Bleomycin is a cell cycle-phase specific drug from the antibiotic class of antineoplastic drugs. Bleomycin is a mixture of 13 glycopeptides isolated from the culture broth of the fungus Streptomyces verticillus. The active component of bleomycin is the A2 peptide, which makes up about 70% of the available formulation. Clinical uses of bleomycin include treatment of Hodgkin lymphoma; non-Hodgkin's lymphoma; testicular carcinoma; and squamous cell carcinomas of the head and neck, penis, cervix, and vulva. Bleomycin also is used as a sclerosing agent to treat pleural effusions. Bleomycin has been designated an orphan drug by the FDA for the treatment of pancreatic cancer and pleural effusions.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: A unit of bleomycin is equal to the formerly used milligram activity (i.e., 1 unit = 1 mg). The term milligram activity is a misnomer and has been changed to units to be more precise.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 1
-NIOSH (Draft) 2020 List: Table 1
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
Emetic Risk
-Minimal
Extravasation Risk
-Nonvesicant
Route-Specific Administration
Injectable Administration
-Bleomycin is administered intramuscularly, subcutaneously, intravenously, intrapleurally, intralesionally, or intraarterially.
-Premedication with acetaminophen may decrease the incidence of fever and chills following bleomycin administration.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution:
-Reconstitute 15 or 30 unit vial with 5 mL or 10 mL 0.9% Sodium Chloride for injection, respectively.
-Do not use dextrose containing solutions for reconstitution or further dilution due to a loss of potency.
-Maximum concentration should be bleomycin 5 units/mL.
-Bleomycin reconstituted with 0.9% Sodium Chloride for injection is stable for 24 hours at room temperature.
Intravenous injection or infusion:
-After reconstitution, inject slowly over a period of 10 minutes.
-Alternatively, after reconstitution, further dilute bleomycin in 50 ml NS and inject IV slowly over 10-15 minutes.
Intramuscular Administration
Reconstitution:
-Reconstitute 15 unit vial with 1-5 mL of sterile water for injection, 0.9% sodium chloride for injection, or bacteriostatic water for injection, or reconstitute 30 unit vial with 2-10 mL sterile water for injection, 0.9% sodium chloride for injection, or bacteriostatic water for injection.
-Do not use dextrose containing solutions for reconstitution or further dilution due to a loss of potency.
-Maximum concentration should be bleomycin 5 units/mL.
-Bleomycin reconstituted with 0.9% sodium chloride for injection is stable for 24 hours at room temperature.
Intramuscular injection:
-Inject into a large muscle mass. Aspirate prior to injection to avoid injection into a blood vessel.
Subcutaneous Administration
Reconstitution:
-Reconstitute 15 unit vial with 1-5 mL of sterile water for injection, 0.9% Sodium Chloride for injection, or bacteriostatic water for injection, or reconstitute 30 unit vial with 2-10 mL sterile water for injection, 0.9% Sodium Chloride for injection, or bacteriostatic water for injection.
-Do not use dextrose containing solutions for reconstitution or further dilution due to a loss of potency.
-Maximum concentration should be bleomycin 5 units/mL.
-Bleomycin reconstituted with 0.9% Sodium Chloride for injection is stable for 24 hours at room temperature.
Subcutaneous injection:
-Avoid intradermal injections when bleomycin is administered subcutaneously.
Other Injectable Administration
Intrapleural instillation:
-Dissolve 60 units in 50-100 mL 0.9% Sodium Chloride for injection.
-Administer through a thoracostomy tube following drainage of excess pleural fluid and confirmation of complete lung expansion. The thoracostomy tube is clamped after instillation of the bleomycin. The patient should be moved from the supine to the left and right lateral positions several times over the next four hours. Afterwards, the clamp is removed and suction reestablished.
Intraarterial infusion:
NOTE: Bleomycin is not approved by the FDA for intraarterial infusion.
-Following reconstitution, further dilute bleomycin in 50 mL 0.9% Sodium Chloride for injection.
-Inject intraarterially slowly over 10-15 minutes.
Intralesional injection:
NOTE: Bleomycin is not approved by the FDA for intralesional injection.
-Inject into the lesion or place on lesion and prick lesion using a Monolet needle.
-Typically, bleomycin is further diluted to a 0.4-2 unit per mL solution.
-Bleomycin intralesional use may be reconstituted with lidocaine to decrease pain on administration.
Renal and hepatic toxicity (e.g., deterioration of renal or liver function tests) has occurred in patients who received bleomycin. Use bleomycin with caution in patients with renal dysfunction; dosage adjustment is necessary in patients with a creatinine clearance less than 50 ml/min.
Pain at the tumor site has also been reported following bleomycin therapy.
Severe pulmonary toxicity, usually presenting as pneumonitis but sometimes progressing to pulmonary fibrosis, has been reported with bleomycin therapy. Elderly patients (aged > 70 years) and patients who have received total bleomycin doses greater than 400 units may be at an increased risk of pulmonary fibrosis. Pulmonary toxicity has occurred in 10% of patients who received bleomycin; nonspecific pneumonitis progressed to pulmonary fibrosis and death in about 1% of patients. Pulmonary adverse effects have also occurred with intrapleural bleomycin administration. The earliest signs and symptoms of pulmonary toxicity include rales, nonspecific patchy opacities on X-ray, decreased lung volume and vital capacity in pulmonary function tests, and dyspnea. Patients should be closely monitored with frequent chest X-rays every 1 to 2 weeks. If evidence of pulmonary toxicity is observed, bleomycin should be discontinued to determine if the toxicity is treatment related. Serial measurements of pulmonary diffusion capacity for carbon monoxide (DLco), which can detect subclinical toxicity, may also be obtained monthly; discontinue bleomycin if the DLco < 30% to 35% of the baseline value.
Sudden onset of an acute chest pain (unspecified) syndrome has been reported with infusions of bleomycin. This syndrome may be suggestive of pleuro pericarditis. Although, each patient must be evaluated individually, further courses of bleomycin appear to be possible.
Skin and mucous membrane (e.g., stomatitis) toxicity have been reported approximately 50% of patients receiving bleomycin. Skin toxicity (e.g., erythema, rash (unspecified), striae, vesiculation, skin hyperpigmentation, and pruritus) is usually a late toxicity of bleomycin developing in the second and third week of treatment after 150-200 units of bleomycin has been administered. Alopecia, hyperesthesia (skin tenderness), hyperkeratosis, nail discoloration, urticaria, and scleroderma-like reactions also have been reported.
Fever, chills, and malaise have been reported with bleomycin therapy. As many as 60% of patients experience fever, even following intrapleural administration. Fever and chills usually occur within 2-8 hours following administration of bleomycin, but may occur up to 18 hours later. Most reactions subside within 12-24 hours. Prophylactic administration of acetaminophen, other antipyretics, or corticosteroids can temper this reaction. Antihistamines were not beneficial in animal models.
Anorexia and weight loss have occurred with bleomycin use and may persist long after stopping treatment. Vomiting has also been reported with bleomycin therapy.
Serious hypersensitivity reactions or anaphylaxis has been reported in approximately 1% of lymphoma patients following bleomycin administration. The reaction may be immediate or delayed several hours, and usually occurs after the first or second dose. The reaction consists of hypotension, fever, chills, wheezing, and mental confusion. Supportive treatment with volume expansion, vasopressor therapy, antihistamines, and/or corticosteroid treatment may be necessary. A test dose of 2 units or less is recommended prior to bleomycin treatment in patients with lymphoma.
Vascular adverse reactions have been reported with the use of bleomycin in combination with other antineoplastic agents. These events may include myocardial infarction, cerebrovascular accident (i.e., stroke), thrombotic microangiopathy/hemolytic-uremic syndrome, or cerebral arteritis. In addition, there have also been reports of Raynaud's phenomenon occurring in patients receiving bleomycin in combination with vinblastine, with or without cisplatin, or as a single agent. The exact cause has not been determined.
Intravenous infusions of bleomycin have been associated with injection site reaction including phlebitis. Localized pain has been reported during intrapleural administration of bleomycin. Palmer swelling, erythema and digital pulp necrosis (tissue necrosis) have been reported secondary to bleomycin extravasations.
Serious hypersensitivity reactions or anaphylaxis may occur with bleomycin. It is contraindicated in patients who have demonstrated bleomycin hypersensitivity or have experienced a hypersensitivity or idiosyncratic reaction to bleomycin (e.g., hypotension, mental confusion, fever, chills, and wheezing). Bleomycin therapy requires an experienced clinician knowledgeable in the use of cancer chemotherapeutic agents. Administration of bleomycin requires a specialized care setting. Because of the possibility of an anaphylactoid or hypersensitivity reaction, lymphoma (i.e., Hodgkin's disease or non-Hodgkin's lymphoma) patients should receive a test dose of bleomycin. The bleomycin test dose consisting of 2 units or less can be given by the IM, IV, or subcutaneous routes. It is recommended that the patient be observed for 24 hours after the test dose. Observational periods of less than 24 hours have been used based on the observation that most patients who are going to react do so within the first two hours after administration. However, a 24-hour observational period may increase the predictive value for a delayed reaction.
Patients should be monitored closely for bleomycin-induced pulmonary toxicity; patients with preexisting pulmonary fibrosis or other pulmonary disease may be at increased risk. The occurrence of bleomycin-induced pulmonary toxicity is unpredictable, but occurs more frequently in geriatric patients and in those receiving more than 400 units cumulative dose of bleomycin (maximum cumulative lifetime dose). However, pulmonary toxicity has been observed in younger patients and in those treated with low doses. In addition, when bleomycin is used with other antineoplastic agents, pulmonary toxicities can occur at lower doses. Frequent roentgenograms are recommended during bleomycin therapy. Studies have suggested that sequential measurement of the pulmonary diffusion capacity for carbon monoxide (DLCO) during bleomycin treatment may be an indicator of subclinical pulmonary toxicity. It is recommended that the DLCO be monitored monthly if it is to be used to detect pulmonary toxicity, and bleomycin treatment be stopped when the DLCO falls below 40% of the pretreatment value. Bleomycin should be used cautiously in patients who have had previous or concurrent thoracic radiation therapy or in patients who are currently or have had a history of tobacco smoking due to an increased risk of pulmonary toxicity. Patients with infectious pneumonitis should be treated immediately. Patients with a pulmonary infection should be treated prior to initiation of bleomycin therapy.
Due to the sensitization of lung tissue by bleomycin, patients who have received bleomycin are at greater risk of developing pulmonary toxicity when oxygen is administered during surgery. While long exposure to very high concentrations of oxygen is known to cause lung damage, after bleomycin administration, lung damage may occur at lower concentrations that are usually considered safe. Suggested preventive measures are: 1) maintain FIO2 at concentration approximating that of room air (25%) during surgery and the postoperative period; and 2) monitor carefully fluid replacement, focusing more on colloid administration rather than crystalloid. Guidelines regarding oxygen use when bleomycin has only be given intrapleurally are not available.
Bleomycin dosage requires adjustment in patients with renal impairment or renal failure due at an increased risk of bleomycin-induced pulmonary toxicity due to decreased clearance of bleomycin. Several different dosage nomograms have been suggested, but none have been clinically validated. Previous treatment with nephrotoxic agents (i.e., aminoglycosides, cisplatin, or cyclosporine) may result in decreased clearance of bleomycin. Fatal pulmonary bleomycin toxicity has been reported in a patient with cisplatin-induced acute renal failure.
Bleomycin is FDA pregnancy risk category D and can harm the fetus when given during pregnancy. Animal studies reveal abortifacient and/or teratogenic effects. Bleomycin should be given to pregnant women only when the benefit to the mother outweighs the risk to the fetus. Females of childbearing potential should be advised to avoid becoming pregnant while receiving bleomycin. If bleomycin is used during pregnancy or if a patient becomes pregnant while receiving bleomycin, the patient should be made aware of the potential harm to the fetus.
It is not known whether bleomycin is excreted into breast milk. Many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from bleomycin, breast-feeding is not advised, and patients should be instructed to discontinue breast-feeding during bleomycin therapy.
Bleomycin should be used with caution in patients with Raynaud's phenomenon or peripheral vascular disease. Raynaud's phenomenon has been reported in patients treated with bleomycin either alone or in combination with other chemotherapy agents.
Avoid extravasation of bleomycin during intravenous administration. Bleomycin is considered an irritant, but may cause necrosis if high doses of a concentrated solution are extravasated. Patients who receive intramuscular administration or subcutaneous administration of bleomycin may be at greater risk for the development of a local reaction. Patients should be monitored for an injection site reaction during therapy with this agent.
Use care to avoid accidental exposure to bleomycin during preparation, handling, and administration. The use of protective gowns, gloves and goggles is recommended. If bleomycin contacts the skin, immediately wash the skin thoroughly with soap and water. Avoid ocular exposure of bleomycin solutions. If exposure occurs to the eye or other mucous membranes, immediately rinse thoroughly with water.
Vaccination during chemotherapy or radiation therapy should be avoided because the antibody response is suboptimal. When chemotherapy is being planned, vaccination should precede the initiation of chemotherapy by >= 2 weeks. The administration of live vaccines to immunocompromised patients should be avoided. Those undergoing chemotherapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts, including health care professionals, of immunocompromised patients. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history.
For the treatment of Hodgkin lymphoma:
NOTE: Because of the possibility of an anaphylactoid reaction, lymphoma patients are usually given 2 units or less IV, IM, or subcutaneous for the first two doses or as a test dose, followed by a 24-hour observation. If no acute reactions occur, the regular doses may be given.
-as a single agent or as part of a regimen:
Intravenous, Intramuscular, or Subcutaneous dosage:
Adults, Adolescents, and Children: If given as a single agent, 5-20 units/m2 (0.25-0.5 units/kg) IV, IM or subcutaneous, administered 1 or 2 times/week. When used as part of ABVD (doxorubicin, vinblastine, and dacarbazine), bleomycin is given in a dose of 10 units/m2 IV. After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly IV, IM, or subcutaneous should be given. Improvement is usually prompt and noted within 2 weeks. If no improvement is seen by this time, benefits are unlikely.
-for the treatment of Hodgkin lymphoma as part of the Stanford V regimen:
Intravenous dosage:
Adults and Adolescents >=15 years: 5 units/m2 IV on weeks 2, 4, 6, 8, 10, and 12 in combination with mechlorethamine (6 mg/m2 IV on weeks 1, 5, and 9), doxorubicin (25 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vinblastine (6 mg/m2 IV on weeks 1, 3, 5, 7, 9, and 11), vincristine (1.4 mg/m2 [Max: 2 mg] IV on weeks 2, 4, 6, 8, 10, and 12), etoposide (60 mg/m2/day IV on 2 consecutive days in weeks 3, 7, and 11), and prednisone (40 mg/m2 PO every other day for 10 weeks then tapered by 10 mg PO every other day between weeks 10 and 12). Total duration of Stanford V regimen is 12 weeks (three 4-week cycles). Doses of mechlorethamine, doxorubicin, vinblastine, and etoposide have been reduced to 65% if ANC < 1000/mm3 (treatment delayed if ANC < 500/mm3). Prophylactic sulfamethoxazole-trimethoprim, acyclovir, and ranitidine were given throughout the treatment period. G-CSF has also been used to maintain dose intensity as needed after the first dose reduction. Alternative prophylactic medications have also been used.
-for the treatment of Hodgkin lymphoma as part of the BEACOPP regimen:
Intravenous dosage:
Adults and Adolescents >=15 years: 10 units/m2 IV on day 8 in combination with etoposide (100 mg/m2/day IV on days 1-3), doxorubicin (25 mg/m2 IV on day 1), cyclophosphamide (650 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max: 2 mg] IV on day 8), procarbazine (100 mg/m2/day PO on days 1-7), and prednisone (40 mg/m2 PO on days 1-14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials. The escalated dose BEACOPP regimen includes bleomycin 10 units/m2 IV on day 8 in combination with etoposide (200 mg/m2/day IV on days 1-3), doxorubicin (35 mg/m2 IV on day 1), cyclophosphamide (1200 mg/m2 IV on day 1), vincristine (1.4 mg/m2 [Max: 2 mg] IV on day 8), procarbazine (100 mg/m2/day PO on days 1-7), and prednisone (40 mg/m2 PO on days 1-14). Cycles are repeated every 21 days for up to 8 cycles. Filgrastim was administered beginning on day 8 of each cycle and continued until the leukocyte count returned to normal in some clinical trials. The standard dose BEACOPP and escalated dose BEACOPP regimens have shown benefit for the treatment of advanced Hodgkin lymphoma in clinical trials. Escalated dose BEACOPP has shown a significantly better freedom from treatment failure at 10 years (82% vs. 70%, p < 0.0001) and overall survival at 10 years (86% vs. 80%, p = 0.0053) compared to standard dose BEACOPP. A regimen of 4 cycles of escalated dose BEACOPP followed by 4 cycles of standard dose BEACOPP has also been used in patients who achieve a complete response after the initial 4 cycles of escalated dose BEACOPP.
For the treatment of non-Hodgkin's lymphoma (NHL):
Intravenous, Intramuscular, and Subcutaneous dosage (test dose):
Adults, Adolescents and Children*: Because of the possibility of an anaphylactoid reaction, lymphoma patients are usually given 2 units or less IV, IM, or subcutaneous for the first 2 doses or as a test dose, followed by a 24-hour observation. If no acute reactions occur, the regular doses may be given.
Intravenous, Intramuscular, and Subcutaneous dosage:
Adults, Adolescents and Children*: If given as a single agent, 10-20 units/m2 (0.25-0.5 units/kg) IV, IM or subcutaneous, administered 1 or 2 times/week. Other treatment regimens also include bleomycin with the dose varying from regimen to regimen. In CHOP-Bleo, a fixed single dose of 15 units IV is given on days 1 and 5 with cyclophosphamide, doxorubicin, vincristine, and prednisone. In m-BACOD, the dose of bleomycin is 4 units/m2 IV on day 1.
For the treatment of cervical cancer, head and neck cancer, or vulvar cancer (specifically squamous cell cancer):
Intravenous, Intramuscular, and Subcutaneous dosage:
Adults: 5-20 units/m2 (0.25-0.5 units/kg) IV, IM, or subcutaneous, administered 1 or 2 times/week. Because squamous cell carcinomas usually respond slower, improvements may not be noted for as long as 3 weeks. The response to bleomycin is poorer in patients with previously irradiated head and neck cancer.
Intraarterial dosage*:
Adults: Bleomycin in doses up to 60 units/day have been given intraarterially to provide increased local concentrations in the treatment of squamous cell carcinoma of the cervix and head and neck cancer.
For the treatment of testicular cancer, including embryonal cell, choriocarcinoma, and teratocarcinoma:
-for the treatment of testicular cancer, in combination with cisplatin and etoposide (BEP regimen):
Intravenous dosage:
Adults: 30 units IV on days 1, 8, and 15, in combination with cisplatin and etoposide, every 21 days for 3 cycles. In a randomized clinical trial, treatment with BEP resulted in a response rate of 94% of patients with disseminated germ cell tumors compared with 88% for those treated with etoposide plus cisplatin. In a randomized clinical trial of patients with favorable-prognosis germ-cell cancer, there was not a significant difference between 3 cycles of BEP and 4 cycles in terms of overall or disease-free survival.
For the treatment of osteogenic sarcoma*:
Intravenous dosage:
Adults, Adolescents, and Children: 15 units/m2/day IV on days 1 and 2 or on days 1, 2, and 3 in combination with cyclophosphamide and dactinomycin (BCD regimen) has been incorporated into multiple treatment protocols for osteogenic sarcoma. In the POG-8651 protocol, 106 patients (< 30 years old) with previously untreated nonmetastatic high-grade osteogenic sarcoma were randomized to receive 3 days of BCD each cycle as part of a multiagent chemotherapy regimen in sequence with doxorubicin and cisplatin, and high-dose methotrexate, either before or after surgical resection. Event-free survival (EFS), the primary endpoint, was not significantly different between the treatment arms, and reached 69% at 5 years in the post-operative group. In a comparison of the Memorial Sloan-Kettering Cancer Center T-10 and T-12 protocols, 73 patients (ages 4.6-36.4 years) with previously untreated, high-grade osteogenic sarcoma received BCD on days 1 and 2 of each cycle as part of a multiagent chemotherapy regimen in sequence with doxorubicin and cisplatin, high-dose methotrexate, and surgical resection. The 5-year EFS was 78% and 73% in the T-12 and T-10 protocols, respectively. The use of BCD alone has also been studied in 8 pediatric patients (ages 9.1-16.4 years) with previously treated metastatic osteogenic sarcoma. Patients received 1-5 courses of BCD. No tumor regression could be measured for any of the patients, and progressive tumor enlargement was demonstrated in 2 patients.
For the treatment of AIDS-related Kaposi's sarcoma in combination with doxorubicin and vincristine*:
Intravenous dosage:
Adults: 15 units IV on day 1 in combination with doxorubicin (10 mg/m2 IV on day 1) and vincristine (1 mg IV on day 1), repeated every 2 weeks. Alternately, bleomycin 10 mg/m2 IV on day 1 has been given in combination with doxorubicin (20 mg/m2 IV on day 1) and vincristine (1 mg IV on day 1), repeated every 2 weeks for 6 cycles.
For the treatment of malignant ascites*:
Intracavitary dosage:
Adults: 150 units mixed in 2 L 1.5% warmed dineal solution via peritoneal dialysis catheter for 4 hours has been studied with some success in a small clinical trial (n = 10).
For the treatment of verruca vulgaris* (i.e., common warts) or verruca plantaris* (i.e., plantar warts):
Intralesional dosage:
Adults: Typically, 1 mL of bleomycin 1 unit/mL solution is injected into the lesion every 2 weeks. Alternatively, bleomycin 1 unit/mL solution may be dropped onto the lesion and pricked into the wart using a needle. Patients who do not respond to 3 injections are usually considered treatment failures. Premedication with a topical local anesthetic is recommended to decrease pain on injection. Alternatively, a single dose of 0.5 mg/mL solution with 2% lidocaine injected into the lesion using an insulin syringe has been used. NOTE: 1 unit = 1 mg. Response rates to bleomycin range from 33-92%.
Adolescents: A single dose of 0.5 mg/mL solution with 2% lidocaine injected into the lesion using an insulin syringe has been used. NOTE: 1 unit = 1 mg.
For the treatment of hemangioma*:
Intralesional dosage:
Children and Adolescents: Bleomycin has been used via intravesical injection for the treatment of hemangiomas. In one report, 5 patients age 5-19 years with massive inoperable hemangiomas were treated with intralesional injections of 2 units bleomycin as a 0.4 unit/mL solution. The injections were repeated after 4-6 weeks for a total of 6-10 treatments. Pain relief and decreased swelling was noted in all cases. In a similar report, bleomycin injections of 0.5-2 units/mL were used for a total dose of 0.3-0.6 units/kg per treatment session every 6 weeks for up to 3 sessions. Lesions regressed 60-100% during 6-14 months following bleomycin injections; the lesions of 3 patients were completely excised after 1 bleomycin injection.
For the treatment of penile cancer:
-for the treatment of squamous cell penile cancer:
Intravenous, Intramuscular, or Subcutaneous dosage:
Adults: 10-20 units/m2 (0.25-0.5 units/kg) IV, IM, or subcutaneous, administered 1 or 2 times per week. Because squamous cell carcinomas usually respond slower, improvements may not be noted for as long as 3 weeks.
-for the treatment of locally advanced or metastatic penile cancer in combination with cisplatin and methotrexate:
Intravenous dosage:
Adults: 10 units/m2 IV on days 1 and 8 in combination with cisplatin 75 mg /m2 IV on day 1 and methotrexate 25 mg/m2 IV bolus on days 1 and 8, repeated every 21 days. Treatment was given for 6 cycles if a complete remission was achieved. Patients who achieved stable disease or a partial response, continued treatment until disease progression. Bleomycin was discontinued after a maximum cumulative dose of 200 units/m2 was given.
For the treatment of malignant pleural effusion:
Intrapleural dosage:
Adults: 60 units administered as a single bolus intrapleural injection.
Maximum Dosage Limits:
The suggested maximum tolerated dose (MTD) for bleomycin, which is dependent on performance status, other chemotherapy agents or radiation given in combination, and disease state, is as follows:
NOTE: The correct dose of bleomycin will vary from protocol to protocol. Clinicians should consult the appropriate references to verify the dose.
-Adults
Maximum lifetime cumulative dosage of bleomycin is 400 units intravenous (IV), intramuscular (IM), or subcutaneous.
-Geriatric
Maximum lifetime cumulative dosage of bleomycin is 400 units intravenous (IV), intramuscular (IM), or subcutaneous. However, elderly patients may develop pulmonary toxicity at lower cumulative bleomycin doses.
-Adolescents
Maximum lifetime cumulative dosage of bleomycin is 400 units intravenous (IV), intramuscular (IM), or subcutaneous.
-Children
Maximum lifetime cumulative dosage of bleomycin is 400 units intravenous (IV), intramuscular (IM), or subcutaneous.
Patients with Hepatic Impairment Dosing
No dosage adjustment required.
Patients with Renal Impairment Dosing
CrCl 40-50 mL/min: reduce bleomycin dose by 30%.
CrCl 30-39 mL/min: reduce bleomycin dose by 40%.
CrCl 20-29 mL/min: reduce bleomycin dose by 45%.
CrCl 10-19 mL/min: reduced bleomycin dose by 55%.
CrCl 5-10 mL/min: reduce bleomycin dose by 60%.
Various recommendations for bleomycin dosage reduction in renal impairment are reported in the literature. Bleomycin is not removed by hemodialysis.
*non-FDA-approved indication
Amikacin: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
Aminoglycosides: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
Ascorbic Acid, Vitamin C: (Moderate) Monitor for decreased efficacy of bleomycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration of ascorbic acid and bleomycin may result in decreased efficacy of bleomycin.
Brentuximab vedotin: (Contraindicated) Concomitant administration of brentuximab vedotin and bleomycin is contraindicated due to an increased risk for non-infectious pulmonary toxicities. Pulmonary toxicies are a known adverse reaction associated with bleomycin therapy. In studies of chemotherapeutic regimens containing bleomycin (without brentuximab vedotin), some degree of pulmonary toxicity occurs in up to 10% of patients; however, in one study in which bleomycin was administered in combination with brentuximab vedotin, doxorubicin, vinbalstine, and darcarbazine (ABVD), approximately 40% of patients experienced pulmonary toxicities.
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Cisplatin: (Moderate) Monitor for an increase in bleomycin-related adverse reactions if coadministration with cisplatin is necessary. Bleomycin is primarily eliminated through renal excretion; therefore, its clearance may be affected by nephrotoxic agents such as cisplatin. In one report of 2 children receiving concomitant cisplatin with bleomycin, total body clearance of bleomycin decreased from 39 mL/min/m2 to 18 mL/min/m2 as the cumulative dose of cisplatin exceeded 300 mg/m2; the terminal half-life of bleomycin also increased from 4.4 hours to 6 hours. Fatal bleomycin pulmonary toxicity has been reported in a patient with unrecognized cisplatin-induced oliguric renal failure.
Cranberry, Vaccinium macrocarpon Ait.: (Moderate) Monitor for decreased efficacy of bleomycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration of ascorbic acid and bleomycin may result in decreased efficacy of bleomycin.
Cyclosporine: (Minor) Previous treatment with nephrotoxic agents, like cyclosporine, may result in decreased bleomycin clearance if renal function has been impaired. Monitor for signs/symptoms of bleomycin toxicity in patients with concomittant or prior cyclosporine therapy.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa; the effect on digoxin liquid is not known. The reduction in digoxin tablet absorption has resulted in plasma concentrations that are 50% of pretreatment levels and has been clinically significant in some patients. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin while receiving antineoplastic therapy.
Ethotoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and bleomycin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Foscarnet: (Minor) Previous treatment with nephrotoxic agents, like foscarnet, may result in decreased bleomycin clearance if renal function has been impaired. Monitor for signs/symptoms of bleomycin toxicity in patients with concomittant or prior foscarnet therapy.
Fosphenytoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and bleomycin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Gentamicin: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
Hydantoins: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and bleomycin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Paromomycin: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
Pentamidine: (Moderate) Previous or concurrent treatment with nephrotoxic agents, like pentamidine, may result in decreased bleomycin clearance if renal function has been impaired. Monitor for signs/symptoms of bleomycin toxicity (e.g., pulmonary toxicity) in patients with concomittant or prior history of systemic pentamidine therapy.
Phenytoin: (Major) Patients receiving antineoplastic agents concurrently with hydantoins may be at risk for toxicity or loss of clinical efficacy and seizures; anticonvulsant therapy should be monitored closely during and after administration of antineoplastic agents. Concurrent therapy with phenytoin and bleomycin has been associated with subtherapeutic phenytoin serum concentrations and seizure activity. Phenytoin dosage increases of 20 to 100% have been required in some patients, depending on the chemotherapy administered.
Plazomicin: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Streptomycin: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
Tobramycin: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
Vancomycin: (Minor) Previous treatment with nephrotoxic agents, like vancomycin, may result in decreased bleomycin clearance if renal function has been impaired. Monitor for signs/symptoms of bleomycin toxicity in patients with concomittant or prior vancomycin therapy.
Vitamin C: (Moderate) Monitor for decreased efficacy of bleomycin during coadministration; discontinue ascorbic acid therapy if decreased efficacy is suspected. Coadministration of ascorbic acid and bleomycin may result in decreased efficacy of bleomycin.
Bleomycin exerts its cytotoxic effects by binding directly to DNA. Other potential areas of cytotoxic activity include affects on lipid peroxidation and oxidative degradation of RNA. Bleomycin exerts its effects on DNA through a multi-step process. Initially, an iron (Fe), bleomycin, oxygen complex is formed. This complex is formed in the presence of DNA, which stabilizes it. The binding of the bleomycin complex to DNA occurs at certain nucleotide sequences via electrostatic interactions and partial intercalation of bleomycin. Lastly, the bleomycin complex functions as ferrous oxide during DNA cleavage, resulting in single- and double-strand breaks. Cells are most susceptible to bleomycin in the G2 or M phase of the cell cycle. Although increased toxicity occurs in the G2 phase, it is not clear if bleomycin has preferential activity for rapidly (i.e., logarithmically) dividing cells or non-dividing (i.e., plateau-phase) cells.
Factors of resistance to bleomycin include increased drug inactivation, decreased drug accumulation, and increased DNA repair. Bleomycin hydrolase converts bleomycin to an inactive form, and increased levels of this enzyme have been associated with bleomycin resistance. In addition, normal tissues with high levels of this enzyme (e.g., liver, spleen, and bone marrow) are less susceptible to the toxic effects of the drug. As opposed to other natural antineoplastic agents, bleomycin is not affected by P-glycoprotein, which is coded for by the mutidrug resistance 1 (MDR1) gene.
Bleomycin is poorly absorbed across the GI tract and must be administered parenterally. Bleomycin distributes mainly into the tissues of the skin, lungs, kidneys, peritoneum, and lymphatics. Only 10% of a dose binds to plasma proteins.
Bleomycin appears to undergo extensive metabolism by a specific cysteine proteinase, bleomycin hydrolase. Bleomycin hydrolase is found in most tissues except for the lungs and skin, which are the primary sites of bleomycin toxicity. Bleomycin is excreted primarily by the kidneys. Approximately 45-70% of a dose can be recovered in the urine in the first 24 hours. The half-life in patients with normal renal function is 2-4 hours. Bleomycin clearance correlates well with creatinine clearance.
-Route-Specific Pharmacokinetics
Intravenous Route
After IV administration, bleomycin distributes to intracellular and extracellular spaces in 10-20 minutes.
Intramuscular Route
After IM administration of bleomycin, peak concentrations are only one-tenth those occurring after IV administration.
Other Route(s)
Intrapleural Route
Bleomycin may be administered into pleural or peritoneal spaces. Approximately 45% of a dose can be absorbed systemically, but cavitary concentrations are 10-22% higher than the corresponding plasma concentrations. Only 17% of the intrapleural dose is recovered in the urine.
-Special Populations
Renal Impairment
Dosage adjustment is necessary in patients with creatinine clearances of less than 50 ml/min (see Dosage). Pulmonary toxicity is probably enhanced when dosage is not adjusted for renal dysfunction. Bleomycin is not removed by hemodialysis.