Summary Of Exposure |
A) Overdose information is limited, toxicity is thought to be an extension of adverse effects reported with therapeutic use.
B) Pulmonary toxicity appears to be the primary dose-limiting effect, with pulmonary fibrosis the most severe toxicity associated with bleomycin use.
C) Other effects reported during therapeutic use: dermatitis, mucositis, alopecia, and fever. Renal and hepatic toxicity are rare events.
D) A severe idiosyncratic condition has been reported in approximately 1% of lymphoma patients receiving bleomycin, and can result in mental confusion, hypotension, fever, chills, and wheezing.
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Vital Signs |
3.3.1) SUMMARY
A) WITH THERAPEUTIC USE 1) Fever and chills occur frequently with therapeutic use.
3.3.3) TEMPERATURE
A) WITH THERAPEUTIC USE 1) Fever and chills occur frequently with therapeutic use (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006). The manufacturer reports that fever may occur as an idiosyncratic reaction presenting after the first one to two doses, and accompanied by hypotension, confusion and wheezing.
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Cardiovascular |
3.5.1) SUMMARY
A) WITH THERAPEUTIC USE 1) Hypotension may occur as a part of an idiosyncratic reaction during therapy.
3.5.2) CLINICAL EFFECTS
A) HYPOTENSIVE EPISODE 1) WITH THERAPEUTIC USE a) Hypotension has been infrequently reported as a part of an idiosyncratic reaction along with fever, confusion, chills and wheezing, usually occurring after the first or second dose (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
B) CARDIOVASCULAR FINDING 1) WITH THERAPEUTIC USE a) The following cardiovascular events have been rarely reported following combination therapy with bleomycin and other antineoplastic agents: myocardial infarction, CVA, thrombotic microangiopathy, and cerebral arteritis (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006). Raynaud's syndrome has developed with bleomycin therapy, but the etiology is not fully understood.
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Respiratory |
3.6.1) SUMMARY
A) WITH THERAPEUTIC USE 1) Pneumonitis develops in about 10 percent of bleomycin treated patients; about one percent progress to a potentially fatal pulmonary fibrosis. Fatalities are more frequently associated with cumulative doses of 400 Units or higher.
3.6.2) CLINICAL EFFECTS
A) PNEUMONITIS 1) SUMMARY a) WITH THERAPETIC USE 1) INCIDENCE - Approximately 10% of all patients receiving bleomycin develop pneumonitis; of those, approximately 1% have nonspecific pneumonitis which progresses to pulmonary fibrosis and death (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
2) RISK FACTORS - Cumulative bleomycin doses higher than 400 Units increases the risk of fatal pulmonary toxicity (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006); Smith, 1990; (Real et al, 1999). However, infrequent cases of pulmonary toxicity have occurred at doses of 100 Units or less (McLeod et al, 1987). Other factors include: advanced age, previous lung disease or injury, lung irradiation, combination chemotherapy (e.g., GCS-F or other cytokines), and intravenous administration of bleomycin (Smith, 1990).
3) TREATMENT - High-dose corticosteroid therapy has been effective in improving lung function and reversing bleomycin-induced interstitial pneumonitis in some patients (Maher & Dally, 1993; (Kozielski, 1994).
b) CASE REPORT 1) LACK OF SYMPTOMS - An unusual case of bleomycin-induced pulmonary toxicity was reported in a 7-year-old male with NO symptoms of pulmonary involvement and a negative physical exam, but pulmonary nodules on a routine chest radiograph. A lung biopsy to rule out possible tumor or infection confirmed interstitial pneumonitis with bronchiolitis obliterans consistent with bleomycin toxicity. Parenchymal abnormalities had improved within one month of cessation of drug therapy (Glasier & Siegel, 1981). 2) ACUTE TOXICITY a) SUMMARY - Although infrequently reported in the literature, low cumulative doses (range 34 to 120 mg total dose) of bleomycin have resulted in severe pulmonary toxicity in both adults and children (Ganick et al, 1980; McLeod et al, 1987; Real et al, 1999).
3) PEDIATRIC - An 11-year-old male with Hodgkin's disease developed a sudden onset of cough, dyspnea and fever (103 degrees F) after a total dose of 120 mg bleomycin (Ganick et al, 1980). Chest radiograph indicated bilateral alveolar densities. Despite aggressive treatment, the patient's respiratory status rapidly deteriorated and the patient died within 60 hours of the last dose. 4) ADULT - A 63-year-old male with stage 1A Hodgkin's disease presented with fever, breathlessness, and a non-productive cough one week after receiving a cumulative dose of 34 Units bleomycin (Real et al, 1999). Admission chest x-ray showed bilateral basal diffuse interstitial infiltrates and a transbronchial biopsy indicated a large number of atypical pneumocytes. Sudden respiratory failure developed, requiring mechanical ventilation. Pulmonary signs and symptoms improved within one week of starting corticosteroid therapy. 5) ADULT - Fatal bleomycin toxicity occurred in a 54-year-old male with advanced non-Hodgkin's lymphoma and chronic renal insufficiency after receiving a total dose of 60 Units bleomycin over a 6-week period (McLeod et al, 1987). High-dose corticosteroid therapy did not result in any clinical improvement. Autopsy findings were consistent with bleomycin-induced pulmonary fibrosis. c) CHRONIC TOXICITY 1) ADULT - An adult female developed Stevens-Johnson Syndrome, pneumonitis, and acute renal failure after receiving combination chemotherapy with bleomycin (total dose was approximately 450 mg) and cisplatin (Brodsky et al, 1989). The authors suggested a drug interaction (i.e. the nephrotoxic effects of cisplatin decreased bleomycin elimination) between the two agents produced the fatal bleomycin-induced respiratory failure.
B) CHEST PAIN 1) WITH THERAPEUTIC USE a) A sudden onset of chest pain related to pleuropericarditis has been rarely reported following bleomycin therapy (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
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Neurologic |
3.7.1) SUMMARY
A) Confusion is rarely reported with therapeutic use.
3.7.2) CLINICAL EFFECTS
A) CENTRAL NERVOUS SYSTEM FINDING 1) WITH THERAPEUTIC USE a) INCIDENCE - Confusion has been observed in approximately 1% of lymphoma patients treated with bleomycin and is considered an idiosyncratic reaction occurring most often within the first one to two doses (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
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Gastrointestinal |
3.8.1) SUMMARY
A) Nausea, vomiting, and weight loss occur frequently during therapy; stomatitis (mucositis) may also develop.
3.8.2) CLINICAL EFFECTS
A) NAUSEA AND VOMITING 1) WITH THERAPEUTIC USE a) Nausea and vomiting are frequent adverse effects reported with therapeutic use (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
B) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE 1) WITH THERAPEUTIC USE a) Anorexia and weight loss occur frequently with treatment and may persist for many months after the cessation of therapy (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
C) INFLAMMATORY DISEASE OF MUCOUS MEMBRANE 1) WITH THERAPEUTIC USE a) Stomatitis is a frequent effect of therapy (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
2) INCIDENCE - Up to 50% of patients treated with bleomycin develop some form of mucositis (Prod Info Blenoxane(R), Bleomycin, 1998). |
Hepatic |
3.9.2) CLINICAL EFFECTS
A) INJURY OF LIVER 1) WITH THERAPEUTIC USE a) Hepatotoxicity is a rare effect of therapy (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
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Genitourinary |
3.10.2) CLINICAL EFFECTS
A) TOXIC NEPHROPATHY 1) WITH THERAPEUTIC USE a) Renal toxicity is a rare effect of therapy (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
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Dermatologic |
3.14.2) CLINICAL EFFECTS
A) DERMATITIS 1) INCIDENCE - Up to 50% of patients treated with bleomycin develop some type of adverse integumentary effect, which can include erythema, rash, pruritus, striae, vesiculation, hyperpigmentation, hyperkeratosis, nail changes, and tenderness of the skin (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006). Dermatologic effects appear to be related to cumulative dose.
2) ONSET - Generally, skin toxicity occurs within the first 2 to 3 weeks of the start of therapy after a cumulative dose of 150 to 200 Units of bleomycin (Prod Info BLENOXANE(R) IV, IM, SC, intrapleural injection, 2006).
B) CUTANEOUS ERUPTION 1) WITH THERAPEUTIC USE a) CASE REPORTS - Flagellate dermatitis is a relatively common adverse effect of bleomycin therapy (Miori et al, 1990; Tsuji & Sawabe, 1993; Mowad et al, 1994; Mullai et al, 1998).
2) ONSET - Symptoms may develop within the first several hours of administration and begin as intense itching, erythema, followed by urticarial linear bands and flagellate pigmentation. 3) ETIOLOGY - Bleomycin is toxic to melanocytes causing cellular damage and an increase in melanosome density in the keratinocytes with a reduced epidermal turnover which produces the hyperpigmentation (Tsuji & Sawabe, 1993; Centeno et al, 1998). 4) INCIDENCE - Its estimated that 8% to 38% of patients treated with bleomycin develop signs and symptoms of linear (flagellate) hyperpigmentation (Mullai et al, 1998). 5) TREATMENT - Topical corticosteroid therapy has been an effective treatment, with the gradual decline of linear hyperpigmentation (Miori et al, 1990; Mowad et al, 1994). Mullai et al (1998) suggested that the appearance of these lesions does not necessitate discontinuation of therapy, if a benefit is observed. C) GENERALIZED EXFOLIATIVE DERMATITIS 1) WITH THERAPEUTIC USE a) CASE REPORT - A 19-year-old female with stage III ovarian germ cell tumor developed erythema, peeling of fingers and hands, and generalized hyperpigmentation of the skin following combination chemotherapy which included bleomycin (Yeo & Johnson, 1998). Bleomycin was discontinued after 8 doses and the symptoms eventually resolved over a 3-month period.
D) ERYTHEMA MULTIFORME 1) WITH THERAPEUTIC USE a) CASE REPORT - Stevens-Johnson syndrome along with pulmonary toxicity occurred in an adult following combination therapy with bleomycin (total dose approximately 450 mg) and cisplatin (Brodsky et al, 1989). The patient died of respiratory failure despite aggressive pulmonary management. Its been suggested that the nephrotoxic effects of cisplatin decreased the renal elimination of bleomycin (Brodsky et al, 1989) Reynolds, 2000).
E) MUCOSITIS FOLLOWING CHEMOTHERAPY 1) WITH THERAPEUTIC USE a) CASE REPORTS 1) A 32-year-old female developed mucositis and alopecia, 3 weeks after receiving an intracavitary dose (total 50 mg) of bleomycin (Siegel & Schiffman, 1990). Symptoms resolved within one week following drug cessation and supportive care. 2) A 52-year-old male with disseminated centroblastic malignant lymphoma was treated with a combination chemotherapy which included bleomycin (Haerslev et al, 1993). During the first 24-hours after receiving a 20 mg dose, the patient developed severe pain and burning in the mouth, with redness and superficial ulcerations in the mouth. During a subsequent exposure, the patient developed a symmetrical linear maculopapular exanthema on the neck, trunk and arms, as well as, burning in the mouth. a) The authors suggested an idiosyncratic response based on the sudden onset of symptoms, and the unusual findings after a low dose (normal range 200 to 300 mg).
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Reproductive |
3.20.1) SUMMARY
A) Bleomycin is classified as FDA pregnancy category D. Bleomycin was shown to be teratogenic and abortifacient in rats and rabbits, respectively. Data regarding bleomycin use in pregnant women are not available. No data are available to assess the potential effects of bleomycin on nursing infants or fertility.
3.20.2) TERATOGENICITY
A) CONGENITAL ANOMALIES 1) Leukopenia, neutropenia, and bilateral hearing loss were observed in an infant born at 27 weeks gestation. The mother had been treated for 3 days with bleomycin, etoposide, and cisplatin one week before delivery. Leukopenia and neutropenia resolved by day 13. Hearing loss may have been caused by maternal and neonatal gentamicin therapy or maternal cisplatin therapy. Etoposide was thought to have caused the neutropenia, because it is the most myelosuppressive of the three chemotherapeutic agents given (Raffles et al, 1989).
2) The teratogenic potential of chemotherapeutic agents is difficult to assess because of the relatively small number of reports, variation in dosages, routes of administration, timing of administration with respect to gestational age, and the variety of combinations of drugs administered. Although fetal exposure to chemotherapy throughout all trimesters of pregnancy has been reported to not induce abnormalities, there is no assurance that deleterious fetal effects will not occur. Exposure during the first trimester is still considered by most practitioners as the critical for abnormal fetal development (Glantz, 1994).
B) LACK OF EFFECT 1) There have been no studies on the use of bleomycin during pregnancy or reports of congenital malformations caused by maternal use. Combination chemotherapy that included bleomycin did not cause congenital malformation in the infants of 22 women treated during pregnancy (Aviles et al, 1991).
C) ANIMAL STUDIES 1) In rat studies, skeletal malformations, shortened innominate artery and hydroureter were reported following administration of intraperitoneal bleomycin doses of 1.5 mg/kg/day (1.6 times the recommended human dose based on surface area) on gestation days 6 through 15 (Prod Info bleomycin intramuscular injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, subcutaneous injection lyophilized powder for solution, intrapleural injection lyophilized powder for solution, 2014).
3.20.3) EFFECTS IN PREGNANCY
A) PREGNANCY CATEGORY 1) The manufacturer has classified bleomycin as FDA pregnancy category D (Prod Info bleomycin intramuscular injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, subcutaneous injection lyophilized powder for solution, intrapleural injection lyophilized powder for solution, 2014)
2) Because of the potential for fetal harm with bleomycin use, women should be advised of the potential risk to the fetus if bleomycin is used during pregnancy or if pregnancy occurs during treatment. Advise women of childbearing potential to avoid pregnancy during bleomycin therapy (Prod Info bleomycin intramuscular injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, subcutaneous injection lyophilized powder for solution, intrapleural injection lyophilized powder for solution, 2014).
B) ANIMAL STUDIES 1) ABORTION a) Bleomycin was abortifacient in rabbits treated with intravenous bleomycin doses of 1.2 mg/kg/day (about 2.4 times the recommended human dose) on gestation days 6 through 18 (Prod Info bleomycin intramuscular injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, subcutaneous injection lyophilized powder for solution, intrapleural injection lyophilized powder for solution, 2014).
3.20.4) EFFECTS DURING BREAST-FEEDING
A) BREAST MILK 1) It is unknown whether bleomycin is excreted in human milk. Due to the potential for serious adverse events and until further data are available, it is recommended that nursing be discontinued in women receiving bleomycin treatment (Prod Info bleomycin intramuscular injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, subcutaneous injection lyophilized powder for solution, intrapleural injection lyophilized powder for solution, 2014).
3.20.5) FERTILITY
A) FERTILITY 1) At the time of this review, no data were available to assess the potential effects of exposure to bleomycin on fertility in humans (Prod Info bleomycin intramuscular injection lyophilized powder for solution, intravenous injection lyophilized powder for solution, subcutaneous injection lyophilized powder for solution, intrapleural injection lyophilized powder for solution, 2014).
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Carcinogenicity |
3.21.2) SUMMARY/HUMAN
A) The carcinogenic potential of bleomycin has yet to be determined.
3.21.3) HUMAN STUDIES
A) LACK OF INFORMATION 1) At the time of this review, studies to determine the carcinogenic potential of bleomycin in humans have not been conducted (Prod Info Blenoxane(R), Bleomycin, 1998).
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