VA Class:AN200

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Bleomycin Sulfate

Bleomycin sulfate, a mixture of basic cytotoxic glycopeptide antibiotics produced by Streptomyces verticillus (bleomycin A₂ and bleomycin B₂ are the major components), is an antineoplastic agent.

Hodgkin's Disease

Bleomycin is used in combination chemotherapy for the treatment of Hodgkin's disease.121,144 Combination therapy for induction of remissions in Hodgkin's disease is superior to single-drug therapy.142,143,144 Various regimens have been used in combination therapy and comparative efficacy is continually being evaluated.142,143,144

Bleomycin is used with doxorubicin, vinblastine, and dacarbazine (known as the ABVD regimen) for the treatment of Hodgkin's disease.122,142,143,144,217 Use of the ABVD regimen for 6-8 months is as effective and less myelotoxic than use of an alternating schedule of ABVD with the MOPP regimen (mechlorethamine, vincristine, procarbazine, and prednisone) for 12 months for the treatment of advanced Hodgkin's disease.144,217

Bleomycin also has been used in hybrid regimens in which 7 or 8 active antineoplastic agents are given during the same course of treatment;122,142,143,144 however, a large randomized trial comparing the ABVD regimen with the MOPP/ABV hybrid regimen in patients with stage III or IV Hodgkin's disease or recurrent Hodgkin's disease following radiation therapy shows equivalent rates of complete response, failure-free survival, and overall survival, but greater incidence of toxicity, including life-threatening hematologic toxicity and secondary hematologic malignancies, in those receiving the hybrid regimen.218

Testicular Cancer

Bleomycin is labeled for use in the treatment of testicular embryonal cell carcinoma, choriocarcinoma, and teratocarcinoma.121

For the treatment of advanced nonseminomatous testicular carcinoma, combination chemotherapy with bleomycin, cisplatin, and etoposide is a regimen of choice;122,123,126,127,128,129,130,132 this regimen also is used for the treatment of disseminated seminoma testis.123,128,129,131,132,140 Although testicular cancer often is curable, all newly diagnosed patients may be considered for enrollment in clinical trials investigating therapies to improve cure rates and reduce treatment-related morbidity.123

Pleural Effusions

Bleomycin is used by intracavitary injection as a sclerosing agent for the management of pleural effusions and for prevention of recurrent pleural effusions caused by metastatic tumors.121 Patients with pleural effusions frequently have symptoms of dyspnea, cough, and chest pain and heaviness.104,120,148,149,150,159,165 Although thoracentesis (needle aspiration) may provide temporary relief of such symptoms, the effusion often reaccumulates rapidly;104,149,153,155,159,160,165 surgical insertion of a thoracostomy tube with subsequent intrapleural instillation of a sclerosing agent generally is considered the treatment of choice for such effusions in patients with neoplasms unresponsive to systemic antineoplastic or radiation therapy.112,113,120,149,150,153,165,168 When instilled into the pleural space, sclerosing agents cause inflammation that results in fibrosis and adherence of serosal surfaces (pleurodesis), thereby obliterating the pleural space and reducing the chance of fluid reaccumulation;104,112,148,162,165,167 however, most current pleurodesis procedures for malignant pleural effusion appear to be associated with a substantial risk of recurrence.112,168

Bleomycin appears to be at least as effective121,147,148,149,151,154,155,156 as and possibly better tolerated147,151 than tetracycline in the treatment of these effusions. Therefore, bleomycin has been suggested as a suitable alternative to tetracycline, which no longer is commercially available in the US as a parenteral preparation, for pleural effusions when intracavitary therapy is indicated.101,102,104,105,112,115,116,119,120,153

In a randomized, multicenter clinical study in patients with malignant pleural effusions, intracavitary administration of 60 units of bleomycin was associated with substantial lower recurrence rate and longer time to recurrence compared to those associated with intracavitary administration of 1 g of tetracycline;121,147,148,149 toxicity121,147,150,156 and overall survival121,147,155 were similar in both groups. Recurrence rates within 30 days of drug administration were 36 or 67% for patients receiving bleomycin or tetracycline, respectively,121,147,148,153,155 while corresponding recurrence rates within 90 days of drug administration were 30 or 53% for patients receiving bleomycin or tetracycline, respectively.147,148,149,155 In addition, the median time to recurrence was at least 46 days in patients receiving bleomycin and 32 days in patients receiving tetracycline.147,148

The efficacy and safety of intrapleural bleomycin compared with intrapleural administration of doxycycline, minocycline, talc slurry, or other therapies (e.g., talc insufflation during thoracoscopy or open thoracotomy) for the management of malignant pleural effusions remain to be determined.112,154,222 In one randomized trial, similar response rates were observed in patients receiving bleomycin or doxycycline sclerotherapy for the treatment of malignant pleural effusions.223 Limited evidence from small randomized studies suggests that talc slurry, a less costly drug, is as effective as bleomycin as a sclerosing agent administered via bedside thoracostomy for the treatment of malignant pleural effusions,219,220,221 but further study is needed to establish these findings.222 A large, randomized trial comparing the safety and efficacy of bleomycin, doxycycline, or talc administered via an indwelling pleural catheter for the treatment of malignant pleural effusions is under way.224

Head and Neck Cancer

Bleomycin is labeled for use in the palliative treatment of squamous cell carcinomas of the head and neck (including mouth, tongue, tonsils, nasopharynx, oropharynx, sinuses, palate, lip, buccal mucosa, gingiva, epiglottis, larynx, skin).121 A poorer response to bleomycin has been reported in patients who have received prior radiation therapy for the treatment of head and neck cancer.121

Bleomycin has been used in the treatment of advanced head and neck cancer.122,225 In a randomized trial, patients receiving bleomycin, cisplatin, methotrexate, and vincristine for recurrent or metastatic head and neck cancer had higher rates of complete response than those receiving cisplatin and fluorouracil. 225 Although both combination regimens produced a higher rate of objective response than cisplatin alone, no difference in survival was detected among the treatment groups.225

Cervical Cancer

Bleomycin is labeled for use in the palliative treatment of squamous cell carcinoma of the cervix.121

Although bleomycin has been shown to be an active agent in cervical cancer and has been used in various combination chemotherapy regimens (bleomycin, cisplatin, and ifosfamide with mesna [BIP]; bleomycin, cisplatin, mitomycin, and vincristine [BOMP]) for the treatment of metastatic or recurrent cervical cancer,122,226,228,229,230 most experts currently do not consider it a drug of choice for the treatment of advanced cervical cancer.232 The benefit of combination cisplatin-based chemotherapy regimens versus cisplatin alone has not been fully established,227,228,230 and further study is needed to determine the role of bleomycin, which can cause pulmonary toxicity, in the treatment of advanced cervical cancer.227,231,232 (See Uses: Cervical Cancer in Cisplatin 10:00 for overview of treatment for cervical cancer.)

AIDS-related Kaposi's Sarcoma

Bleomycin sulfate is used in combination chemotherapy for the palliative treatment of AIDS-related Kaposi's sarcoma†.122,146,172,173,174,175,176,177 Combination chemotherapy with the drug (e.g., bleomycin, doxorubicin, and a vinca alkaloid [ vinblastine or vincristine]) has been considered a regimen of choice,122,146,175,177 but many clinicians currently consider a liposomal anthracycline (doxorubicin or daunorubicin) the first-line therapy of choice for advanced AIDS-related Kaposi's sarcoma (see Uses: AIDS-related Kaposi's Sarcoma in Doxorubicin 10:00 for overview and further discussion of therapy; also see Daunorubicin 10:00).146,185

Combination chemotherapy with conventional antineoplastic agents (e.g., bleomycin, conventional doxorubicin, etoposide, vinblastine, vincristine) usually has been used for more advanced disease (e.g., extensive mucocutaneous disease, lymphedema, symptomatic visceral disease).146,175,177,213,214 However, the results of several randomized, multicenter trials indicate that patients receiving a liposomal anthracycline for the treatment of advanced AIDS-related Kaposi's sarcoma experience similar or higher response rates with a more favorable toxic effects profile than those receiving combination therapy with conventional chemotherapeutic agents.146,184,185,211

Bleomycin sulfate also has been used alone for the palliative treatment of AIDS-related Kaposi's sarcoma.146,169,170,171 Response rates observed with bleomycin monotherapy in early stage AIDS-related Kaposi's sarcoma appear to be similar to those observed with other single-agent chemotherapy (e.g., conventional doxorubicin, etoposide, vinblastine, vincristine).169,170,171 Although single-agent therapy usually has not been used in the management of advanced stages of AIDS-related Kaposi's sarcoma, in one study in patients with advanced-stage disease who received a 72-hour continuous IV infusion of bleomycin (20 units/m²daily) every 3 weeks, partial response was reported in up to 65% of patients.171,177

Other Uses

Bleomycin is labeled for use in the palliative treatment of squamous cell carcinomas of the penis and vulva.121 Bleomycin has been used in combination with other antineoplastic agents for the treatment of advanced or recurrent penile cancer.234

Bleomycin has been used in the treatment of non-Hodgkin's lymphoma;121,122 however, several randomized controlled trials235,236,237,238 and an analysis of pooled data239 from several randomized studies indicate that second- or third-generation combination regimens containing bleomycin are no more effective than the standard CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) for the treatment of advanced intermediate-grade or high-grade non-Hodgkin's lymphoma.

Bleomycin is used in combination with cisplatin and etoposide for the treatment of ovarian germ cell tumors†.122,216

Bleomycin in combination with cisplatin and vinblastine has been used for the treatment of intracranial germ cell tumors†.122,178

Bleomycin has been used intrapleurally for sclerotherapy in the management of pneumothorax† in a limited number of patients (e.g., pneumothorax associated with acquired immunodeficiency syndrome [ AIDS] and Pneumocystis jiroveci [formerly Pneumocystis carinii ] pneumonia).108,112

Reconstitution and Administration

Bleomycin sulfate is administered by IV, IM, subcutaneous, or intrapleural (intracavitary) injection.121

For IM or subcutaneous administration, the drug is reconstituted by adding 1-5 or 2-10 mL of sterile water for injection, 0.9% sodium chloride injection, or bacteriostatic water for injection to the vial labeled as containing 15 or 30 units of bleomycin, respectively, to provide solutions containing 3-15 units/mL.121 For IV administration, a minimum of 5 or 10 mL of 0.9% sodium chloride injection is added to the vial labeled as containing 15 or 30 units of bleomycin, respectively, to provide a solution containing not more than 3 units/mL.121 IV administration of bleomycin should be made slowly over a 10-minute period.121 For intrapleural administration, 60 units of bleomycin should be dissolved in 50-100 mL of 0.9% sodium chloride injection and administered through a thoracostomy tube.121

Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.121

Dosage

Dosage of bleomycin sulfate is expressed in terms of bleomycin. Dosage of bleomycin must be based on the tolerance and clinical response of the patient in order to obtain optimum therapeutic results with minimum adverse effects. Clinicians should consult published protocols for the dosage of bleomycin and other chemotherapeutic agents and the method and sequence of administration.

Hodgkin's Disease

Because of an increased possibility of anaphylactoid reactions in lymphoma patients, these patients should receive test doses of 2 units of bleomycin or less for the first 2 doses.121 If no acute reaction occurs, the recommended adult dosage may then be administered.121

For the treatment of Hodgkin's disease in adults, the manufacturer recommends weekly or twice weekly IV, IM, or subcutaneous bleomycin doses of 0.25-0.5 units/kg (10-20 units/m²).121 Following a 50% regression of tumor size in adults with Hodgkin's disease, a maintenance IM or IV dose of 1 unit of bleomycin daily or 5 units weekly can be given.121 If improvement occurs in patients with Hodgkin's disease, it is usually evident within 2 weeks.121

Testicular Cancer

For the treatment of testicular cancer in adults, the manufacturer recommends weekly or twice weekly IV, IM, or subcutaneous bleomycin doses of 0.25-0.5 units/kg (10-20 units/m²).121 If improvement occurs in patients with testicular cancer, it is usually evident within 2 weeks.121

Pleural Effusions

Drainage of the pleural fluid is necessary prior to instillation of bleomycin.121 When used as a sclerosing agent to control pleural effusions caused by metastatic tumors in adults, 50-60 units (but generally not exceeding 1 unit/kg or 40 units/m² in geriatric patients) of bleomycin usually should be diluted with 50-100 mL of 0.9% sodium chloride and instilled into the chest through a thoracostomy tube followed by clamping of the tube, periodic rotation (from the supine to the left and right lateral position) of the patient during the next 4 hours, and subsequent removal of the fluid.101,104,105,107,110,113,118,119,120,121 Some clinicians state that periodic rotation of patients is not necessary since repositioning is unlikely to increase efficacy of sclerotherapy.148,149

Prior to instillation of bleomycin in patients with effusions, the pleural cavity should be drained via the thoracostomy by gravity or suction;102,103,104,110,118,119,120,121 confirmation of complete expansion of the lungs is recommended.121,148,153 Complete drainage of the pleural fluid and reestablishment of negative intrapleural pressure prior to instillation of sclerotherapy is considered necessary for successful pleurodesis; therefore, the amount of drainage from the chest tube should be as minimal as possible prior to the instillation of bleomycin.121 Efficacy may be reduced if the solution were introduced into the pleural cavity while fluid drainage continued to exceed 100 mL per 24 hours.120 However, the manufacturer states that intrapleural administration of bleomycin sulfate may be initiated when drainage is 100-300 mL in 24 hours provided that the patient's clinical condition requires sclerotherapy.121

The manufacturer states that the length of time the chest tube remains in the pleural space after instillation of the drug should be individualized depending on the clinical status of the patient;121 some clinicians recommend that the chest tube remain for at least 4 days after instillation, in order to prevent pneumothorax.153

Squamous Cell Carcinomas

For the treatment of squamous cell carcinoma in adults, the manufacturer recommends weekly or twice weekly IV, IM, or subcutaneous bleomycin doses of 0.25-0.5 units/kg (10-20 units/m²).121 Three weeks of bleomycin therapy may be required before improvement is seen in patients with squamous cell carcinoma.121

Dosage Modification for Toxicity and Contraindications to Continued Therapy

Because of the increased incidence of toxicity, especially pulmonary toxicity, associated with large cumulative dosages, cumulative dosages exceeding 400 units of bleomycin in adults should be given with great caution.121 When bleomycin is used in conjunction with other antineoplastic agents, pulmonary toxicity may occur at lower cumulative dosages of bleomycin.121

Pulmonary Toxicity

Bleomycin therapy should be promptly discontinued with the appearance of clinical manifestations or radiologic evidence of pulmonary toxicity until it can be determined whether it is drug related.121 Bleomycin should be discontinued when the pulmonary diffusion capacity for carbon monoxide (DL_co) is less than 30-35% of the pretreatment value.121

Monitoring of pulmonary function tests for alteration in the pulmonary status, such as decreased total lung volume and decreased vital capacity, is not reliable for predicting the development of pulmonary fibrosis.121 Some clinicians suggest that bleomycin should be discontinued if forced vital capacity decreases rapidly.

Reduction in the infusion rate of bleomycin or discontinuance of the drug is advised in patients experiencing acute chest pain syndrome suggestive of pleuropericarditis.121,133 (See Dosage Modification for Toxicity and Contraindications to Continued Therapy: Cardiac Toxicity, under Dosage and Administration: Dosage.)

Cardiac Toxicity

Reduction in the infusion rate of bleomycin or discontinuance of the drug is advised in patients experiencing acute chest pain syndrome suggestive of pleuropericarditis.121,133 (See Cautions: Respiratory Effects.) The manufacturer states that further courses of bleomycin therapy do not appear to be contraindicated, although careful evaluation of the patient must precede continuation of therapy.121 Some clinicians recommend discontinuance of the drug in patients with intractable pain or ECG changes suggestive of pericarditis.133

Dermatologic and Mucocutaneous Toxicity

Discontinuance of therapy because of mucocutaneous toxicity may be required in patients receiving bleomycin.121

Dosage in Renal Impairment

Clearance of bleomycin may be reduced in patients with renal impairment; there are no guidelines for dosage adjustments in such patients, but the manufacturer states that the drug should be used with extreme caution in patients with severe renal impairment.121

Respiratory Effects

The most serious toxic effect of bleomycin is pulmonary reactions, usually presenting as interstitial pneumonitis, which occurs in approximately 10% of patients receiving the drug.121 Bleomycin pneumonitis occasionally progresses to pulmonary fibrosis and has resulted in death in approximately 1% of patients receiving the drug.121 Pulmonary toxicity generally appears to be dose and age related, occurring most frequently in patients older than 70 years of age and those receiving a total dosage of more than 400 units; however, pulmonary toxicity is unpredictable and reportedly has developed in younger patients receiving lower doses (e.g., after a total dosage of less than 200 units).121 Fatal pulmonary fibrosis occurred in a geriatric patient who received a total dosage of only 20 units of the drug.100

Dyspnea and fine rales are early manifestations of pulmonary toxicity.121 Because of the nonspecific signs and symptoms, identification of patients with bleomycin-induced pulmonary toxicity has been extremely difficult.121 Radiographic changes associated with bleomycin-induced pneumonitis consist of nonspecific patchy opacities, usually in the lower lung fields.121 Microscopic tissue changes also are nonspecific and are similar to the alterations seen with radiation pneumonitis or pneumocystic pneumonitis.121 The acute pulmonary tissue changes may include capillary changes and subsequent fibrinous exudation into the alveoli (similar to hyaline membrane formation), which may progress to diffuse interstitial fibrosis resembling Hamman-Rich syndrome.121 Other microscopic tissue changes include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, and fibrinous edema.121

Appropriate anti-infectives are indicated if bleomycin-induced pneumonitis proves to be infectious. Although it has been suggested that the use of corticosteroids in patients with bleomycin pneumonitis may prevent the development of pulmonary fibrosis or reverse pulmonary toxicity, some clinicians report that this measure has little value.

Rarely, sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been reported during continuous infusions of bleomycin.121,133 Improvement of this syndrome may be noted with slower infusion rates of the drug and patients may require analgesics for treatment of pain;133 total recovery usually occurs after discontinuance of the drug.133

In at least one patient, cavitary pulmonary nodules associated with granuloma developed after combination therapy containing bleomycin;122,139 spontaneous resolution of these lesions occurred despite continuation of therapy.139

Careful monitoring for clinical manifestations and evidence of pulmonary toxicity is required in patients receiving bleomycin.121 (See Cautions: Precautions and Contraindications.) Dosage modification or discontinuance of the drug may be necessary in patients experiencing pulmonary toxicity.121 (See Dosage Modification for Toxicity and Contraindications for Continued Therapy in Dosage and Administration: Dosage.)

Dermatologic and Mucocutaneous Effects

Mucocutaneous toxicity is the most frequent adverse effect of bleomycin, occurring in at least 50% of patients receiving the drug.121 Adverse mucocutaneous effects, including erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of the skin, usually develop in the second or third week of bleomycin therapy.121 Mucocutaneous effects appear to be related to total dosage, usually occurring after 150-200 units of bleomycin have been administered.121 Discontinuance of therapy because of mucocutaneous toxicity has been required in 2% of patients receiving bleomycin.121

The onset of skin toxicity may be accompanied by hypoesthesia which may progress to hyperesthesia; paresthesia has also been reported. Skin toxicity may be initially manifested as urticaria or erythematous swelling; lesions may then become tender and pruritic. Hyperpigmentation121 is a frequently reported adverse effect, occurring particularly in those areas subject to friction or pressure and in skin folds, nail cuticles, scars, and IM injection sites. Hyperkeratosis, nail changes, and pruritus also have been reported.121 Diffuse alopecia121 of varying degrees may occur in patients receiving bleomycin therapy. Other reported skin reactions include ichthyosis, peeling, and bleeding. Scleroderma-like skin changes121 have been reported in patients receiving bleomycin. Mucosal lesions, including stomatitis121 and ulcerations of the tongue and lips also may occur.

Sensitivity Reactions

Anaphylactoid reactions, consisting of hypotension, fever, chills, mental confusion, and wheezing, have occurred in approximately 1% of patients with lymphomas receiving bleomycin.121 This idiosyncratic reaction may be immediate or delayed for several hours, and usually occurs after the first or second dose.121 The reaction has resulted in death. Treatment of anaphylactoid reactions is supportive and symptomatic and may include volume expansion, vasopressor therapy, antihistamines, and corticosteroids.121

Cardiovascular Effects

Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been reported rarely during continuous infusions of bleomycin.121,133 (See Cautions: Respiratory Effects.)

Rarely, vascular toxicities have been associated with the use of bleomycin-containing combination chemotherapy.121 The adverse vascular effects are clinically heterogeneous121,137 and may include myocardial infarction,121,137 cerebrovascular accident,121,137,141 thrombotic microangiopathy,121 or cerebral arteritis.121 Various mechanisms have been suggested,121,137 including endothelial cell damage.137

Raynaud's phenomenon has occurred in patients receiving bleomycin and vinblastine, with or without cisplatin,121,134,135,137 and in a few patients receiving bleomycin as a single agent.121,136 Cisplatin-induced hypomagnesemia may be an additional, although not essential, factor associated with its occurrence in patients receiving combination regimens including bleomycin and cisplatin.135 (For further information on hypomagnesemia associated with the use of cisplatin, see Hypomagnesemia and Other Electrolyte Effects in Cautions: Renal and Electrolyte Effects in Cisplatin 10:00.) The cause of Raynaud's phenomenon in these cases, however, is not clearly established and may involve the underlying disease or vascular compromise, bleomycin, vinblastine, hypomagnesemia, or some combination of these factors.121,134,135,136,137

Renal Effects

Renal toxicity, initially manifested by abnormal renal function test results, has been reported infrequently in patients receiving bleomycin.121 Renal toxicity may occur at any time following initiation of bleomycin therapy.121

Febrile Reactions

Fever and chills frequently follow parenteral administration of bleomycin.121 Febrile reactions have been reported to occur most frequently with large single doses within a few hours after bleomycin administration and last for 4-12 hours. Usually, febrile reactions become less frequent with continued use of the drug; however, they may occur sporadically and recur later in the course of therapy. Salicylates and antihistamines have not produced uniform results in reducing the fever associated with bleomycin administration. Fever is one of the most common adverse effects of intracavitary administration of sclerosing agents (e.g., bleomycin).104,147,148,150,159,160,161,166

GI Effects

Vomiting frequently occurs in patients receiving bleomycin;121,122 nausea also has been reported.122

Metabolic Effects

Anorexia and weight loss are common and may persist after discontinuance of bleomycin.121

Intrapleural Administration-related Effects

Because bleomycin is well absorbed systemically following intrapleural instillation,117 the possibility of systemic toxicity, particularly in patients receiving systemic chemotherapy, immunocompromised patients, or those with impaired renal function, should be considered.102,108,118,153,157 In most patients, however, evidence of systemic toxicity is minimal.101,102,103,104,107,108,110,118,119,120,148,153

The most common adverse effects reported with intracavitary administration of sclerosing agents into the pleural space are chest pain and fever.104,121,147,148,150,153,159,160,161,166 Opiate analgesics may be administered prior to the procedure to relieve pain associated with pleurodesis;104,120,153,160,163,166 lidocaine also has been instilled into the chest tube prior to pleurodesis to help alleviate discomfort.104,120,153,164 The manufacturer states that the intrapleural injection of local anesthetics or systemic administration of opiates generally is not necessary.121 Mild analgesics and/or antipyretics also may be used for management of pain and fever.153

Intrapleural administration of bleomycin sulfate has been associated infrequently with hypotension requiring symptomatic treatment.121 Other adverse effects associated with intrapleural administration of bleomycin sulfate include nausea, vomiting, diarrhea, hemoptysis, fluid accumulations, septic shock, rash, and alopecia.148,150 Adverse pulmonary effects possibly related to the intrapleural administration of bleomycin have been reported rarely.121 Death attributed to bleomycin pleurodesis has been reported rarely.102,121,148,152,157

Hematologic Effects

Unlike many other antineoplastic agents, bleomycin does not frequently produce serious bone marrow toxicity. The adverse hematologic effects of bleomycin therapy that have been reported include thrombocytopenia, leukopenia, and slight depression of hemoglobin levels. In one study, all of these levels reached a nadir by the twelfth day and returned to pretreatment levels by the seventeenth day of continued daily IV bleomycin doses of 0.25 units/kg.

Hepatic Effects

Hepatic toxicity, initially manifested by abnormalities in liver function test results, has been reported infrequently in patients receiving bleomycin.121 Hepatotoxicity may occur at any time following initiation of bleomycin therapy.121

Genitourinary Effects

Hematuria, cystitis, and hemorrhagic cystitis122,138 have been reported rarely in patients receiving bleomycin.

Other Adverse Effects

Pain at the tumor site and local reactions (e.g., phlebitis) at the injection site have been reported infrequently.121 Malaise121 and general weakness also have been reported. Rarely, disorientation and aggressive behavior have been reported.

Precautions and Contraindications

Bleomycin is a toxic drug with a low therapeutic index. The drug should be used only under constant supervision by physicians experienced in cancer chemotherapy, and it should be administered only in settings where adequate diagnostic and treatment facilities are readily available for management of therapy and potential complications.121 Patients receiving bleomycin must be monitored carefully and frequently during and after therapy.121

Bleomycin should be administered with extreme caution to patients with clinically important impairment of renal function or compromised pulmonary function.121 Some clinicians recommend that use of bleomycin as a sclerosing agent be avoided in patients with underlying lung disease or lung metastases.149

Patients receiving bleomycin should be closely monitored for signs of pulmonary toxicity and chest radiographs should be taken every 1-2 weeks.121 Sequential measurement of pulmonary diffusion capacity for carbon monoxide (DL_co) performed monthly during bleomycin therapy may be of value in predicting pulmonary toxicity.121 (Also see Pulmonary Toxicity in Dosage and Administration: Dosage: Dosage Modification for Toxicity and Contraindications to Continued Therapy.)

Because of bleomycin's effects on lung tissue, patients who have received the drug are at increased risk of developing pulmonary toxicity when oxygen is administered during surgery.121 Long exposure to very high concentrations of oxygen is a known cause of lung damage, but after administration of bleomycin, lung damage can occur at oxygen concentrations lower than those usually considered safe.121 To minimize the risk in patients undergoing surgery who have received bleomycin, the FI O₂ concentration should be maintained at approximately that of room air (25%) during surgery and the postoperative period; in addition, fluid replacement should be carefully monitored, with emphasis on administration of colloid rather than crystalloid.121

Limited data indicate that risk of bleomycin-induced pulmonary toxicity may be increased in patients receiving filgrastim or other cytokines concomitantly.121 However, increased risk of pulmonary toxicity was not reported in randomized clinical studies in patients receiving bleomycin concomitantly with filgrastim.121

All lymphoma patients should receive test doses of bleomycin before initiating full-dose therapy.121 (See Dosage and Administration: Dosage.) Careful monitoring of patients with lymphoma is essential after administration of the first and second doses of bleomycin since that is when severe idiosyncratic reactions have most commonly occurred.121

Bleomycin is contraindicated in patients with known hypersensitivity or idiosyncrasy to the drug.121

Pediatric Precautions

The manufacturer states that safety and efficacy of bleomycin in children have not been established.121

Geriatric Precautions

The risk of pulmonary toxicity associated with bleomycin is greater in patients older than 70 years of age than in younger patients.240 While clinical experience has not revealed other age-related differences in response or tolerance, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.240 Because geriatric patients may have decreased renal function and because patients with renal impairment may be at increased risk of bleomycin-induced toxicity, patients in this age group should be monitored closely and dosage adjusted accordingly.240

Mutagenicity and Carcinogenicity

Bleomycin has been shown to be mutagenic in vitro and in vivo.121 It is not known if bleomycin is carcinogenic in humans.121 However, an increased incidence of nodular hyperplasia was observed in F344/N male rats that received bleomycin following nitrosamine-induced lung carcinogenesis.121 In another study, necropsy findings included dose-related injection site fibrosarcomas and various renal tumors in rats receiving subcutaneous bleomycin dosages of 0.35 mg/kg weekly (3.82 units/m² weekly, about 30% of the recommended human dosage).121

Pregnancy, Fertility, and Lactation

Pregnancy

Bleomycin sulfate can cause fetal toxicity when administered to pregnant women.121 The drug has been shown to be teratogenic in rats receiving intraperitoneal dosages of 1.5 mg/kg daily (about 1.6 times the recommended human dosage on a units/m² basis) on days 6-15 of gestation.121 Fetal malformations included skeletal defects, shortened innominate artery, and hydroureter.121 The drug has been shown to be abortifacient, but not teratogenic in rabbits receiving IV dosages of 1.2 mg/kg daily (about 2.4 times the recommended human dosage on a units/m² basis) on days 6-18 of gestation.121 There are no adequate and controlled studies to date using bleomycin sulfate in pregnant women.121 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.121 Women of childbearing potential should be advised to avoid becoming pregnant during bleomycin sulfate therapy.121

Fertility

The effects of bleomycin on fertility have not been studied.121

Lactation

It is not known whether bleomycin is excreted in human milk.121 Because of the potential for serious adverse reactions to bleomycin in nursing infants if it were distributed, the manufacturer recommends that women receiving bleomycin discontinue nursing.121

Vitamins may decrease the activity of certain antibiotics; bleomycin has been shown to be inactivated in vitro by ascorbic acid and riboflavin.233

Pharmacology

Bleomycin is an antineoplastic antibiotic. The drug is active against gram-positive and gram-negative bacteria and fungi, but its cytotoxicity precludes its use as an anti-infective agent. The precise mechanism(s) of action of bleomycin is not fully known. Several studies in Escherichia coli and HeLa cells suggest that the drug inhibits the incorporation of thymidine into DNA. In these in vitro studies, DNA synthesis was inhibited to a greater extent than was RNA or protein synthesis. Bleomycin also appears to labilize the DNA structure, resulting in scission of both single- and double-stranded DNA. The drug has no immunosuppressive activity in mice.

Pharmacokinetics

Absorption

Bleomycin sulfate is not significantly absorbed from the GI tract and the drug must be administered parenterally. Bleomycin is absorbed systemically following intrapleural or intraperitoneal administration. Systemic absorption of 45% has been reported following intrapleural administration of bleomycin.121,150,153

Distribution

Following parenteral administration of bleomycin in animals, the drug is distributed mainly into the skin, lungs, kidneys, peritoneum, and lymphatics. Concentrations of the drug in tumor cells of the skin and lungs are higher than those in hematopoietic tissue. The low concentrations of bleomycin found in bone marrow may be related to the high concentrations of bleomycin degradative enzymes present in that tissue. Results of an animal study suggest that the concentration of bleomycin in chemically induced squamous cell carcinomas is higher than that in sarcomas, partially as a result of a lower concentration of bleomycin degradative enzymes in squamous cell carcinomas than in sarcomas.

Elimination

In patients with creatinine clearance exceeding 35 mL/minute, the serum or plasma terminal half-life of bleomycin is about 2 hours.121 In patients with creatinine clearances less than 35 mL/minute, the terminal half-life of the drug is inversely related to creatinine clearance.121

The metabolic fate of bleomycin has not been determined. In patients with normal renal function, 60-70% of a parenterally administered dose is excreted in the urine as active drug. In patients with moderately severe renal impairment (creatinine clearance of less than 35 mL/minute), less than 20% of a parenterally administered dose is excreted in urine as active drug, indicating that accumulation of the drug may occur in patients with severe renal impairment.112,121

Chemistry and Stability

Chemistry

Bleomycin sulfate is a mixture of basic cytotoxic glycopeptide antibiotics produced by Streptomyces verticillus; bleomycin A₂ and bleomycin B₂ are the major components. Bleomycin sulfate occurs as a cream-colored, amorphous powder and is very soluble in water and sparingly soluble in alcohol. The potency of bleomycin is assayed microbiologically; the activity of 1 unit of bleomycin is equivalent to the formerly used reference standard, the activity of 1 mg of bleomycin A₂. The previously used term mg activity has been replaced with the more precise term of units.121 Following reconstitution, bleomycin sulfate injection has a pH of 4.5-6, depending upon the diluent used.

Stability

In vitro, bleomycin is inactivated by agents containing sulfhydryl groups, hydrogen peroxide, and ascorbic acid. Bleomycin sulfate sterile powder is stable under refrigeration at 2-8°C and should not be used after the expiration date is reached.121

Following reconstitution with 0.9% sodium chloride injection, the manufacturer states that bleomycin sulfate solutions are stable for 24 hours at room temperature. The manufacturer states that 5% dextrose injection or other diluents containing dextrose should not be used to reconstitute bleomycin sulfate injection since losses of potency (determined by high-performance liquid chromatography [HPLC]) of bleomycin A₂ and bleomycin B₂ have been reported when 5% dextrose was used as diluent.121 It has been suggested that loss of bleomycin potency in dextrose solutions probably results from formation of Schiff base-type adducts with dextrose.106 Although reconstituted solutions of bleomycin sulfate are reportedly stable for 2 weeks at room temperature and 4 weeks at 2-8°C, the reconstituted solutions contain no preservatives and the manufacturer recommends that they be used within 24 hours of reconstitution; unused portions should be discarded.

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

Only references cited for selected revisions after 1984 are available electronically.

100. Bechard DE, Fairman RP, DeBlois GG et al. Fatal pulmonary fibrosis from low-dose bleomycin therapy. South Med J . 1987; 80:646-9. [PubMed 2437659]

101. Ostrowski MJ. An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavity bleomycin. Cancer . 1986; 57:721-7. [PubMed 2417681]

102. Kessinger A, Wigton RS. Intracavitary bleomycin and tetracycline in the management of malignant pleural effusions: a randomized study. J Surg Oncol . 1987; 36:81-3. [PubMed 2443762]

103. Paladine W, Cunningham TJ, Sponzo R et al. Intracavitary bleomycin in the management of malignant effusions. Cancer . 1976; 38:1903-8. [PubMed 62609]

104. Hausheer FH, Yarbro JW. Diagnosis and treatment of malignant pleural effusion. Semin Oncol . 1985; 12:54-75. [PubMed 2579439]

105. Ruckdeschel J, Moores D, Lee J et al. Management of malignant pleural effusions (MPE): a randomized comparison of tetracycline (TETRA) and bleomycin (BLEO). Proc ASCO . 1990; 9. Abstract No. 1247.

106. Koberda M, Zieske PA, Raghavan NV et al. Stability of bleomycin sulfate reconstituted in 5% dextrose injection or 0.9% sodium chloride injection stored in glass vials or polyvinyl chloride containers. Am J Hosp Pharm . 1990; 47:2528-9. [PubMed 1703725]

107. Ostrowski MJ. Intracavitary therapy with bleomycin for the treatment of malignant pleural effusions. J Surg Oncol . 1989; (Suppl 1):7-13.

108. Hnatiuk OW, Dillard TA, Oster CN. Bleomycin sclerotherapy for bilateral pneumothoraces in a patient with AIDS. Ann Intern Med . 1990; 113:988-90. [PubMed 1700656]

109. Benvenuto JA, Anderson RW, Kerkof K et al. Stability and compatibility of antitumor agents in glass and plastic containers. Am J Hosp Pharm . 1981; 38:1914-8. [PubMed 7325172]

110. Ostrowski MJ, Priestman TJ, Houston RF et al. A randomized trial of intracavitary bleomycin and Corynebacterium parvum in the control of malignant pleural effusions. Radiother Oncol . 1989; 14:19-26. [PubMed 2467327]

111. Stajich GV, Miyahara RK, Alonso K. In vitro evaluation of bleomycin-induced cell lethality from plastic and glass containers. DICP . 1991; 25:14-6. [PubMed 1706902]

112. Reviewers' comments (personal observations).

113. Moores DW. Malignant pleural effusion. Semin Oncol . 1991; 18(Suppl 2):59-61. [PubMed 1704153]

114. Hamed H, Fentiman IS, Chaudar MA et al. Comparison of intracavitary bleomycin and talc for control of pleural effusions secondary to carcinoma of the breast. Br J Surg . 1989; 76:1265-7.

115. Lees AW, Hoy W. Management of pleural effusions in breast cancer. Chest . 1979; 75:51-3. [PubMed 421524]

116. Ostrowski MJ, Halsall GM. Intracavity bleomycin in the management of malignant effusions: a multicenter study. Cancer Treat Rep . 1982; 66:1903-7. [PubMed 6182995]

117. Alberts DS, Chen HS, Mayersohn M et al. Bleomycin pharmacokinetics in man. II. Intracavitary administration. Cancer Chemother Pharmacol . 1979; 2:127-32. [PubMed 93985]

118. Siegel RD, Schiffman FJ. Systemic toxicity following intracavitary administration of bleomycin. Chest . 1990; 98:507. [PubMed 1695874]

119. Ruckdeschel JC, Moores D, Lee JY et al. Intrapleural therapy for malignant pleural effusions: a randomized comparison of bleomycin and tetracycline. Paper presented in part at the Proceedings of the American Society of Clinical Oncology, Washington, DC, 22 May 1990 and at the Annual Meeting of the American College of Chest Physicians, Toronto, Canada, 1990 Oct 25.

120. Ruckdeschel JC, Moores DW. Recent findings in the clinical management of malignant pleural effusions: continuing medical education monograph. Albany, NY: The Albany Medical Colle 1990 May (publication No. N-W268).

121. Bristol-Myers Squibb. Blenoxane^® (bleomycin sulfate for injection, USP) prescribing information. Princeton, NJ; 1999 Apr.

122. Anon. Drugs of choice for cancer chemotherapy. Med Lett Drugs Ther . 2000; 42:83-92. [PubMed 10994034]

123. Testicular cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Aug.

124. Ozols RF, Yagoda A. Genitourinary cancer. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biologic response modifiers. Annual 9. New York: Elsevier Science Publishers B.V. (Biomedical Division); 1987:280-302.

125. Ozols RF, Yagoda A. Genitourinary cancer. In: Pinedo HM, Longo DL, Chabner BA, eds. Cancer chemotherapy and biologic response modifiers. Annual 10. New York: Elsevier Science Publishers B.V. (Biomedical Division); 1988:271-90.

126. Bergmann KA. Current concepts in clinical therapeutics: Testicular cancer. Clin Pharm . 1987; 6:693-706. [PubMed 2445518]

127. Priest ER, Vogelzang NJ. Optimal drug therapy in the treatment of testicular cancer. Drugs . 1991; 42:52-64. [PubMed 1718685]

128. Peckham MJ, Barrett A, Liew KH et al. The treatment of metastatic germ-cell testicular tumours with bleomycin, etoposide and cis -platin (BEP). Br J Cancer . 1983; 47:613-9. [PubMedCentral][PubMed 6189504]

129. Williams SD, Birch R, Einhorn LH et al. Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med . 1987; 316:1435-40. [PubMed 2437455]

130. Oncolytic drugs: principles of cancer chemotherapy. In: Drug evaluations subscription. Chicago, IL; American Medical Association, III/ONC-1:27, Summer 1993.

131. Oncolytic drugs: antineoplastic agents: antibiotics, alkaloids, and enzymes. In: Drug evaluations subscription. Chicago, IL; American Medical Association, III/ONC-4:8-9, Spring 1993.

132. Loehrer PJ, Williams SD, Einhorn LH. Testicular cancer: the quest continues. J Natl Cancer Inst . 1988; 80:1373-83. [PubMed 3050140]

133. White DA, Schwartzberg LS, Kris MG et al. Acute chest pain syndrome during bleomycin infusions. Cancer . 1987; 59:1582-5. [PubMed 2435402]

134. Vogelzang NJ, Bosl GJ, Johnson K et al. Raynaud's phenomenon: a common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med . 1981; 95:288-92. [PubMed 6168223]

135. Vogelzang NJ, Torkelson JL, Kennedy BJ. Hypomagnesemia, renal dysfunction, and Raynaud's phenomenon in patients treated with cisplatin, vinblastine, and bleomycin. Cancer . 1985; 56:2765-70. [PubMed 2413982]

136. Adoue D, Arlet P. Bleomycin and Raynaud's phenomenon. Ann Intern Med . 1984; 100:770. [PubMed 6201095]

137. Doll DC, List AF, Greco FA et al. Acute vascular ischemic events after cisplatin-based combination chemotherapy for germ-cell tumors of the testis. Ann Intern Med . 1986; 105:48-51. [PubMed 2424354]

138. Cantwell BMJ, Harris AL, Patrick D et al. Hemorrhagic cystitis after iv bleomycin, vinblastine, cisplatin, and etoposide for testicular cancer. Cancer Treat Rep . 1986; 70:548-9. [PubMed 2421895]

139. Talcott JA, Garnick MB, Stomper PC et al. Cavitary lung nodules associated with combination chemotherapy containing bleomycin. J Urol . 1987; 138:619-20. [PubMed 2442421]

140. Loehrer PJ, Birch R, Williams SD et al. Chemotherapy of metastatic seminoma: the Southeastern Cancer Study Group experience. J Clin Oncol . 1987; 5:1212-20. [PubMed 2442317]

141. Gerl A, Clemm C, Schleuning M et al. Fatal cerebrovascular accident associated with chemotherapy for testicular cancer. Eur J Cancer . 1993; 29A:1220-1. [PubMed 7686022]

142. Urba WJ, Longo DL. Hodgkin's disease. N Engl J Med . 1992; 326:678-87. [PubMed 1736106]

143. DeVita VT Jr, Hubbard SM. Hodgkin's disease. N Engl J Med . 1993; 328:560-5. [PubMed 8426624]

144. Adult Hodgkin's disease. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.

145. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD; 1996 Jul.

146. Kaposi's sarcoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 May.

147. Ruckdeschel JC, Moores D, Lee JY et al. Intrapleural therapy for malignant pleural effusions: a randomized comparison of bleomycin and tetracycline. Chest . 1991; 100:1528-35. [PubMed 17,20370]

148. Andrews CO, Gora ML. Pleural effusions: pathophysiology and management. Ann Pharmacother . 1994; 28:894-903. [PubMed 7524816]

149. Fenton KN, Richardson JD. Diagnosis and management of malignant pleural effusions. Am J Surg . 1995; 170:69-74. [PubMed 7793501]

150. Walker-Renard PB, Vaughan LM, Sahn SA. Chemical pleurodesis for malignant pleural effusions. Ann Intern Med . 1994; 120:56-64. [PubMed 8250457]

151. Fuller DK. Controversy over sclerotherapy for malignant pleural effusions. Ann Intern Med . 1994; 121:150. [PubMed 7517112]

152. Vaughan LM, Sahn SA. Controversy over sclerotherapy for malignant pleural effusions. Ann Intern Med . 1994; 121:151.

153. Windsor PG, Como JA, Windsor KS. Sclerotherapy for malignant pleural effusions: alternatives to tetracycline. South Med J . 1994; 87:709-14. [PubMed 7517579]

154. DeVries BC, Bitran JD. On the management of malignant pleural effusions. Chest . 1994; 105:1-2. [PubMed 7506134]

155. Keller SM. Current and future therapy for malignant pleural effusion. Chest . 1993; 103(Suppl):63-7S.

156. Lynch TJ Jr. Management of malignant pleural effusions. Chest . 1993; 103(Suppl):385-9S.

157. Audu PBD, Sing RF, Mette SA et al. Fatal diffuse alveolar injury following use of intrapleural bleomycin. Chest . 1993; 103:1638. [PubMed 7683596]

158. Ruckdeschel JC. Controversy over sclerotherapy for malignant pleural effusions. Ann Intern Med . 1994; 121:150. [PubMed 7517113]

159. Kitamura S, Sugiyama Y, Izumi T et al. Intrapleural doxycycline for control of malignant pleural effusion. Curr Ther Res . 1981; 30:515-21.

160. Mansson T. Treatment of malignant pleural effusion with doxycycline. Scand J Infect Dis Suppl . 1988; 53:29-34. [PubMed 3166542]

161. Walker-Renard PB, Vaughan LM, Sahn SA. Chemical pleurodesis for malignant pleural effusions. Arch Intern Med . 1994; 120:56-64.

162. Homma T, Yoneda S, Komuro Y et al. Pharmacokinetics and pleural reaction of doxycycline after intrapleural administration. Gan To Kagaku Ryoho (Japanese with English abstract.) . 1983; 10(4 Part 2):1129-34.

163. Gericke KR. Doxycycline as a sclerosing agent. Ann Pharmacother . 1992; 26:648-49. [PubMed 1375521]

164. Hatta T, Tsubota N, Yoshimura M et al. [Intapleural minocycline for postoperative air leakage and control of malignant pleural effusion]. Kyobu Geka (Japanese with English abstract) . 1990; 43:283-6.

165. Ruckdeschel JC. Management of malignant pleural effusion: an overview. Semin Oncol . 1988; 15(Suppl 3):24-8. [PubMed 3293215]

166. Vaughan LM, Walker PB, Sahn SA. Alternatives to tetracycline pleurodesis. Ann Pharmacother . 1992; 26:562-3. [PubMed 1576396]

167. Heffner JE, Unruh LC. Tetracycline pleurodesis: adios, farewell, adieu. Chest . 1992; 101:5-7. [PubMed 1729109]

168. Rusch VW. The optimal treatment of malignant pleural effusions: a continuing dilemma. Chest . 1991; 100:1483-4. [PubMed 17,20369]

169. Caumes E, Guermonprez G, Katlama C et al. AIDS-associated mucocutaneous Kaposi's sarcoma treated with bleomycin. AIDS . 1992; 6:1483-7. [PubMed 1283521]

170. Lassoued K, Clauvel JP, Katlama C et al. Treatment of the acquired immune deficiency syndrome-related Kaposi's sarcoma with bleomycin as a single agent. Cancer . 1990; 66:1869-72. [PubMed 1699652]

171. Remick SC, Reddy M, Herman D et al. Continuous infusion bleomycin in AIDS-related Kaposi's sarcoma. J Clin Oncol . 1994; 12:1130-6. [PubMed 7515412]

172. Laubenstein LJ, Krigel RL, Odajnyk CM et al. Treatment of epidemic Kaposi's sarcoma with etoposide or a combination of doxorubicin, bleomycin, and vinblastine. J Clin Oncol . 1984; 2:1115-20. [PubMed 6208343]

173. Gelmann EP, Longo D, Lane HC et al. Combination chemotherapy of disseminated Kaposi's sarcoma in patients with the acquired immune deficiency syndrome. Am J Med . 1987; 82:456-62. [PubMed 2435150]

174. Gill P, Rarick M, Bernstein-Singer M et al. Treatment of advanced Kaposi's sarcoma using a combination of bleomycin and vincristine. Am J Clin Oncol . 1990;13:315-9. [PubMed 1696066]

175. Gill PS, Rarick M, McCutchan JA et al. Systemic treatment of AIDS-related Kaposi's sarcoma: results of a randomized trial. Am J Med . 1991; 90:427-33. [PubMed 1707230]

176. Rarick MU, Gill PS, Montgomery T et al. Treatment of epidemic Kaposi's sarcoma with combination chemotherapy (vincristine and bleomycin) and zidovudine. Ann Oncol . 1990; 1:147-9. [PubMed 1706615]

177. Northfelt DW. Treatment of Kaposi s sarcoma: current guidelines and future perspectives. Drugs . 1994; 48:569-82. [PubMed 7528130]

178. Matsutani M, Sano K, Takakura K et al. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg . 1997; 86:446-55. [PubMed 9046301]

179. Northfelt DW. Efficacy of Doxil^® (doxorubicin HCl liposome injection) in the treatment of refractory AIDS-related Kaposi's sarcoma. In: Doxil Clinical Series. Vol 1, No 3. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-8.

180. Coleman R. Treatment of refractory AIDS-related Kaposi's sarcoma with Doxil^® (doxorubicin HC liposome injection): a pharmacy perspective. In: Doxil Clinical Series. Vol 1, No 4. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-12.

181. Dezube BJ. Safety assessment: Doxil^® (doxorubicin HCl liposome injection) in refractory AIDS-related Kaposi's sarcoma. In: Doxil Clinical Series. Vol 1, No 2. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-8.

182. Alza Pharmaceuticals, Inc. Doxil^® (doxorubicin HCl liposome injection) prescribing information. Palo Alto, CA; 1999 Jul.

183. Sequus Pharmaceuticals, Menlo Park, CA: Personal communication.

184. Stewart S, Jablonowski H, Goebel FD et al. Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. J Clin Oncol . 1998; 16:683-91. [PubMed 9469358]

185. Northfelt DW, Dezube BJ, Thommes JA et al. Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial. J Clin Oncol . 1998; 16:2445-51. [PubMed 9667262]

186. Bogner JR, Kronawitter U, Rolinski B et al. Liposomal doxorubicin in the treatment of advanced AIDS-related Kaposi sarcoma. J Acquir Immune Defic Syndr . 1994; 7:463-8. [PubMed 8158540]

187. Esser S, Bleil M, Reimann G et al. Long term treatment with liposomal doxorubicin in patients with AIDS-related Kaposi s sarcoma. In: XI International Conference on AIDS, 1996: Vancouver, BC; 1996 Jul 7-12. Abstract No. Th.A.4077.

188. Northfelt DW, Martin FJ, Working P et al. Doxorubicin encapsulated in liposomes containing surface-bound polyethylene glycol: pharmacokinetics, tumor localization, and safety in patients with AIDS-related Kaposi s sarcoma. J Clin Pharmacol . 1996; 36:55-63. [PubMed 8932544]

189. Gruenaug M, Bogner JR, Loch O et al. Liposomal doxorubicin in pulmonary Kaposi's sarcoma: improved survival as compared to patients without liposomal doxorubicin. In: XI International Conference on AIDS, 1996: Abstracts-on-disk^®. Vancouver, BC; 1996 Jul 7-12. Abstract No. Tu.B.2221.

190. Harrison M, Tomlinson D, Stewart S. Liposomal-entrapped doxorubicin: an active agent in AIDS-related Kaposi's sarcoma. J Clin Oncol . 1995; 13:914-20. [PubMed 7707119]

191. Moran TA. Treatment of refractory AIDS-related Kaposi's sarcoma with Doxil^® (doxorubicin HCl liposome injection): a nursing perspective. In: Doxil Clinical Series. Vol 1, No 5. Menlo Park, CA: Sequus Pharmaceuticals, Inc; 1996:1-8.

192. Gill PS, Rarick MU, Espina B et al. Advanced acquired immune deficiency syndrome-related Kaposi's sarcoma: results of pilot studies using combination chemotherapy. Cancer . 1990; 65:1074-8. [PubMed 1689209]

193. De Wit R, Schattenkerk JKME, Boucher CAB et al. Clinical and virological effects of high-dose recombinant interferon-α in disseminated AIDS-related Kaposi's sarcoma. Lancet . 1988; 2:1214-7. [PubMed 2903953]

194. Groopman JE, Gottlieb MS, Goodman J et al. Recombinant alpha-2 interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome. Ann Intern Med . 1984; 100:671-6. [PubMed 6712031]

195. Mayer-da-Silva A, Stadler R, Imcke E et al. Disseminated Kaposi's sarcoma in AIDS: histogenesis-related populations and influence of long-term treatment with rIFN-αA. J Invest Dermatol . 1987; 89:618-24. [PubMed 3680987]

196. Groopman JE. Biology and therapy of epidemic Kaposi's sarcoma. Cancer . 1987; 59:633-7. [PubMed 10822462]

197. Volberding PA, Mitsuyasu R. Recombinant interferon alpha in the treatment of acquired immune deficiency syndrome—related Kaposi's sarcoma. Semin Oncol . 1985; 12:2-6. [PubMed 3909416]

198. Mitsuyasu RT, Taylor JMG, Glaspy J et al. Heterogeneity of epidemic Kaposi's sarcoma: implications for therapy. Cancer . 1986; 57:1657-61. [PubMed 3081246]

199. Safai B. Pathophysiology and epidemiology of epidemic Kaposi's sarcoma. Semin Oncol . 1987; 14(Suppl 3):7-12. [PubMed 3299718]

200. Krown SE. The role of interferon in the therapy of epidemic Kaposi's sarcoma. Semin Oncol . 1987; 14(Suppl 3):27-33. [PubMed 2440110]

201. Gelmann EP, Preble OT, Steis R et al. Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immune deficiency syndrome: clinical response and prognostic parameters. Am J Med . 1985; 78:737-41. [PubMed 3838854]

202. Kovacs JA, Deyton L, Davey R et al. Combined zidovudine and interferon-α therapy in patients with Kaposi's sarcoma and the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1989; 111:280-7. [PubMed 2757312]

203. Krown SE, Real FX, Vadhan-Raj S et al. Kaposi's sarcoma and the acquired immune deficiency syndrome: treatment with recombinant interferon alpha and analysis of prognostic factors. Cancer . 1986; 57:1662-5. [PubMed 3081247]

204. Krown SE, Gold JWM, Niedzwiecki D et al. Interferon-α with zidovudine: safety, tolerance, and clinical and virologic effects in patients with Kaposi sarcoma associated with the acquired immunodeficiency syndrome (AIDS). Ann Intern Med . 1990; 112:812-21. [PubMed 1971504]

205. Karp JE, Groopman JE, Broder S. Cancer in AIDS In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology. 4th ed. Philadelphia: JB Lippincott Company; 1993:2093-2110.

206. Anon. Treatment of AIDS-related Kaposi's sarcoma. Am J Hosp Pharm . 1989; 46:1211.

207. Abrams DI, Volberding PA. Alpha interferon therapy of AIDS-associated Kaposi's sarcoma. Semin Oncol . 1986; XIII(Suppl 2):43-7.

208. Reviewers' comments (personal observations) on Interferon 10:00.

209. NeXstar Pharmaceuticals, Inc. DaunoXome^® (daunorubicin citrate liposome injection) prescribing information. San Dimas, CA; 1999 Apr.

210. Presant CA, Scolaro M, Kennedy P et al. Liposomal daunorubicin treatment of HIV-associated Kaposi's sarcoma. Lancet . 1993; 341:1242-3. [PubMed 8098393]

211. Gill PS, Wernz J, Scadden DT et al. Randomized phase III trial of liposomal daunorubicin versus doxorubicin, bleomycin, and vincristine in AIDS-related Kaposi's sarcoma. J Clin Oncol . 1996; 14:2353-64. [PubMed 8708728]

212. Schurmann D, Dormann A, Grunewald T et al. Successful treatment of AIDS-related pulmonary Kaposi's sarcoma with liposomal daunorubicin. Eur Respir J . 1994; 7:824-5. [PubMed 8005268]

213. Shields PG, Dawkins F, Holmlund J et al. Low-dose multidrug chemotherapy plus pneumocystis carinii pneumonia prophylaxis for HIV-related Kaposi's sarcoma. J Acquir Immune Defic Syndr . 1990; 3:695-700. [PubMed 1693677]

214. Miles SA, Mitsuyasu RI, Aboulafia DM. AIDS-related malignancies. In: deVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 5th ed. Philadelphia: Lippincott-Raven Publishers; 1997:2445-67.

215. Ligand Pharmaceuticals, Inc. Panretin^® (alitretinoin) gel prescribing information. San Diego, CA; 1999 Jan.

216. Ovarian germ cell tumor. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2001 Sep.

217. Canellos GP, Anderson JR, Propert KJ et al. Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med . 1992; 327:1478-84. [PubMed 1383821]

218. Duggan DB, Petroni GR, Johnson JL et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: report of an intergroup trial. J Clin Oncol . 2003; 21:607-14. [PubMed 12586796]

219. Noppen M, Degreve J, Mignolet M et al. A prospective, randomised study comparing the efficacy of talc slurry and bleomycin in the treatment of malignant pleural effusions. Acta Clin Belg . 1997; 52:258-62. [PubMed 9489119]

220. Zimmer PW, Hill M, Casey K et al. Prospective randomized trial of talc slurry vs bleomycin in pleurodesis for symptomatic malignant pleural effusions. Chest . 1997; 112:430-4. [PubMed 9266880]

221. Hamed H, Fentiman IS, Chaudary MA et al. Comparison of intracavitary bleomycin and talc for control of pleural effusions secondary to carcinoma of the breast. Br J Surg . 1989; 76:1266-7. [PubMed 2481558]

222. Grossi F, Pennucci MC, Tixi L et al. Management of malignant pleural effusions. Drugs . 1998; 55:47-58. [PubMed 9463789]

223. Patz EF Jr, McAdams HP, Erasmus JJ et al. Sclerotherapy for malignant pleural effusions: a prospective randomized trial of bleomycin vs doxycycline with small-bore catheter drainage. Chest . 1998; 113:1305-11. [PubMed 9596311]

224. Comis RL, chair. Phase III randomized study of bleomycin vs doxycycline vs talc for malignant pleural effusions. Protocol IDs: E-8592, NCI-P96-0076, NCCTG-942853. From PDQ Clinical Trials (database). Bethesda, MD: National Library of Medicine; 1999 Nov.

225. Clavel M, Vermorken JB, Cognetti F et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol . 1994; 5:521-6. [PubMed 7522527]

226. Shimizu Y, Akiyama F, Umezawa S et al. Combination of consecutive low-dose cisplatin with bleomycin, vincristine, and mitomycin for recurrent cervical carcinoma. J Clin Oncol . 1998; 16:1869-78. [PubMed 9586903]

227. Omura GA, Blessing JA, Vaccarello L et al. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol . 1997; 15:165-71. [PubMed 8996138]

228. Kumar L, Pokharel YH, Kumar S et al. Single agent versus combination chemotherapy in recurrent cervical cancer. J Obstet Gynaecol Res . 1998; 24:401-9. [PubMed 10063235]

229. Buxton EJ. Experience with bleomycin, ifosfamide, and cisplatin in primary and recurrent cervical cancer. Semin Oncol . 1992; 19(2 Suppl 5):9-18. [PubMed 1384148]

230. Alberts DS, Kronmal R, Baker LH et al. Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study. J Clin Oncol . 1987; 5:1791-5. [PubMed 2445932]

231. Thigpen T, Vance R, Khansur T et al. The role of ifosfamide and systemic therapy in the management of carcinoma of the cervix. Semin Oncol . 1996; 23(3 Suppl 6):56-64. [PubMed 8677451]

232. Reviewers' comments (personal observations) on cervical cancer.

233. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: M.V.I. Pediatric (multivitamin) injection [September 21, 2000]. From FDA web site [Web].

234. Penile cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2003 Jun 20.

235. Linch DC, Vaughan Hudson B, Hancock BW et al. A randomised comparison of a third-generation regimen (PACEBOM) with a standard regimen (CHOP) in patients with histologically aggressive non-Hodgkin's lymphoma: a British National Lymphoma Investigation report. Br J Cancer . 1996; 74:318-22. [PubMedCentral][PubMed 8688344]

236. Cooper IA, Wolf MM, Robertson TI et al. Randomized comparison of MACOP-B with CHOP in patients with intermediate-grade non-Hodgkin's lymphoma. The Australian and New Zealand Lymphoma Group. J Clin Oncol . 1994; 12:769-78. [PubMed 7512131]

237. Fisher RI, Gaynor ER, Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med . 1993; 328:1002-6. [PubMed 7680764]

238. Gordon LI, Harrington D, Andersen J et al. Comparison of a second-generation combination chemotherapeutic regimen (m-BACOD) with a standard regimen (CHOP) for advanced diffuse non-Hodgkin's lymphoma. N Engl J Med . 1992; 327:1342-9. [PubMed 1383819]

239. Messori A, Vaiani M, Trippoli S et al. Survival in patients with intermediate or high grade non-Hodgkin's lymphoma: meta-analysis of randomized studies comparing third generation regimens with CHOP. Br J Cancer . 2001; 84:303-7. [PubMedCentral][PubMed 11161392]

240. Food and Drug Administration. MedWatch—Safety-related drug labeling changes: Bleomycin [March 2003]. From FDA web site [Web].