It is recommended that Bleomycin (Bleomycin sulfate) for Injection be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

Pulmonary fibrosis is the most severe toxicity associated with Bleomycin (Bleomycin sulfate) for Injection. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Its occurrence is higher in elderly patients and in those receiving greater than 400 units total dose, but pulmonary toxicity has been observed in young patients and those treated with low doses.

A severe idiosyncratic reaction consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with Bleomycin (Bleomycin sulfate) for Injection.

Bleomycin (Bleomycin sulfate) for Injection, USP is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of and is freely soluble in water.

It is available as a lyophilized powder for intramuscular, intravenous or subcutaneous injection. Each vial contains sterile Bleomycin (Bleomycin sulfate) sulfate equivalent to 15 units or 30 units of Bleomycin (Bleomycin sulfate) . Sulfuric acid or Sodium hydroxide used, if necessary to adjust the pH.

Bleomycin (Bleomycin sulfate) s are a group of related basic glycopeptides which differ in the terminal amine substituent of the common structural unit, Bleomycin (Bleomycin sulfate) acid. The main components of Bleomycin (Bleomycin sulfate) for Injection are Bleomycin (Bleomycin sulfate) s A and B. Chemically, Bleomycin (Bleomycin sulfate) A is N-[3-(dimethylsulfonio)propyl]-Bleomycin (Bleomycin sulfate) amide and Bleomycin (Bleomycin sulfate) B is N-[4-(aminoiminomethyl)amino]butyl]-Bleomycin (Bleomycin sulfate) amide.

The molecular formula of Bleomycin (Bleomycin sulfate) A is CHNOS and a calculated molecular weight of 1414. The molecular formula of Bleomycin (Bleomycin sulfate) B is CHNOS and a calculated molecular weight of 1425. The structural formula of Bleomycin (Bleomycin sulfate) s A and B are shown below.

Although the exact mechanism of action of Bleomycin (Bleomycin sulfate) is unknown, available evidence would seem to indicate that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis.

In mice, high concentration of Bleomycin (Bleomycin sulfate) are found in the skin, lungs, kidneys, peritoneum, and lymphatics. Tumor cells of the skin and lungs have been found to have high concentrations of Bleomycin (Bleomycin sulfate) in contrast to the low concentrations found in hematopoietic tissue. The low concentrations of Bleomycin (Bleomycin sulfate) found in bone marrow may be related to high levels of Bleomycin (Bleomycin sulfate) degradative enzymes found in that tissue.

In patients with normal renal function, 60% to 70% of an administered dose is recovered in the urine as active Bleomycin (Bleomycin sulfate) . In patients with a creatinine clearance of > 35 mL per minute, the serum or plasma terminal elimination half-life of Bleomycin (Bleomycin sulfate) is approximately 115 minutes. In patients with a creatinine clearance of

Information on the dose proportionality of Bleomycin (Bleomycin sulfate) is not available.

Bleomycin (Bleomycin sulfate) for Injection should be considered a palliative treatment. It has been shown to be useful in the management of the following neoplasms either as a single agent or in proven combinations with other approved chemotherapeutic agents:

Bleomycin (Bleomycin sulfate) for Injection is contraindicated in patients who have demonstrated a hypersensitive or an idiosyncratic reaction to it.

Patients receiving Bleomycin (Bleomycin sulfate) must be observed carefully and frequently during and after therapy. It should be used with extreme caution in patients with significant impairment of renal function or compromised pulmonary function.

Pulmonary toxicities occur in 10% of treated patients. In approximately 1%, the nonspecific pneumonitis induced by Bleomycin (Bleomycin sulfate) progresses to pulmonary fibrosis, and death. Although this is age and dose related, the toxicity is unpredictable. Frequent roentgenograms are recommended (see ).

A severe idiosyncratic reaction (similar to anaphylaxis) consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported in approximately 1% of lymphoma patients treated with Bleomycin (Bleomycin sulfate) . Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses (see ).

Renal or hepatic toxicity, beginning as a deterioration in renal or liver function tests, have been reported, infrequently. These toxicities may occur, however, at any time after initiation of therapy.

WARNINGS
In clinical trials, pulmonary toxicity was more common in patients older than 70 years than in younger patients (see , and ). Other reported clinical experience has not identified other differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Bleomycin (Bleomycin sulfate) is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

This is potentially the most serious side effect, occurring in approximately 10% of treated patients. The most frequent presentation is pneumonitis occasionally progressing to pulmonary fibrosis. Approximately 1% of patients treated have died of pulmonary fibrosis. Pulmonary toxicity is both dose and age related, being more common in patients over 70 years of age and in those receiving over 400 units total dose. This toxicity, however, is unpredictable and has been seen occasionally in young patients receiving low doses.

Some published reports have suggested that the risk of pulmonary toxicity may be increased when Bleomycin (Bleomycin sulfate) is used in combination with G-CSF (filgrastim) or other cytokines. However, randomized clinical studies completed to date have not demonstrated an increased risk of pulmonary complications in patients treated with Bleomycin (Bleomycin sulfate) and G-CSF.

Because of lack of specificity of the clinical syndrome, the identification of patients with pulmonary toxicity due to Bleomycin (Bleomycin sulfate) sulfate has been extremely difficult. The earliest symptom associated with Bleomycin (Bleomycin sulfate) sulfate pulmonary toxicity is dyspnea. The earliest sign is fine rales.

Radiographically, Bleomycin (Bleomycin sulfate) -induced pneumonitis produces nonspecific patchy opacities, usually of the lower lung fields. The most common changes in pulmonary function tests are a decrease in total lung volume and a decrease in vital capacity. However, these changes are not predictive of the development of pulmonary fibrosis.

The microscopic tissue changes due to Bleomycin (Bleomycin sulfate) toxicity include bronchiolar squamous metaplasia, reactive macrophages, atypical alveolar epithelial cells, fibrinous edema, and interstitial fibrosis. The acute stage may involve capillary changes and subsequent fibrinous exudation into alveoli producing a change similar to hyaline membrane formation and progressing to a diffuse interstitial fibrosis resembling the Hamman-Rich syndrome. These microscopic findings are nonspecific; e.g. similar changes are seen in radiation pneumonitis and pneumocystic pneumonitis.

To monitor the onset of pulmonary toxicity, roentgenograms of the chest should be taken every 1 to 2 weeks (see ). If pulmonary changes are noted, treatment should be discontinued until it can be determined if they are drug related. Recent studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DL ) during treatment with Bleomycin (Bleomycin sulfate) for Injection, USP may be an indicator of subclinical pulmonary toxicity. It is recommended that the DL be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DL falls below 30% to 35% of the pretreatment value.

Because of Bleomycin (Bleomycin sulfate) ’s sensitization of lung tissue, patients who have received Bleomycin (Bleomycin sulfate) are at greater risk of developing pulmonary toxicity when oxygen is administered in surgery. While long exposure to very high oxygen concentrations is a known cause of lung damage, after Bleomycin (Bleomycin sulfate) administration, lung damage can occur at lower concentrations that are usually considered safe.

Suggested preventive measures are:

Sudden onset of an acute chest pain syndrome suggestive of pleuropericarditis has been rarely reported during Bleomycin (Bleomycin sulfate) for Injection infusions. Although each patient must be individually evaluated, further courses of Bleomycin (Bleomycin sulfate) for Injection do not appear to be contraindicated.

These are the most frequent side effects, being reported in approximately 50% of treated patients. These consist of erythema, rash, striae, vesiculation, hyperpigmentation, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. It was necessary to discontinue Bleomycin (Bleomycin sulfate) therapy in 2% of treated patients because of these toxicities.

Scleroderma-like skin changes have also been reported as part of postmarketing surveillance.

Skin toxicity is a relatively late manifestation usually developing in the 2nd and 3rd week of treatment after 150 to 200 units of Bleomycin (Bleomycin sulfate) have been administered and appears to be related to the cumulative dose.

Vascular toxicities coincident with the use of Bleomycin (Bleomycin sulfate) in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogenous and may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (HUS) or cerebral arteritis. Various mechanisms have been proposed for these vascular complications. There are also reports of Raynaud’s phenomenon occurring in patients treated with Bleomycin (Bleomycin sulfate) in combination with vinblastine with or without cisplatin, or, in a few cases, with Bleomycin (Bleomycin sulfate) as a single agent. It is currently unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular compromise, Bleomycin (Bleomycin sulfate) , vinblastine, hypomagnesemia, or a combination of any of these factors.

Fever, chills and vomiting were frequently reported side effects. Anorexia and weight loss are common and may persist long after termination of this medication. Pain at tumor site, phlebitis, and other local reactions were reported infrequently.

Malaise was also reported as part of postmarketing surveillance.

The following dose schedule is recommended:

Hodgkin’s Disease - 0.25 to 0.50 units/kg (10 to 20 units/m) given intravenously, intramuscularly or subcutaneously weekly or twice weekly. After a 50% response, a maintenance dose of 1 unit daily, or 5 units weekly intravenously or intramuscularly should be given.

Pulmonary toxicity of Bleomycin (Bleomycin sulfate) appears to be dose related with a striking increase when the total dose is over 400 units. Total doses over 400 units should be given with great caution.

Improvement of Hodgkin’s Disease and testicular tumors is prompt and noted within 2 weeks. If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.

Bleomycin (Bleomycin sulfate) for Injection, USP contains sterile Bleomycin (Bleomycin sulfate) sulfate equivalent to 15 units or 30 units of Bleomycin (Bleomycin sulfate) .

NDC 61703-332-18, 15 units per vial, packaged individually.

NDC 61703-323-22, 30 units per vial, packaged individually.