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    Other Cytotoxic Antibiotics

    BOXED WARNING

    Bleomycin hypersensitivity, fever, idiosyncratic reaction, requires a specialized care setting, requires an experienced clinician, serious hypersensitivity reactions or anaphylaxis

    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.

    Geriatric, infection, maximum cumulative lifetime dose, pulmonary disease, pulmonary fibrosis, pulmonary toxicity, radiation therapy, tobacco smoking

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Antibiotic antineoplastic
    Mixture of 13 glycopeptides; active component is the A-2 peptide
    Used for Hodgkin lymphoma, NHL, testicular cancer, squamous cell cancer of the head and neck and cervix, and malignant pleural effusions.

    COMMON BRAND NAMES

    Blenoxane

    HOW SUPPLIED

    Blenoxane/Bleomycin/Bleomycin Sulfate Intramuscular Inj Pwd F/Sol: 15U, 30U
    Blenoxane/Bleomycin/Bleomycin Sulfate Intrapleural Inj Pwd F/Sol: 15U, 30U
    Blenoxane/Bleomycin/Bleomycin Sulfate Intravenous Inj Pwd F/Sol: 15U, 30U
    Blenoxane/Bleomycin/Bleomycin Sulfate Subcutaneous Inj Pwd F/Sol: 15U, 30U

    DOSAGE & INDICATIONS

    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.
    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.

    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 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.
    Intravenous dosage
    Adults

    10—20 units/m2 (0.25—0.5 units/kg) IV, IM, or subcutaneous given 1 or 2 times/week. As part of combination therapy, bleomycin 30 units IV is administered on days 2, 9, and 16 in combination with cisplatin and etoposide (BEP regimen). Improvement is usually prompt and noted within 2 weeks. If no improvement is seen by this time, benefits are unlikely.

    For the treatment of penile cancer.
    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 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 malignant pleural effusion.
    Intrapleural dosage
    Adults

    60 units administered as a single bolus intrapleural injection.

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment required.

    Renal Impairment

    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.

    ADMINISTRATION

     
    CAUTION: Observe and exercise usual cautions for handling, preparing, and administering solutions of cytotoxic drugs.
     
    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.

    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.

    STORAGE

    Blenoxane:
    - Discard unused portion. Do not store for later use.
    - Store reconstituted product in accordance with package insert instructions
    - Store unreconstituted product in refrigerator (36 to 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Bleomycin hypersensitivity, fever, idiosyncratic reaction, requires a specialized care setting, requires an experienced clinician, serious hypersensitivity reactions or anaphylaxis

    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.

    Geriatric, infection, maximum cumulative lifetime dose, pulmonary disease, pulmonary fibrosis, pulmonary toxicity, radiation therapy, tobacco smoking

    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.

    Surgery

    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.

    Renal failure, renal impairment

    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.

    Pregnancy

    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.

    Breast-feeding

    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.

    Peripheral vascular disease, Raynaud's phenomenon

    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.

    Extravasation, intramuscular administration, subcutaneous administration

    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.

    Accidental exposure, ocular exposure

    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

    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.

    ADVERSE REACTIONS

    Severe

    pulmonary fibrosis / Delayed / 2.0-3.0
    serious hypersensitivity reactions or anaphylaxis / Rapid / 0-1.0
    pulmonary toxicity / Early / Incidence not known
    pericarditis / Delayed / Incidence not known
    hemolytic-uremic syndrome / Delayed / Incidence not known
    stroke / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    tissue necrosis / Early / Incidence not known

    Moderate

    pneumonitis / Delayed / Incidence not known
    dyspnea / Early / Incidence not known
    chest pain (unspecified) / Early / Incidence not known
    hyperesthesia / Delayed / Incidence not known
    stomatitis / Delayed / Incidence not known
    erythema / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    wheezing / Rapid / Incidence not known
    confusion / Early / Incidence not known
    phlebitis / Rapid / Incidence not known

    Mild

    fever / Early / 60.0
    alopecia / Delayed / Incidence not known
    rash / Early / Incidence not known
    skin hyperpigmentation / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    nail discoloration / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known
    hyperkeratosis / Delayed / Incidence not known
    striae / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    malaise / Early / Incidence not known
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    weight loss / Delayed / Incidence not known
    injection site reaction / Rapid / Incidence not known

    DRUG INTERACTIONS

    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Aminoglycosides: (Moderate) Previous treatment with nephrotoxic agents, like aminoglycosides, may result in decreased clearance of bleomycin if renal function has been impaired.
    Antithymocyte Globulin: (Moderate) Because antithymocyte globulin is an immunosuppressant, additive affects may be seen with other immunosuppressives or antineoplastic agents. While therapy is designed to take advantage of this effect, patients may be predisposed to over-immunosuppression resulting in an increased risk of infection or other side effects.
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bacillus Calmette-Guerin Vaccine, BCG: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Brentuximab vedotin: (Severe) 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.
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Carbamazepine: (Moderate) Myelosuppressive antineoplastic agents and radiation therapy possess hematologic toxicities similar to carbamazepine, and should be used concomitantly with caution. Dosage adjustments may be necessary. Monitor patient closely.
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cisplatin: (Moderate) Cisplatin may impair renal clearance of bleomycin over time. Cumulative nephrotoxicity of repeated courses of cisplatin eventually will decrease bleomycin renal clearance and increase the risk of pulmonary toxicity. Fatal pulmonary bleomycin toxicity has been reported in a patient with cisplatin-induced acute renal failure. Patients with a significant history of cisplatin administration should be observed closely for changes in the pulmonary exam.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Corticotropin, ACTH: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    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.
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Diclofenac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diclofenac; Misoprostol: (Minor) An increased risk of bleeding may occur when NSAIDs, such as diclofenac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    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.
    Diphenhydramine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Diphenhydramine; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Esomeprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Etodolac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as etodolac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Famotidine; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as fenoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flurbiprofen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as flurbiprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    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.
    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.
    Hydrocodone; Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Ibuprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Oxycodone: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) An increased risk of bleeding may occur when NSAIDs, such as ibuprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Indomethacin: (Major) An increased risk of bleeding may occur when NSAIDs, such as indomethacin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ketoprofen: (Major) An increased risk of bleeding may occur when NSAIDs, such as ketoprofen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Lansoprazole; Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Live Vaccines: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) An increased risk of bleeding may occur when NSAIDs, such as meclofenamate, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Mefenamic Acid: (Major) An increased risk of bleeding may occur when NSAIDs, such as mefenamic acid, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Meloxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as meloxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Nabumetone: (Minor) An increased risk of bleeding may occur when NSAIDs, such as nabumetone, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Pseudoephedrine: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Naproxen; Sumatriptan: (Minor) An increased risk of bleeding may occur when NSAIDs, such as naproxen, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Oxaprozin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as oxaprozin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    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.
    Piroxicam: (Minor) An increased risk of bleeding may occur when NSAIDs, such as piroxicam, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Rofecoxib: (Minor) An increased risk of bleeding may occur when NSAIDs, such as rofecoxib, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Rotavirus Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Sulindac: (Minor) An increased risk of bleeding may occur when NSAIDs, such as sulindac, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Tobacco: (Major) Patients who smoke tobacco may be at increased risk for bleomycin-induced pulmonary toxicity. Patients should be advised not to smoke and should be monitored closely and report any unusual or persistant cough or shortness of breath while receiving bleomycin treatment.
    Tolmetin: (Minor) An increased risk of bleeding may occur when NSAIDs, such as tolmetin, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. Monitor closely for bleeding.
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    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.
    Typhoid Vaccine: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Valdecoxib: (Minor) An increased risk of bleeding may occur when NSAIDs, such as valdecoxib, are used with agents that cause clinically significant thrombocytopenia, such as myelosuppressive antineoplastic agents. However, valdecoxib may be associated with less risk than other NSAIDs due to its relative minimal platelet inhibitory effects and gastric ulceration or hemorrhagic potential.
    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.
    Varicella-Zoster Virus Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    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.
    Yellow Fever Vaccine, Live: (Severe) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    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.

    MECHANISM OF ACTION

    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.

    PHARMACOKINETICS

    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.

    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.