Blenoxane

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

• Blenoxane^®

Pregnancy Category: D

Lactation: It is not known whether the drug is excreted in milk. Because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued by women receiving bleomycin therapy.

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Blenoxane is a prescription medication used to treat various types of cancer. It is also used to treat pleural effusions (a condition when fluid collects in the lungs) that are caused by cancerous tumors. Blenoxane belongs to a group of drugs called antibiotics that are only used in cancer chemotherapy. It slows or stops the growth of cancer cells in your body.

This medication is available in an injectable form to be given directly into a vein (IV), muscle (IM), under the skin, or into the pleural space by a healthcare professional.

Common side effects of this medication include skin reactions, hair loss, and sores on the mouth or tongue.

Storage

Parenteral

2–8°C; do not use after the expiration date is reached.121

Use reconstituted solutions stored at room temperature within 24 hours.121 b

Although stable for 2 weeks at room temperature or 4 weeks at 2–8°C, reconstituted solutions contain no preservatives; discard within 24 hours of reconstitution.b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Inactivated by agents containing sulfhydryl groups, hydrogen peroxide, and ascorbic acid.b

Forms Schiff base-type adducts with dextrose.106

Bleomycin belongs to the general group of medicines called antineoplastics. It is used to treat several types of cancer, including cervix and uterus cancer, head and neck cancer, testicle and penile cancer, and certain types of lymphoma. Bleomycin also may used for other conditions, as determined by your doctor.

Bleomycin seems to act by interfering with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by bleomycin, other effects will also occur. Some of these may be serious and must be reported to your doctor. Other effects, like darkening of skin or hair loss, may not be serious but may cause concern. Some effects may not occur for months or years after the medicine is used.

Before you begin treatment with bleomycin, you and your doctor should talk about the good this medicine will do as well as the risks of using it.

Bleomycin is to be administered only by or under the immediate supervision of your doctor.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Fever and chills (occurring within 3 to 6 hours after a dose)

• Confusion
• faintness
• wheezing

• Chest pain (sudden severe)
• weakness in arms or legs (sudden)

Check with your doctor as soon as possible if any of the following side effects occur:

• Cough
• shortness of breath
• sores in mouth and on lips

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Darkening or thickening of skin
• dark stripes on skin
• itching of skin
• skin rash or colored bumps on fingertips, elbows, or palms
• skin redness or tenderness
• swelling of fingers
• vomiting and loss of appetite

• Changes in fingernails or toenails
• weight loss

Bleomycin may cause a temporary loss of hair in some people. After treatment has ended, normal hair growth should return, although it may take several months.

Side effects that affect your lungs (for example, cough and shortness of breath) may be more likely to occur if you smoke.

After you stop using this medicine, it may still produce some side effects that need attention. During this period of time, check with your doctor immediately if you notice the following side effects:

• Cough
• shortness of breath

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

General

Patients with creatinine clearance values of less than 50 mL/min should be treated with caution and their renal function should be carefully monitored during the administration of bleomycin. Lower doses of Blenoxane may be required in these patients than those with normal renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Carcinogenesis, Mutagenesis, Impairment of Fertility

The carcinogenic potential of Blenoxane in humans is unknown. A study in F344-type male rats demonstrated an increased incidence of nodular hyperplasia after induced lung carcinogenesis by nitrosamines, followed by treatment with bleomycin. In another study where the drug was administered to rats by subcutaneous injection at 0.35 mg/kg weekly (3.82 units/m2 weekly or about 30% at the recommended human dose), necropsy findings included dose-related injection site fibrosarcomas as well as various renal tumors. Bleomycin has been shown to be mutagenic both in vitro and in vivo. The effects of bleomycin on fertility have not been studied.

Pregnancy

See WARNINGS.

Nursing Mothers

It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued by women receiving Blenoxane therapy.

Pediatric Use

Safety and effectiveness of Blenoxane in pediatric patients have not been established.

Geriatric Use

In clinical trials, pulmonary toxicity was more common in patients older than 70 years than in younger patients (see BOX WARNING, WARNINGS, and ADVERSE REACTIONS: Pulmonary). 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 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.

Pulmonary

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 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 and G-CSF.

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

Radiographically, Blenoxane-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 Blenoxane 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; eg, 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 WARNINGS). 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 (DLCO) during treatment with Blenoxane may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLCO be monitored monthly if it is to be employed to detect pulmonary toxicities, and thus the drug should be discontinued when the DLCO falls below 30% to 35% of the pretreatment value.

Because of bleomycin’s sensitization of lung tissue, patients who have received bleomycin 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 administration, lung damage can occur at lower concentrations that are usually considered safe. Suggested preventive measures are:

1. Maintain FIO2 at concentrations approximating that of room air (25%) during surgery and the postoperative period.
2. Monitor carefully fluid replacement, focusing more on colloid administration rather than crystalloid.

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

Pulmonary adverse events which may be related to the intrapleural administration of Blenoxane have been reported only rarely.

Idiosyncratic Reactions

In approximately 1% of the lymphoma patients treated with Blenoxane (bleomycin sulfate for injection, USP), an idiosyncratic reaction, similar to anaphylaxis clinically, has been reported. The reaction may be immediate or delayed for several hours, and usually occurs after the first or second dose (see WARNINGS). It consists of hypotension, mental confusion, fever, chills, and wheezing. Treatment is symptomatic including volume expansion, pressor agents, antihistamines, and corticosteroids.

Integument and Mucous Membranes

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 Blenoxane 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 second and third week of treatment after 150 to 200 units of Blenoxane have been administered and appears to be related to the cumulative dose.

Intrapleural administration of Blenoxane has occasionally been associated with local pain. Hypotension possibly requiring symptomatic treatment has been reported infrequently. Death has been very rarely reported in association with Blenoxane pleurodesis in these very seriously ill patients.

Other

Vascular toxicities coincident with the use of Blenoxane in combination with other antineoplastic agents have been reported rarely. The events are clinically heterogeneous 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 Blenoxane in combination with vinblastine with or without cisplatin or, in a few cases, with Blenoxane as a single agent. It is currently unknown if the cause of Raynaud’s phenomenon in these cases is the disease, underlying vascular compromise, Blenoxane, 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.

Because of the possibility of an anaphylactoid reaction, lymphoma patients should be treated with 2 units or less for the first two doses. If no acute reaction occurs, then the regular dosage schedule may be followed.

The following dose schedule is recommended:

Squamous cell carcinoma, non-Hodgkin’s lymphoma, testicular carcinoma0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.

Hodgkin’s Disease0.25 to 0.50 units/kg (10 to 20 units/m2) 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 Blenoxane 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.

Note: When Blenoxane (bleomycin sulfate for injection, USP) is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.

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.

Malignant Pleural Effusion60 units administered as a single dose bolus intrapleural injection (see Administration: Intrapleural).

Use in Patients with Renal Insufficiency

The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:

CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockcroft and Gault formula:

Administration

Blenoxane may be given by the intramuscular, intravenous, subcutaneous, or intrapleural routes.

To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Blenoxane for injection. This includes all handling activities in clinical settings, pharmacies, storerooms, and home healthcare settings, including during unpacking and inspection, transport within a facility, and dose preparation and administration.

The Blenoxane 15 units vial should be reconstituted with 1 to 5 mL of Sterile Water for Injection, USP, Sodium Chloride for Injection, 0.9%, USP, or Sterile Bacteriostatic Water for Injection, USP. The Blenoxane 30 units vial should be reconstituted with 2 to 10 mL of the above diluents.

The contents of the 15 units or 30 units vial should be dissolved in 5 mL or 10 mL, respectively, of Sodium Chloride for Injection, 0.9%, USP, and administered slowly over a period of 10 minutes.

Sixty units of Blenoxane are dissolved in 50–100 mL Sodium Chloride for Injection, 0.9%, USP, and administered through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The literature suggests that successful pleurodesis is, in part, dependent upon complete drainage of the pleural fluid and reestablishment of negative intrapleural pressure prior to instillation of a sclerosing agent. Therefore, the amount of drainage from the chest tube should be as minimal as possible prior to instillation of Blenoxane. Although there is no conclusive evidence to support this contention, it is generally accepted that chest tube drainage should be less than 100 mL in a 24-hour period prior to sclerosis. However, Blenoxane instillation may be appropriate when drainage is between 100–300 mL under clinical conditions that necessitate sclerosis therapy. The thoracostomy tube is clamped after Blenoxane instillation. The patient is moved from the supine to the left and right lateral positions several times during the next four hours. The clamp is then removed and suction reestablished. The amount of time the chest tube remains in place following sclerosis is dictated by the clinical situation.

The intrapleural injection of topical anesthetics or systemic narcotic analgesia is generally not required.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.