Bleomycin

History:
Bleomycin was first discovered in 1966 when the Japanese scientist Hamao Umezawa found anti-cancer activity while screening culture filtrates of S. verticullus.
In the US bleomycin gained Food and Drug Administration (FDA) approval in July 1973.
It was initially marketed in the US by the Bristol-Myers Squibb precursor Bristol Laboratories under the brand name Blenoxane.

Description:

Bleomycin for Injection USP is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain of Streptomyces verticillus.
It is freely soluble in water.
Bleomycin for injection is provided as a sterile, white to off-white, lyophilized cake or powder in vials for intramuscular, intravenous, or subcutaneous administration.
Each 15 unit and 30 unit vial contains sterile Bleomycin sulfate equivalent to 15 or 30 units of Bleomycin, respectively.
The pH range is 4.0 to 6.0 in a solution reconstituted with Sterile Water for Injection.
Its chemical name is N1-[3-(dimethylsulphonio)propyl]Bleomycin-amide (Bleomycin A2) and N1-4-(guanidobutyl)Bleomycinamide (Bleomycin B2).
A unit of Bleomycin is equal to the formerly used milligram activity. The term milligram activity is a misnomer and was changed to units to be more precise.
Each mg of bleomycin contains 1.5 to 2.0 units of sterile bleomycin.


Mechanism of Action

Although the exact mechanism of action of Bleomycin is unknown, available evidence indicates that the main mode of action is the inhibition of DNA synthesis with some evidence of lesser inhibition of RNA and protein synthesis.

Bleomycin is known to cause single, and to a lesser extent, double stranded breaks in DNA. In in vitro and in vivo experiments, Bleomycin has been shown to cause cell cycle arrest in G2 and in mitosis.

When administered into the pleural cavity for the treatment of malignant pleural effusion, Bleomycin acts as a sclerosing agent.


Pharmacokinetics

Absorption
Bleomycin is rapidly absorbed following either intramuscular (IM), subcutaneous (SC), intraperitoneal (IP) or intrapleural (IPL) administration reaching peak plasma concentrations in 30 to 60 minutes.
Systemic bioavailability of Bleomycin is 100% and 70% following IM and SC administrations, respectively, and 45% following both IP and IPL administrations, compared to intravenous and bolus administration.
Following IV bolus administration of 30 units of Bleomycin to one patient with a primary germ cell tumor of the brain, a peak CSF level was 40% of the simultaneously-obtained plasma level and was attained in two hours after drug administration.

Distribution
Bleomycin is widely distributed throughout the body with a mean volume of distribution of 17.5 L/m2 in patients following a 15 units/m2 IV bolus dose. Protein binding of Bleomycin has not been studied.

Metabolism
Bleomycin is inactivated by a cystolic cysteine proteinase enzyme, Bleomycin hydrolase. The enzyme is widely distributed in normal tissues with the exception of the skin and lungs, both targets of Bleomycin toxicity. Systemic elimination of the drug by enzymatic degradation is probably only important in patients with severely compromised renal function.

Excretion
The primary route of elimination is via the kidneys. About 65% of the administered IV dose is excreted in urine within 24 hours.
In patients with normal renal function, plasma concentrations of Bleomycin decline biexponentially with a mean terminal half-life of 2 hours following IV bolus administration.
Total body clearance and renal clearance averaged 51 mL/min/m2 and 23 mL/min/m2, respectively.
Following intrapleural administration to patients with normal renal function, a lower percentage of drug (40%) is recovered in the urine, as compared to that found in the urine after IV administration.


Clinical Studies

Malignant Pleural Effusion
The safety and efficacy of Bleomycin 60 units and tetracycline (1 g) as treatment for malignant pleural effusion were evaluated in a multicenter, randomized trial. Patients were required to have cytologically positive pleural effusion, good performance status (0,1,2), lung re-expansion following tube thoracostomy with drainage rates of 100 mL/24 hours or less, no prior intrapleural therapy, no prior systemic Bleomycin therapy, no chest irradiation and no recent change in systemic therapy. Overall survival did not differ between the Bleomycin (n=44) and tetracycline (n=41) groups. Of patients evaluated within 30 days of instillation, the recurrence rate was 36% (10/28) with Bleomycin and 67% (18/27) with tetracycline (p=0.023). Toxicity was similar between groups.


Indications and Usage for Bleomycin

Bleomycin 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:

Squamous Cell Carcinoma

Head and neck (including mouth, tongue, tonsil, nasopharynx, oropharynx, sinus, palate, lip, buccal mucosa, gingivae, epiglottis, skin, larynx), penis, cervix, and vulva. The response to Bleomycin is poorer in patients with previously irradiated head and neck cancer.

Lymphomas

Hodgkin's Disease, non-Hodgkin's lymphoma.

Testicular Carcinoma

Embryonal cell, choriocarcinoma, and teratocarcinoma.

Bleomycin has also been shown to be useful in the management of:

Malignant Pleural Effusion

Bleomycin is effective as a sclerosing agent for the treatment of malignant pleural effusion and prevention of recurrent pleural effusions.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Bleomycin and other antibacterial drugs, Bleomycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Contraindications

Bleomycin is contraindicated in patients who have demonstrated a hypersensitive or an idiosyncratic reaction to it.

Warnings

Patients receiving Bleomycin 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 progresses to pulmonary fibrosis, and death. Although this is age and dose related, the toxicity is unpredictable. Frequent roentgenograms are recommended (see ADVERSE REACTIONS: Pulmonary).

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. Since these reactions usually occur after the first or second dose, careful monitoring is essential after these doses (see ADVERSE REACTIONS: Idiosyncratic Reactions).

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.

Adverse Reactions

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 Bleomycin has been extremely difficult. The earliest symptom associated with Bleomycin pulmonary toxicity is dyspnea. The earliest sign is fine rales.

Radiographically, Bleomycin-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 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 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 Bleomycin 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:

Maintain FI02 at concentrations approximating that of room air (25%) during surgery and the postoperative period.
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 Bleomycin infusions. Although each patient must be individually evaluated, further courses of Bleomycin do not appear to be contraindicated.

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

Idiosyncratic Reactions

In approximately 1% of the lymphoma patients treated with Bleomycin, 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 Bleomycin 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 Bleomycin have been administered and appears to be related to the cumulative dose.

Intrapleural administration of Bleomycin 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 Bleomycin pleurodesis in these very seriously ill patients.

Other

Vascular toxicities coincident with the use of Bleomycin 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 Bleomycin in combination with vinblastine with or without cisplatin or, in a few cases, with Bleomycin 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, 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.

Bleomycin Dosage and Administration

Because of the possibility of an anaphylactold 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 carcinoma— 0.25 to 0.50 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.

Hodgkin's Disease—0.25 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 Bleomycin 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 Bleomycin for injection 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 Effusion–60 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:

Patient CrCL
(mL/min)

Bleomycin
Dose (%)

50 and above 100
40-50 70
30-40 60
20-30 55
10-20 45
5-10 40
CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockroft and Gault formula:
Males CrCL = [weight x (140 – Age)]/(72 x Scr)
Females CrCL = 0.85 x [weight x (140 – Age)]/(72 x Scr)

Where CrCL in mL/min/1.73 m2, weight in kg, age in years, and Scr in mg/dL.

Administration

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

Intramuscular or Subcutaneous

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

Intravenous

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%, and administered slowly over a period of 10 minutes.

Intrapleural

Sixty units of Bleomycin are dissolved in 50 to 100 mL sodium chloride injection 0.9%, 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 Bleomycin. 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, Bleomycin instillation may be appropriate when drainage is between 100 to 300 mL under clinical conditions that necessitate sclerosis therapy. The thoracostomy tube is clamped after Bleomycin 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.

How is Bleomycin Supplied

Bleomycin for Injection USP is available as follows:

NDC 55390-005-01, 15 units of Bleomycin per vial as Bleomycin sulfate USP.

NDC 55390-006-01, 30 units of Bleomycin per vial as Bleomycin sulfate USP.

Stability

The sterile powder is stable under refrigeration 2° to 8°C (36° to 46°F) and should not be used after the expiration date is reached.

Bleomycin should not be reconstituted or diluted with D5W or other dextrose containing diluents. When reconstituted in D5W and analyzed by HPLC, Bleomycin demonstrates a loss of A2 and B2 potency that does not occur when Bleomycin is reconstituted in 0.9% sodium chloride.

Bleomycin is stable for 24 hours at room temperature in sodium chloride.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate



courtesy: drugs.com