de bleomicina en pos de tratamiento, lo cual nos haría solución al 0,1%.

descartar la natural regresión espon- La utilización de la concentración 

tánea que pudiesen presentar nues- del 23,4% en la solución salina, se 

tros pacientes. basó en los trabajos de esclerotera-

Según la localización las V.V. se pia en varicosidades en '~estallido de

distribuyeron en los grupos de trata- cohete",10 pero probablemente mayo-

miento como sigue; solución hipertó- res concentraciones pudiesen au-

nica: manos 14, pies 1, periungueal mentar su efectividad, sin que nece-

6 y para la bleomicina: manos 8, pies sariamente aumenten los efectos

6, periungueal 4 y otras 1 (ver Cua- indeseables, por lo que actualmente 

dro N0 3). nos encontramos ensayando con soluciones

salinas hipertónicas de mayores concentraciones.

CUADRO N~ 3

LOCALIZACIÓN DE LAS VERRUGAS VULGARES

TRATADAS CON SOLUCIÓN SALINA HIPERTÓNICA AL 23,4%

Y CON SULFATO DE BLEOMICINA AL 0,1%

Manos Pies Periungueal Otras

Solución Salina 14 1 6 O 

Sulfato Bleomicina 8 6 4 1

Los efectos colaterales sensiblemente iguales para las dos sustancias empleadas fueron: dolor local al momento de la inyeccion y signos inflamatorios de intensidad variable en los proximos dias a la infiltracion de las lesiones.

Aunque la casuística total es baja (37 pacientes), la rigurosidad del estudio doble ciego, convierte a la solución salina hipertónica al 23,4% en una alternativa tan eficaz como el sulfato de bleomicina, exento de los efectos colaterales de este último y con una muy importante reducción de los costos del tratamiento.

DISCUSION (continuación)

Algunos pocos pacientes fueron tratados con solución salina isotóni-ca (0,9%), no logrando las curaciones obtenidas con los otros preparados; no se incluyeron estos pacientes en los análisis por ser una muestra muy escasa (10 pacientes) y no considerarse estadísticamente representativa.

CONCLUSIÓN

La solución salina hipertónica al 23,4% intralesional, en el tratamiento de V.V. ofrece una alternativa segura, económica y tan efectiva como el sulfato de bleomicina al 0,1%.

BIBLIOGRAFíA

1.- Michima 1, Matunake M: Effect of bleomycin on benign and malignant cutaneous tumors. Acta Dermatov~ ner 1972; 52: 211-215.

2.- Bremmer RM: Warts: Treatment with intralesional bleomycin. Cutis 1976; 18: 2~266.

3.- Abbott LG: Treatment of warts with bleomycin. Arch Dermatol 1976; 112:

1179.

4.- Hudson AL: Treatment of plantar warts with bleomycin. Arch Dermatol

1976; 112: 1179.

5.- Rassi E, Soto JM, Battan J, Villalba

L: Bleomicina intralesional en verru-gas vulgares. Presentado en el XIV Reunión Anual de la Sociedad Ven~ zolana de Dermatología. Caracas, 1978.

6.- Munkvad M, Genner J, Staberg B, Kongshólm H: Dermatologica. 1983; 167: 8689.

7. - Olson Rl: Plantar warts yield to DNA inhibitor. JAMA 1977; 237: 94~941.

Los efectos colaterales, sensible-mente iguales para las dos sustancias empleadas fueron: dolor local en el momento de la inyección y signos inflamatorios de intensidad variable en los próximos días posterior a la infiltración de la o las lesiones.

8.- Alderman DB: Therapy for essential cutaneous telangectasia. Postgrad Med 1977; 61: 91-95.

9.- McPheeters HO, Anderson JK:

Treatment of varicose veins and hemorrhoids. Philadelphia, F.A. Da-vis, 1938.

10.- Bodian EL: Techniques of

sclerotherapy for sunburst venous blemishes. J Dermatol Surg Oncol

1985; 11: 6~704.

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2.) Dermatography with bleomycin as a new treatment for verrucae vulgaris.

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van der Velden EM; Ijsselmuiden OE; Drost BH; Baruchin AM

Department of Dermatovenerology, Academic Hospital Rotterdam-Dijkzigt, The 

Netherlands.

Int J Dermatol (UNITED STATES) Feb 1997 36 (2) p145-50 ISSN: 0011-9059

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE 

Journal Announcement: 9709

Subfile: INDEX MEDICUS

BACKGROUND: Common warts are caused by infection with human papillomaviruses (HPVs). 

Many, largely ineffective, treatment modalities have been tried in the past. The 

cytostatic drug bleomycin has been found to selectively affect squamous cell and 

reticuloendothelial tissue, but the method of its delivery directly into affected 

tissue such as warts has been of little efficacy. This study assessed the efficacy 

of a new mode of intralesional administration of bleomycin by dermatography. 

METHODS: The warts of patients were treated with increasing concentrations of 

bleomycin using the van der Velden Derma-Injector, a modified tattooing machine, 

under local or block anesthesia. The effects of the procedure were evaluated 1, 24, 

and 48 h later and the patients followed for up to 2 years. RESULTS: Thirteen 

patients with warts on the hands and/or feet, resistant to conventional therapy, were 

entered into the study, and two patients dropped out. Of the 11 remaining patients, 

seven went into full remission that was maintained for at least 2 years. One patient 

showed moderate progress and in three patients little progress was noted and 

dermatography was stopped. The dosage of bleomycin varied between 0.1 and 1.0 mg/mL. 

CONCLUSIONS: Dermatography proved to be an effective technique for intralesional 

administration of bleomycin in more than two-thirds of patients resistant to 

conventional therapy. Treatment failures in this study could in part be explained by 

a defective immune system in the patients. Dermatography is a technique that can be 

learned by any skillful dermatologist or plastic surgeon.

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3.) Bleomycin: revival of an old drug.

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Mir LM; Tounekti O; Orlowski S

Laboratoire de Physicochimie et Pharmacologie des Macromolecules Biologiques, URA 

147 CNRS, Institute Gustave-Roussy, Villejuif, France.

Gen Pharmacol (ENGLAND) Jul 1996 27 (5) p745-8 ISSN: 0306-3623

Language: ENGLISH

Document Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL 

Journal Announcement: 9704

Subfile: INDEX MEDICUS

1. Bleomycin (BLM) is a cytotoxic drug currently used in anticancer chemotherapy. 

We present here a summary of the well established "old" knowledge concerning BLM 

structure, properties and activity at the molecular level, as well as its current 

clinical uses. 2. Then, we introduce "new" recent facts concerning BLM interaction 

with animal cells, that demonstrate the peculiar characteristics of that drug and its 

potentialities. Indeed, BLM has an high intrinsic cytotoxicity (i.e. it is a very 

potent drug once inside the cell). However, BLM cytotoxicity is limited because BLM 

is unable to diffuse through the plasma membrane. The very low amounts of BLM that 

can reach the cell interior enter the cells by a mechanism that requires BLM 

interaction with a plasma membrane protein. 3. Finally, we present and discuss a new 

possible use of BLM in an antitumor approach that we term electrochemotherapy. This 

new treatment, still under development, is based on the increased BLM delivery into 

tumor cells after cell permeabilization by electric pulses administered locally at 

the solid tumor site. This results in a huge local potentiation of BLM activity, in 

the absence of systemic adverse effects. Clinical trials are in progress. (30 

References)

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4.) Bleomycin sulfate in the treatment of mosaic plantar verrucae: a follow-up study.

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AU: Sollitto-RJ; Pizzano-DM

AD: Saddle Brook Surgicenter, New Jersey 07663, USA.

SO: J-Foot-Ankle-Surg. 1996 Mar-Apr; 35(2): 169-72

ISSN: 1067-2516

PY: 1996

LA: ENGLISH

CP: UNITED-STATES

AB: In this report, the authors will supplement research performed in 1989 by Sollitto, Napoli, and Gazivoda on the use of intralesional bleomycin for the treatment of verrucae. With various alterations of technique, their original success rate of 32.2% was improved to 65.4%. Thus, bleomycin is a very effective first line treatment for multiple verrucae, particularly of the mosaic variety. An association is also made between patients with pedal hyperhidrosis and the occurrence of multiple verrucae, notably lesions that prove recalcitrant to initial therapy.

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5.) Histologic, pharmacologic, and immunocytochemical effects of injection of bleomycin into viral warts [see comments]

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CM - Comment in: J Am Acad Dermatol 1994 May; 30(5 Pt 1):812

SO - J Am Acad Dermatol 1993 Jun;28(6):933-7

AU - James MP; Collier PM; Aherne W; Hardcastle A; Lovegrove S

AB - BACKGROUND: The plasma concentration of bleomycin after injection of bleomycin into warts is unknown, as is the long-term stability of bleomycin solution. OBJECTIVE: Our purpose was to measure plasma bleomycin concentration after injection of bleomycin into warts, to relate histologic and immunocytochemical changes in warts to possible mechanisms of action of bleomycin, and to asses the long-term stability of stored frozen bleomycin solution. METHODS: One milligram of bleomycin was injected into warts on the hands of seven men. Blood samples were taken 15 to 120 minutes after injection, and plasma bleomycin was measured by radioimmunoassay. Warts were removed 2 hours and 48 hours after treatment and studied histologically by light microscopy and for the presence of bleomycin by immunocytochemistry. The bleomycin concentration in 8 aliquots of solution stored at -20 degrees C for varying periods was measured by radioimmunoassay. RESULTS: Peak levels of bleomycin of 7 to 113 ng/ml were reached by 45 minutes after injection. Plasma bleomycin exposure ranged from 515 to 5137 ng/ml/min between 15 and 120 minutes after injection. The most pronounced histologic changes at 48 hours were individual keratinocyte apoptosis throughout the epidermis merging into areas of complete epidermal necrosis, diffuse neutrophil accumulation, and microabscess formation at the granular layer. Immunocytochemistry demonstrated tissue-fixed bleomycin in all levels of the epidermis except the basal layer and most prominently in the granular layer. Bleomycin in solution stored for up to 27 months at -20 degrees C in glass showed no significant loss of immunoreactivity. CONCLUSION: The use of bleomycin for the treatment of warts results in significant systemic drug exposure; thus it would be prudent to exclude pregnancy before treating women of child-bearing age. Bleomycin probably has a direct toxic effect on keratinocytes. Dilute bleomycin solution stored at -20 degrees C in glass is stable.

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6.) Intralesional injection of bleomycin sulphate into resistant warts in renal transplant recipients versus non-transplant warty patients.

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SO - Acta Derm Venereol 1991;71(1):63-6

AU - Sobh MA; Abd El-Razic MM; Rizc RA; Eid MM; Abd el-Hamid IA; Ghoneim MA

AB - Sixteen adult renal transplant patients and 20 non-transplant patients with warts underwent intralesional therapy with bleomycin sulphate. One unit/ml bleomycin sulphate was injected in 93 warts in renal transplant recipients and 100 warts in non-transplant patients with proven resistance to conventional treatment for at least 6 months. The treatment was compared with a normal saline placebo injected into the paired warts in the same patient. Thirty-four out of 93 warts (37%) in renal transplant recipients vs. 59 out of 100 warts (59%) in non-transplant patients were completely cured after one to three injections. We found bleomycin completely ineffective in 56 warts (60%) in renal transplant recipients, but ineffective in only 17 warts (17%) in non-transplant warty patients. None of the patients treated experienced any side effects except for local pain which was well tolerated, especially by non-transplant patients.

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7.) Therapeutic evaluation for intralesional injection of bleomycin sulfate in 143 resistant warts.

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SO - J Am Acad Dermatol 1988 Jun;18(6):1313-6

AU - Amer M; Diab N; Ramadan A; Galal A; Salem A

AB - A 1 U/ml solution of bleomycin sulfate in physiologic saline solution was injected intralesionally in 38 patients, and was compared with physiologic saline solution injection into paired warts in the same patient. No patient received more than 2 ml of bleomycin. Ninety-seven of 143 warts (67.8%) showed complete resolution after one or two bleomycin injections, while 25 warts (17.5%) showed incomplete resolution. Bleomycin local injection failed to elicit any therapeutic response in 21 warts (14.7%). The cure rate was 77% for warts on the extremities, 71.4% for periungual warts, and 47.6% for the plantar warts. The responsive warts showed hemorrhagic eschars that healed without scarring. It is concluded that this form of treatment for resistant warts, up to the dose used, is safe, reliable, and accepted by the patient.

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8.) Reduced dose of bleomycin in the treatment of recalcitrant warts.

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SO - J Am Acad Dermatol 1986 Nov;15(5 Pt 1):1002-6

AU - Hayes ME; O'Keefe EJ

AB - The effectiveness of intralesional bleomycin (1 U/ml) in the treatment of warts refractory to conventional methods of treatment has been shown in well-controlled studies. We have now evaluated more dilute concentrations of bleomycin in the treatment of recalcitrant warts. Warts were assigned for therapy with intralesional bleomycin at a concentration of 0.25 U/ml, 0.5 U/ml, or 1 U/ml at 3-week intervals. If warts persisted after three injections or had recurred by 3 months' follow-up, treatment was considered a failure. Twenty-six patients whose warts had persisted after conventional treatment entered the study. Three patients had spontaneous regression of untreated warts during therapy and were not included in the results. Of seventy-nine warts treated with intralesional bleomycin, sixty-two (78%) were cured after one to three injections. Responding warts showed a hemorrhagic eschar even with the lower bleomycin concentrations and healed without complication. Almost all treated warts responded, although not all were cured. Treatment with bleomycin at 0.5 U/ml was as effective as treatment with 1 U/ml. Bleomycin at 0.25 U/ml is effective therapy but not enough warts were treated to permit a conclusion when compared with higher concentrations.

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9.) The treatment of resistant warts with intralesional bleomycin: a controlled clinical trial.

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SO - Br J Dermatol 1984 Aug;111(2):197-207

AU - Bunney MH; Nolan MW; Buxton PK; Going SM; Prescott RJ

AB - A controlled double-blind trial was carried out on fifty-nine matched pairs of hand warts in a group of twenty-four patients, with proven resistance to treatment, to study the effectiveness of the intralesional injection of 0.1% solution of bleomycin sulphate in normal saline, compared with a normal saline placebo injected into the paired warts in the same patient. We found that 87.5% of patients showed a more favourable response to bleomycin (P less than 0.001); 76% of the fifty-nine warts treated with bleomycin were cured by one to three injections of up to 0.2 ml of solution. Subsequently 75% of thirty-two patients with resistant hand warts and 66% of fifteen patients with mosaic plantar warts were cured of all their warts. No patient received more than 4 mg of bleomycin. No toxicity was experienced. Local pain was on the whole well tolerated. This form of treatment for resistant warts is reliable, safe and acceptable to patients.

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10.) Bleomycin in the treatment of recalcitrant warts.

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SO - J Am Acad Dermatol 1983 Jul;9(1):91-6

AU - Shumer SM; O'Keefe EJ

AB - Bleomycin is gaining increasing popularity in the treatment of warts, but its efficacy has not been examined in well-controlled studies. We evaluated bleomycin in a double-blind placebo-controlled crossover study in recalcitrant warts treated unsuccessfully by conventional methods. Patients were assigned alternately to placebo or bleomycin groups and treated by intralesional injections of bleomycin, 1 U/ml, or saline, at 2-week intervals. If warts persisted, patients were changed after two injections to the alternate group and retreated with up to two further injections. Forty patients entered the study. Of 151 warts treated with intralesional bleomycin, 123 were cured after one or two injections (81%). The cure rate for plantar warts (60%) was lower than that for periungual warts (94%) and warts elsewhere on the extremities (95%). Fifty-five warts were injected with normal saline; none was cured. Responding warts showed a hemorrhagic eschar and healed without scarring, atrophy, or pigmentary change. Pain was usually mild and patient acceptance superior to that with liquid nitrogen. There was no evidence of systemic toxicity. Bleomycin is highly efficacious in the treatment of recalcitrant warts, is convenient, and has high patient acceptance. Long-term safety requires further study.

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11.) The common wart: intralesional treatment with bleomycin sulfate.

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SO - Cutis 1980 Sep;26(3):319-20, 322, 324

AU - Cordero AA; Guglielmi HA; Woscoff A

AB - Thirty-six patients were treated for single or multiple warts by intralesional injection of bleomycin sulfate (Blenoxane) at the base of the wart. The dose varied according to the size of the lesion and ranged from 0.2 to 0.8 mg per injection, up to a maximum total dose of 2 mg. The cure rates were as follows: 67 percent in plantar warts; 82 percent in ungual warts; and 80 percent in warts located elsewhere. The cure rate for all patients was 75 percent. The drug was well tolerated and the procedure readily accepted by the patients.

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12.) Bleomycin-lidocaine mixture reduces pain of intralesional injection in the treatment of recalcitrant verrucae.

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SO - J Am Acad Dermatol 1991 Sep;25(3):524-6

AU - Manz LA; Pelachyk JM

AB - Intralesional bleomycin has been effective treatment of recalcitrant verrucae since 1970, but one major drawback is the moderate to severe pain associated with the injection. To minimize procedural discomfort, bleomycin can be reconstituted in lidocaine. It is effective, associated with minimal morbidity, and well tolerated by most patients.

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13.) Intralesional bleomycin sulfate therapy for warts. A novel bifurcated needle puncture technique.

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SO - Arch Dermatol 1991 Feb;127(2):234-6

AU - Shelley WB; Shelley ED

AB - A multiple puncture technique using a bifurcated vaccination needle to introduce bleomycin sulfate (1 U/mL sterile saline solution) into warts resulted in elimination of 92% of a random series of 258 warts after a single treatment. Recurrence was not observed during a 6-month follow-up period. Six of the 66 patients required two to seven treatments for wart eradication, and four patients requested alternative therapy after initial failure with a single bleomycin treatment.

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14.) Intradermal bleomycin injections into normal human skin. A histopathologic and immunopathologic study.

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SO - Arch Dermatol 1994 May;130(5):577-83

AU - Templeton SF; Solomon AR; Swerlick RA

AB - BACKGROUND: Intralesionally injected bleomycin is a useful agent for the treatment of recalcitrant warts. The mechanism of action in wart therapy has been thought to be due to DNA and antiviral effects. To further characterize the inflammatory response to intralesional bleomycin injections, we examined the clinical, histologic, and immunopathologic response to intradermal bleomycin injections in normal human skin. RESULTS: Four volunteers were each given four intradermal bleomycin injections (0.01 to 0.5 U/mL) into normal human skin to establish a dose response. These injections induced a localized time and dose-dependent inflammatory reaction and persistent postinflammatory hyperpigmentation. Nine biopsy specimens from two volunteers were taken at different time points after intradermal bleomycin injections (0.1 to 1.0 U/mL) into normal human skin. Routine histologic study demonstrated dyskeratosis and necrosis of epidermal keratinocytes and eccrine epithelium associated with a prominent neutrophilic infiltrate, closely resembling histopathologic findings seen in neutrophilic eccrine hidradenitis. Expression of HLA-DR and intercellular adhesion molecule 1 was induced on keratinocytes; intercellular adhesion molecule 1 was upregulated, and endothelial leukocyte adhesion molecule 1 was induced on superficial dermal blood vessels. CONCLUSIONS: These findings suggest that intradermal bleomycin injection is either directly or indirectly cytotoxic to keratinocytes and eccrine epithelium. Expression and upregulation of activation antigens and cell adhesion molecules suggest that a cellular immune system response and proinflammatory cytokine secretion occur after intralesional bleomycin injection into normal human skin. Histopathologic findings at some injection sites resemble neutrophilic eccrine hidradenitis.

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15.) [Onychodystrophy induced by intralesional injection of bleomycin for periungual wart]

TT - [Onychodystrophie induite par injection intralesionnelle de bleomycine pour verrue periungueale.]

SO - Ann Dermatol Venereol 1985;112(5):463-4

AU - Baran R

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16.) Nail dystrophy following intralesional injections of bleomycin for a periungual wart.

SO - Arch Dermatol 1984 Jul;120(7):963-4

AU - Miller RA

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17.) Raynaud's phenomenon and intralesional bleomycin [letter]

SO - Acta Derm Venereol 1992 Nov;72(6):465

AU - de Pablo P; Aguillar A; Gallego MA

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18.) Intralesional bleomycin and Raynaud's phenomenon [see comments]

CM - Comment in: J Am Acad Dermatol 1992 Feb; 26(2 Pt 1):279-80

SO - J Am Acad Dermatol 1991 May;24(5 Pt 1):785-6

AU - Epstein E

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19.) BLEOMYCIN (Systemic), The Product

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VA CLASSIFICATION (Primary/Secondary)¾AN200/DE600

Commonly used brand name(s): 

Blenoxane.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Category

Antineoplastic.

Indications

Note: Bracketed information in the Indicationssection refers to uses that are not included in U.S. product labeling.

Accepted

Carcinoma, head and neck (treatment)

Carcinoma, laryngeal (treatment)

[Carcinoma, paralaryngeal (treatment)]

Carcinoma, cervical (treatment)

Carcinoma, penile (treatment)

Carcinoma, skin (treatment)

Carcinoma, vulvar (treatment)

Carcinoma, testicular (treatment) or

[Carcinoma, renal (treatment)]¾Bleomycin is indicated for treatment of squamous cell carcinomas of the head and neck (including the mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingiva, epiglottis, and larynx and paralarynx), cervix, penis, skin and vulva1,17. It is also indicated for treatment of testicular carcinoma (including embryonal cell carcinoma, choriocarcinoma, and teratocarcinoma)1,17 and has been used for treatment of renal carcinoma1,17.

Lymphomas, Hodgkin's (treatment) or

Lymphomas, non-Hodgkin's (treatment)¾Bleomycin is indicated for treatment of Hodgkin's and non-Hodgkin's lymphomas (including reticulum cell sarcoma and lymphosarcoma)1,17.

[Sarcomas, soft tissue (treatment)]¾Bleomycin is indicated for treatment of some soft tissue sarcomas17.

[Osteosarcoma (treatment)]*¾Bleomycin is used in the treatment of osteosarcoma2.

[Malignant effusions, peritoneal (treatment)]*

[Malignant effusions, pleural (prophylaxis)]17 or

[Malignant effusions, pleural (treatment)]*¾Bleomycin is used by intracavitary administration for treatment of peritoneal effusions and for prophylaxis and treatment of pleural effusions.

[Tumors, germ cell, ovarian (treatment)]*¾Bleomycin is used for treatment of germ cell ovarian tumors.

[Mycosis fungoides (treatment)]*¾Bleomycin is used, in combination with other agents, for treatment of advanced stage mycosis fungoides13.

[Verruca vulgaris (treatment)]*¾Bleomycin is used by intralesional injection for treatment of severe, recalcitrant common warts (verrucae vulgaris) not responding to conventional treatment.

Extreme caution is recommended in use of bleomycin for non-neoplastic conditions because of potential carcinogenicity with long-term use of this agent.

*Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Hygroscopic; inactivated in vitroby agents containing sulfhydryl groups, hydrogen peroxide, and ascorbic acid

Mechanism of action/Effect:

Bleomycin is classed as an antibiotic but is not used as an antimicrobial agent. Although bleomycin is effective against both cycling and non-cycling cells, it seems to be most effective in the G2 phase of cell division5. Its exact mechanism of antineoplastic action is unknown but may involve binding to DNA, inducing lability of the DNA structure, and reduced synthesis of DNA, and to a lesser extent, RNA and proteins1.

Absorption:

Approximately 45% of a dose is absorbed into the systemic circulation following intrapleural or intraperitoneal administration.

Protein binding:

Very low (1%).

Biotransformation:

Unknown; probably by enzyme degradation in tissues (based on animal studies)5. Tissue enzyme activity varies, which may determine toxicity and antitumor effect of bleomycin5; enzyme activity is high in the liver and kidneys, as well as in bone marrow and lymph nodes5, but is low in the skin and lungs5. It is not known if any metabolites are active5.

Half-life:

Creatinine clearance greater than 35 mL per minute¾115 minutes1.

Creatinine clearance less than 35 mL per minute¾Increased exponentially as creatinine clearance decreases1.

Elimination:

Renal, 60 to 70%, largely as unchanged drug1; markedly reduced in renal failure.

In dialysis¾Probably not dialyzable.

Precautions to Consider

Carcinogenicity/Mutagenicity

Secondary malignancies are potential delayed effects of many antineoplastic agents, although it is not clear whether the effect is related to their mutagenic or immunosuppressive action. The effect of dose and duration of therapy is also unknown, although risk seems to increase with long-term use. Although information is limited, available data seem to indicate that the carcinogenic risk is greatest with the alkylating agents.18

Carcinostatic antibiotics have been shown to be carcinogenic in animals, and have been associated with an increased risk of development of secondary carcinomas in humans.

Bleomycin has not been found to be mutagenic according to the Ames assay. However, chromosomal aberrations were reported in bone marrow cells and spermatogonia of mice given very high doses.

Pregnancy/Reproduction

Fertility¾¾

Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents.18

Pregnancy¾First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered.18

Other hazards to the fetus include adverse reactions seen in adults18.

In general, use of a contraceptive is recommended during cytotoxic drug therapy18.

Bleomycin has been found to be teratogenic in mice given intraperitoneal doses of 0.6 to 5 Units per kg of body weight on days 7 to 12 of gestation; increased fetal resorptions occurred at doses of 3 and 5 Units per kg of body weight.

Breast-feeding

Although very little information is available regarding distribution of antineoplastic agents into breast milk, breast-feeding is not recommended while bleomycin is being administered because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity)18.

Pediatrics

Appropriate studies on the relationship of age to the effects of bleomycin have not been performed in the pediatric population. However, no pediatrics-specific problems have been documented to date.

Geriatrics

Although appropriate studies on the relationship of age to the effects of bleomycin have not been performed in the geriatric population, there may be an increased risk of pulmonary toxicity in the elderly (over 70 years of age)1. In addition, elderly patients are more likely to have age-related renal function impairment, which may require reduction of dosage in patients receiving bleomycin.

Dental

Bleomycin may cause mild stomatitis.

Drug interactions and/or related problems

The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance):

>> Anesthetics, general¾(use in patients previously treated with bleomycin may result in rapid pulmonary deterioration because bleomycin causes sensitization of lung tissue to oxygen; even with concentrations of inspired oxygen considered to be safe, pulmonary fibrosis may develop postoperatively)

1

Antineoplastics, other or

Radiation therapy¾(concurrent use may result in increased bleomycin toxicity, including bone marrow depression, which is rarely caused by bleomycin alone, and mucosal and pulmonary toxicity; dosage adjustment may be necessary)

Cisplatin¾(cisplatin-induced renal function impairment may result in delayed clearance and bleomycin toxicity even at low doses; caution is recommended because of the frequent combined use of these two agents)

Vincristine¾(sequential administration prior to bleomycin arrests cells in mitosis so that they are more susceptible to bleomycin; frequently used to therapeutic advantage)

Medical considerations/Contraindications

The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance).

Risk-benefit should be considered when the following medical problems exist

Hepatic function impairment¾(potential hepatotoxicity)

>> Pulmonary function impairment¾

Raynaud's phenomenon or

Vascular disease, peripheral3¾(for intralesional use in treatment of warts; local Raynaud's phenomenon reported in fingers injected with bleomycin3)

>> Renal function impairment, severe1¾creatinine clearance less than 25 to 35 mL per minute¾(toxicity of bleomycin may be increased; it is recommended that dosage of bleomycin be reduced in patients with renal function impairment)

Sensitivity to bleomycin1¾

>> Caution should be used also in patients who have had previous cytotoxic drug therapy and radiation therapy (especially chest irradiation), as well as in patients who smoke, because of the increased risk of pulmonary toxicity.¾

Patient monitoring

The following are especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; >> = major clinical signficance):

>> Auscultation of the lungs and

>> Chest x-ray1¾(recommended prior to initiation of therapy and at periodic intervals during therapy)

Blood urea nitrogen (BUN) concentrations and

Creatinine concentrations, serum¾(recommended prior to initiation of therapy and at periodic intervals during therapy; frequency varies according to clinical state, agent, dose, and other agents being used concurrently)

>> Pulmonary function studies, including single-breath carbon monoxide diffusion capacity (DLco) and forced vital capacity1¾(recommended at frequent intervals during therapy to detect early asymptomatic interstitial damage; however, DLco results are sometimes difficult to interpret because of the effects of weakness and anemia or the presence of extensive lung tumor or effusion. Therapy with bleomycin should be discontinued at the first sign of pulmonary changes [for example, if forced vital capacity is reduced to 75% or less or DLco to 40% or less of pretreatment level]; if the changes are determined to be drug-related, bleomycin therapy should not be resumed)

Side/Adverse Effects

Note: There is some evidence that administration of bleomycin by continuous intravenous infusion over 24 hours rather than intermittently may be associated with less pulmonary and idiosyncratic toxicity, although mucocutaneous toxicity may be increased.

The main reported side effect with intralesional use is local burning or pain within 24 to 48 hours after injection. Blackening and eschar occur at the site of the lesion within 1 or 2 weeks and healing usually occurs within 2 to 3 weeks without scarring3,4. Cases of urticaria3, nail loss3,7,8,9, and Raynaud's phenomenon3,7,10,11have also been reported.

When bleomycin is used in combination with vinblastine for testicular carcinoma, vasospasm is a common vascular toxicity15.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)¾not necessarily inclusive:

Those indicating need for medical attention

Incidence more frequent

Fever and chills1; pneumonitis, progressing to pulmonary fibrosis (cough; shortness of breath); stomatitis, mild, due to mucocutaneous toxicity1 (sores in mouth and on lips)

Note: Fever and chills occur in approximately 20 to 60% of patients, usually 3 to 6 hours after administration, last 4 to 12 hours, and become less frequent with continued use.

Pulmonary toxicity occurs in 101to 40% of treated patients, usually 4 to 10 weeks after initiation of treatment; approximately 1% of treated patients have died of pulmonary fibrosis1. Pulmonary toxicity is age- and dose-related, occurring most frequently in patients over 70 years of age and/or receiving a total dose greater than 400 Units1 (although it has been reported with doses as low as 20 to 60 Units). It may be irreversible and fatal; however, there is some evidence that in patients who survive, symptoms and pulmonary function parameters return to normal in approximately 2 years7,12. It occurs at lower doses in patients who have received other antineoplastics or thoracic radiation; mortality may be as high as 10% in patients who have received pulmonary irradiation. A low-dose allergic pneumonitis has also been reported.

The earliest signs of pulmonary toxicity are a decrease in diffusion capacity14 and fine rales1. On chest x-ray, pneumonitis is seen as nonspecific patchy opacities, usually of the lower lung fields1. Pulmonary function tests show a decrease in total lung volume and a decrease in vital capacity1.

Incidence less frequent

Idiosyncratic reaction (confusion; faintness; fever and chills; wheezing)

Note: The idiosyncratic reaction occurs in approximately 1% of treated patients (1 to 6% of lymphoma patients). If not promptly treated, it may progress to sweating, dehydration, hypotension, and renal failure or cardiorespiratory collapse. It usually occurs at doses of 25 Units per square meter of body surface or greater, although it has occurred with a dose of 7.5 Units. May be immediate or delayed by several hours, and occurs after the first or second dose1.

Incidence rare

Hepatic toxicity1 (seen as changes in hepatic function tests); pleuropericarditis1 (sudden severe chest pain); renal toxicity1 (seen as changes in renal function tests); vascular toxicity, including cerebral arteritis1, cerebrovascular accident, myocardial infarction, or thrombotic microangiopathy1 (sudden weakness in arms or legs; sudden, severe chest pain)

Those indicating need for medical attention only if they continue or are bothersome

Incidence more frequent

Mucocutaneous toxicity (darkening or thickening of skin; itching of skin; skin rash or colored bumps on fingertips, elbows, or palms; skin redness or tenderness; dark stripes on skin1; swelling of fingers; less frequently, changes in fingernails or toenails); vomiting and loss of appetite1

Note: Skin toxicity occurs in 25 to 50% of treated patients, usually 2 to 4 weeks after initiation of therapy; it appears to be related to cumulative dose and usually develops after 150 to 200 Units have been given.1

Vomiting and loss of appetite occur in 15 to 30% of treated patients.

Incidence less frequent

Weight loss1

Those not indicating need for medical attention

Incidence less frequent

Loss of hair1

Note: Loss of hair begins after several weeks, with regrowth occurring several months later.

Those indicating the need for medical attention if they occur after medication is discontinued

Pulmonary toxicity (cough; shortness of breath)

Note: Pulmonary toxicity may occur up to 1 month after bleomycin is discontinued.

Patient Consultation

As an aid to patient consultation, refer to Advice for the Patient, Bleomycin (Systemic).

In providing consultation, consider emphasizing the following selected information (>> = major clinical significance):

Before using this medication

>> Conditions affecting use, especially:

Sensitivity to bleomycin

Pregnancy¾Use not recommended because of mutagenic, teratogenic, and carcinogenic potential; advisability of using contraception; telling physician immediately if pregnancy is suspected

Breast-feeding¾Not recommended because of risk of serious side effects

Use in the elderly¾Increased risk of pulmonary toxicity

Other medical problems, especially pulmonary function impairment or severe renal function impairment

Previous cytotoxic drug therapy or radiation therapy

History of smoking

Proper use of this medication

Caution in taking combination therapy; taking each medication at the proper time

Frequency of nausea, vomiting, and loss of appetite; importance of continuing medication despite stomach upset

>> Proper dosing

Precautions while using this medication

>> Importance of close monitoring by physician

>> Caution if any kind of surgery (including dental surgery) or emergency treatment is required

Side/adverse effects

May cause adverse effects such as loss of hair and mucocutaneous and lung toxicity; importance of discussing possible effects with physician

Signs of potential side effects, especially fever and chills, pneumonitis and pulmonary fibrosis, stomatitis, mucocutaneous toxicity, and idiosyncratic reaction

Physician or nurse can help in dealing with side effects

Possibility of hair loss; normal hair growth should return after treatment has ended (may take several months)

Pulmonary toxicity more likely in smokers

General Dosing Information

See also Patient monitoring.

It is recommended that bleomycin be administered to patients under supervision of a physician experienced in cancer chemotherapy. It is also recommended that equipment and medications (including epinephrine, oxygen, diphenhydramine, and intravenous corticosteroids) necessary for treatment of a possible anaphylactic reaction be readily available at each administration of bleomycin.

A variety of dosage schedules, routes, and regimens of bleomycin, alone or in combination with other antitumor agents, are used. The prescriber may consult the medical literature in choosing a specific dosage or route.

Because of the risk of an idiosyncratic reaction in lymphoma patients, one test dose of 1 or 2 Units or less1 of bleomycin (base) given 2 to 4 hours prior to initiation of therapy at regular dosage may be used1, although the test dose does not always detect reactors.

Some clinicians recommend premedication of patients receiving bleomycin with acetaminophen16, steroids, and diphenhydramine hydrochloride to reduce drug fever and the risk of anaphylaxis.

Bleomycin may be administered intravenously or intra-arterially slowly over a period of 10 minutes1, or may be further diluted with 50 to 100 mL of the initial diluent for administration by regional infusion.

It is recommended that the dosage of bleomycin be reduced in patients with renal function impairment (creatinine clearance less than 25 to 35 mL per minute). For example, dosage may be adjusted as follows: 

Serum creatinine Fraction of normal

dose to be given

(mg/dL) (micromoles

per liter)6

1.5-2.0 130-180 1/2

2.5-4.0 180-350 1/4

4.0-6.0 350-530 1/5

6.0-10.0 530-900 1/10-1/20

Safety considerations for handling this medication18

There is limited but increasing evidence and concern that personnel involved in preparation and administration of parenteral antineoplastics may be at some risk because of the potential mutagenicity, teratogenicity, and/or carcinogenicity of these agents, although the actual risk is unknown. USP advisory panels recommend cautious handling both in preparation and disposal of antineoplastic agents. Precautions that have been suggested include: 

· Use of a biological containment cabinet during reconstitution and dilution of parenteral medications and wearing of disposable surgical gloves and masks.

· Use of proper technique to prevent contamination of the medication, work area, and operator during transfer between containers (including proper training of personnel in this technique).

· Cautious and proper disposal of needles, syringes, vials, ampuls, and unused medication.

A number of medical centers have developed detailed guidelines for handling of antineoplastic agents.

Combination chemotherapy

Bleomycin is usually used in combination with other agents in various regimens. As a result, incidence and/or severity of side effects may be altered and different dosages (usually reduced) may be used. For example, bleomycin is part of the following chemotherapeutic combinations (some commonly used acronyms are in parentheses): ¾doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

¾mechlorethamine, vincristine, procarbazine, prednisone, and bleomycin (MOPP-LO BLEO).

¾vinblastine, cisplatin, and bleomycin (VBP).

For specific dosages and schedules, consult the literature. For information regarding each agent, consult the individual monographs.

For treatment of adverse effects

Treatment of the idiosyncratic reaction is symptomatic and may consist of volume expansion, pressor agents, antihistamines, and corticosteroids1.

Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

A Unit of bleomycin is equal to the formerly used milligram activity. The term milligram activity is a misnomer and was changed to Units to be more precise.1

BLEOMYCIN SULFATE STERILE USP

Usual adult and adolescent dose

Antineoplastic¾

Initial¾

Hodgkin's disease, squamous cell carcinoma, lymphosarcoma, reticulum cell sarcoma, testicular carcinoma:

Intramuscular, intravenous, or subcutaneous, 0.25 to 0.50 Units (base) per kg of body weight or 10 to 20 Units per square meter of body surface one or two times a week1 or

Intravenous infusion, continuous, 0.25 Units (base) per kg of body weight or 15 Units per square meter of body surface per day (over 24 hours) for four to five days.

Squamous cell carcinoma of the head, neck, or uterine cervix:

Regional arterial infusion, 30 to 60 Units (base) a day over a period of one to twenty-four hours.

[Malignant effusions]*:

Intrapleural, 15 to 120 Units (base) in 100 mL of sodium chloride injection, instilled, and after 24 hours, removed.

Intraperitoneal, 60 to 120 Units (base) in 100 mL of sodium chloride injection, instilled, and after 24 hours, removed.

Maintenance¾

Hodgkin's disease:

Intramuscular or intravenous, after a 50% response occurs, 1 Unit (base) a day or 5 Units a week1.

[Warts, common]*¾

Intralesional, 0.2 to 0.8 Units (base) (according to size) one or more times at intervals of two to four weeks, up to a maximum total dose of 2 Units, using a solution of 15 Units of Sterile Bleomycin Sulfate USP in 15 mL of 0.9% sodium chloride injection or water for injection.

Usual adult prescribing limits

Because of the risk of pulmonary toxicity, total doses exceeding 225 to 400 Units (base) (less in patients with renal or pulmonary function impairment) should be given with great caution. If bleomycin is administered intrapleurally or intraperitoneally, one-half of the administered dose should be counted towards this total.

Usual pediatric dose

See Usual adult and adolescent dose.

Size(s) usually available:

U.S.¾

15 Units (base) (Rx)[Blenoxane].

Canada¾

15 Units (base) (Rx)[Blenoxane].

Packaging and storage:

Store between 2 and 8 °C (36 and 46 °F).

Preparation of dosage form:

U.S.¾

Sterile Bleomycin Sulfate USP may be prepared for intravenous use by dissolving the contents of the ampul (15 Units [base]) in 5 mL or more of 0.9% sodium chloride injection or 5% dextrose injection.

Sterile Bleomycin Sulfate USP may be prepared for intramuscular or subcutaneous use by dissolving the contents of the ampul (15 Units [base]) in 1 to 5 mL of sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, or bacteriostatic water for injection.

Canada¾

Sterile bleomycin sulfate may be prepared for intramuscular or subcutaneous use by dissolving the contents of the vial (15 Units [base]) in 1 to 5 mL of sterile water for injection, sodium chloride injection, or dextrose in water.

Sterile bleomycin sulfate may be prepared for intravenous or intra-arterial use by dissolving the contents of the vial (15 Units [base]) in 5 to 20 mL of 5% dextrose in water, 10% invert sugar in normal saline, 20% mannitol in water (discard if a precipitate forms), or 10% dextrose in water.

Caution¾

Use of diluents containing benzyl alcohol is not recommended for preparation of medications for use in neonates. A fatal toxic syndrome consisting of metabolic acidosis, central nervous system (CNS) depression, respiratory problems, renal failure, hypotension, and possibly seizures and intracranial hemorrhages has been associated with this use.

Stability:

U.S.¾Reconstituted solutions of Sterile Bleomycin Sulfate USP in 0.9% sodium chloride injection or 5% dextrose injection are stable for 24 hours at room temperature, or for at least 14 days if refrigerated.

Canada¾Reconstituted solutions are stable for 8 hours at room temperature and at least 48 hours when refrigerated.

References

Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.

1Blenoxane package insert, Bristol-Myers Oncology, Rev 7/86; Rev 10/87; Rev 3/88.

2Hematology-Oncology Advisory Panel (1985-1990) Memorandum No. 22, 1989. Confirmed by Med Lett Drugs Ther 1989 Jun 2; 31: 49-56.

3Hayes ME, O'Keefe EJ. Reduced dose of bleomycin in the treatment of recalcitrant warts. J Am Acad Dermatol 1986; 15: 1002-6.

4Amer M, Diab N, Ramadan A, et al. Therapeutic evaluation for intralesional injection of bleomycin sulfate in 143 resistant warts. J Am Acad Dermatol 1988: 18: 1313-6.

5Evans WE, Yee GC, Crom WR, et al. Clinical pharmacology of bleomycin and cisplatin. Drug Intell Clin Pharm 1982 Jun; 16: 448-58.

6Per panel comments, 1988 revision.

7Per panel comments, 1988 revision.

8Arch Dermatol 1986; 122: 974-5.

9Arch Dermatol 1984 Jul; 120: 963-4.

10Arthr Rheum 1985; 28: 459-61.

11J Am Acad Dermatol 1985 Sep; 13: 468-9.

12Van Barneveld PWC, Sleijfer DT, Van der Mark TW, et al. Natural course of bleomycin-induced pneumonitis. A follow-up study. Am Rev Resp Dis 1987; 135: 48-51.

13Per responses to panel question #1, 1991 revision. References cited¾Acta Derm Venereol 1987; 67(5): 433-7, Cancer 1987; 60(3): 397-402, Cancer 1986; 58(12): 2611-6, Cancer Treat Rep 1979 Apr, 63: 647-57.

14Per panel comment, 1991 revision.

15Per panel comment, 1991 revision.

16Per responses to panel question #2, 1991 revision. Acetaminophen recommended instead of aspirin because myelosuppression caused by other agents commonly used in combination with bleomycin could result in bleeding.

17Blenoxane package insert, Bristol (Canada), Rev 5/82.

18Standard statement/precaution in antineoplastic monographs.

19Dorr RT, Fritz WL. Cancer chemotherapy handbook. New York: Elsevier, 1980: 274-83.

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DATA-MÉDICOS/DERMAGIC-EXPRESS No (58) 26/05/99 DR. JOSE LAPENTA R. 

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