(US Adopted Name, rINNM)
INNs in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In Europe, International, Japan, and US.
International and Japan also include Bleomycin Hydrochloride.
China, includes Bleomycin A5 Hydrochloride for Injection.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Bleomycin Sulphate). The sulfate of a mixture of glycopeptides obtained by the growth of Streptomyces verticillus or by any other means; the two principal components of the mixture are N-[3-(dimethylsulphonio)propyl]bleomycinamide (bleomycin A2) and N-[4-(carbamimidoylamino)butyl]bleomycina-mide (bleomycin B2). A white or yellowish-white, very hygroscopic powder. It loses not more than 3% of its weight when dried. Very soluble in water; slightly soluble in dehydrated alcohol; practically insoluble in acetone. A 0.5% solution in water has a pH of 4.5 to 6.0. Store in airtight containers at a temperature of 2° to 8°.
The United States Pharmacopeia 31, 2008 (Bleomycin Sulfate). The sulfate salt of a mixture of basic cytotoxic glycopeptides, produced by the growth of Streptomyces verticillus or produced by other means. It has a potency of not less than 1.5 units and not more than 2.0 units/mg. It contains between 55 and 70% of bleomycin A2 and between 25 and 32% of bleomycin B2; the content of bleomycin B4 is not more than 1 %. The combined percentage of bleomycin A2 and B2 is not less than 90%. A cream-coloured, amorphous powder. It loses not more than 6% of its weight when dried. Very soluble in water. A solution in water containing 10 units/mL has a pH of 4.5 to 6.0. Store in airtight containers.
Incompatibility. A loss of bleomycin activity was reported when bleomycin sulfate solutions were mixed with solutions of carbenicillin, cefazolin or cefalotin sodium, nafcillin sodium, benzylpenicillin sodium, methotrexate, mitomycin, hydrocortisone sodium succinate, aminophylline, ascorbic acid, or terbutaline. The interactions of bleomycin have been summarised as the chelation of divalent and trivalent cations (especially copper), inactivation by compounds containing sulfhydryl groups, and precipitation by hydrophobic anions; solutions of bleomycin should not be mixed with solutions of essential amino acids, riboflavin, dexamethasone, or furosemide.
Stability. Bleomycin sulfate solutions appear to be equally stable in plastic or glass, despite some earlier studies suggesting loss of potency in plastic. There is some evidence that bleomycin is more stable in sodium chloride 0.9% than glucose 5%, and sodium chloride 0.9% is the diluent recommended by the licensed product information. UK licensed product information states that bleomycin sulfate is chemically and physically stable, once reconstituted and diluted as directed, for 10 days when refrigerated at 2° to 8° and protected from light. From a microbiological point of view, solutions should be used immediately; storage for longer than 24 hours at 2° to 8° is not recommended, unless prepared under controlled and validated aseptic conditions.
8910 units of bleomycin complex A2/B2 are contained in 5 mg of bleomycin complex in one ampoule of the first International Reference Preparation (1980). The European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 specifies a potency of not less than 1500 international units per mg, calculated with reference to the dried substance. These units differ from those used by the USP: Bleomycin Sulfate (The United States Pharmacopeia 31, 2008) contains 1.5 to 2.0 units of bleomycin in each mg. A change in the labelling of preparations in the UK, from units equivalent to those of the USP to international units in line with the Ph. Europe, resulted in an apparent but artefactual increase in UK doses by a factor of 1000.
In some countries doses were formerly described in terms of mg-potency, where 1 mg-potency corresponded to 1 unit. In the original preparation 1 mg-potency was equivalent to 1 mg-weight but improvements in purification of the product led to a situation in which ampoules labelled as containing 15 mg (i.e. 15 units) contained far fewer mg-weight of bleomycin.
Adverse Effects and Treatment
For a general outline see Antineoplastics.
The most frequent adverse effects with bleomycin involve the skin and mucous membranes and include rash, erythema, pruritus, vesiculation, hyperkeratosis, nail changes, alopecia, hyperpigmentation, striae, and stomatitis. Fever is also common, and acute anaphylac-toid reactions with hyperpyrexia and cardiorespiratory collapse have been reported in about 1% of patients with lymphoma. There is little depression of the bone marrow. Local reactions and thrombophlebitis may occur at the site of parenteral dosage. The most serious delayed effect is pulmonary toxicity; interstitial pneumonitis occurs in about 10% of patients and progresses to fibrosis and death in about 1% of patients treated with bleomycin. Pulmonary toxicity is more likely in elderly patients and those given total doses greater than 400 000 international units (400 USP units). It is also more likely in patients who have had previous radiotherapy to the chest.
Effects on the lungs. Pneumonitis induced by bleomycin can progress to fatal pulmonary fibrosis. The presentation is often delayed; clinical manifestations include non-productive cough, dyspnoea, and sometimes fever (see Effects on the Lungs). Pneumomediastinum has also been reported as an initial manifestation of fatal pulmonary toxicity due to bleomycin. Risk factors for toxicity include increased age, deteriorating renal function, and concurrent or previous radiotherapy. The reaction is dose-related, and maximum doses have been set (see Uses and Administration, below). Other factors that may be implicated include the regimen used, concomitant oxygen supplementation, smoking history, underlying lung disease, and growth factor support. For further details of some of these risk factors, see under Interactions, below. There is no standard treatment for bleomycin-induced pneumonitis. Bleomycin therapy is usually stopped, and corticosteroids may be given although strong evidence to support their use is lacking. There is some suggestion that giving bleomycin by intravenous infusion rather than bolus injection may reduce pulmonary toxicity.
Effects on the skin, hair, and nails. Permanent nail loss and nail loss followed by regrowth with dystrophy have been reported after intralesional injection of bleomycin for periungual warts. In 2 cases this was preceded by blistering and ulcera-tion, or swelling, severe pain, and a burning sensation. All 3 patients had received injections on one or two previous occasions when 2 patients had reported only mild pain. Other reported cutaneous adverse effects of bleomycin include flagellate erythema, Raynaud’s phenomenon, gangrene, fibrotic or sclerotic skin changes, hyperpigmentation, and neutrophilic eccrine hidradenitis (an inflammatory dermatosis with erythematous plaques and nodules, neutrophilic infiltrates of eccrine glands, and degeneration of eccrine cells). Acute generalised exanthe-matous pustulosis and alopecia have also been reported.
Effects on the vascular system. Although thromboembolic disorders and Raynaud’s syndrome have been associated with use of bleomycin in combination regimens, particularly with cisplatin and the vinca alkaloids or etoposide (see Effects on the Cardiovascular System) there is some evidence for an association of Raynaud’s syndrome with the use of bleomycin alone.
There have also been cases of Raynaud’s phenomenon reported after intralesional injection of bleomycin for treatment of warts on the hands and feet. See also Effects on the Skin, Hair, and Nails, above.
For reference to the precautions necessary with antineoplastics.
Bleomycin should be used with caution in the elderly, in patients with renal impairment or pulmonary infection or pre-existing impairment of pulmonary function, and in those who have received radiotherapy, particularly to the thorax. Patients should undergo regular chest X-rays. If these show infiltrates, or if breathlessness occurs, bleomycin should be stopped. In view of the risk of an anaphylactoid reaction it has been suggested that patients with lymphomas should receive two test doses of 2000 international units (2 USP units) or less initially (but see Administration, below).
AIDS. Cutaneous adverse effects occurred in 12 of 50 patients being treated with bleomycin for AIDS-associated Kaposi’s sarcoma and increased in severity until bleomycin was withdrawn. Bleomycin should be stopped in people with AIDS if cutaneous adverse effects are seen, and rechallenge should be avoided. However, the incidence of adverse effects did not appear to be higher in these patients than in cancer patients, and patients with AIDS seem to be less sensitive to bleomycin than to antibacteri-als such as co-trimoxazole and penicillins.
Diving. Since the partial pressure of oxygen in the inspired air of a scuba diver increases with increasing depth, a theoretical possibility exists of a toxic [pulmonary] reaction to oxygen in bleomycin-treated patients who subsequently go diving, and such a risk would increase with the depth and duration of each dive. However, the risks associated with diving after uncomplicated bleomycin-based treatment have been questioned; the authors considered that resuming diving was acceptable 6 to 12 months after completing treatment with BEP (bleomycin, etoposide, and cisplatin), and recommended caution only in those who developed pulmonary function impairment when given bleomycin.
Handling and disposal. Urine produced for up to 72 hours after a dose of bleomycin should be handled wearing protective clothing.
Pregnancy. For a report of use of a bleomycin-containing chemotherapy regimen in a pregnant woman and subsequent adverse effects on the infant, see Pregnancy, under Cisplatin.
For a general outline of antineoplastic drug interactions. There may be an increased risk of pulmonary toxicity in patients given bleomycin who receive oxygen, for example as part of a general anaesthetic procedure; a reduction in inspired oxygen concentration has been recommended.
Antineoplastics. Enhanced pulmonary toxicity, in some cases fatal, has been reported in patients given bleomycin and cisplatin, presumably because cisplatin-induced renal impairment led to a decrease in bleomycin elimination. It seems reasonable to assume that similar interactions might occur if bleomycin were given with other nephrotoxic agents. It has been suggested that apart from a decrease in bleomycin dosage if nephrotoxic ity occurs with such a combination, giving bleomycin by constant infusion rather than intermittent bolus might be less toxic: A study to investigate whether substitution of etoposide with gemcitabine would lead to a less leukaemogenic BEACOPP regimen was stopped early because of unexpectedly common pulmonary toxicity; one patient died. This toxicity was considered to be due to the use of gemcitabine with bleomycin.
Colony-stimulating factors. An increased incidence of pulmonary toxicity has been reported in patients receiving bleomycin as part of the AB VD regimen (with doxorubicin, vinblastine, and dacarbazine) who were given granulocyte colony-stimulating factor to alleviate neutropenia. Another case of rapidly developing and fatal pneumonitis in a patient given BEP (bleomycin, etoposide, and cisplatin) with granulocyte colony-stimulating factor has been reported.
Analyses of study data failed to show increased pulmonary toxicity when granulocyte colony-stimulating factor was added to bleomycin-containing regimens in patients with germ cell tumours or non-Hodgkin’s lymphomas. In a retrospective review of patients with Hodgkin’s lymphoma, however, use of bleomycin with granulocyte colony-stimulating factor was associated with a statistically significant increase of pulmonary toxicity.
Oxygen. Because bleomycin is thought to cause pulmonary toxicity partly by induction of free radicals, use with high concentrations of oxygen could be hazardous, and reductions in inspired oxygen concentration have been recommended by licensed product information where oxygen supplementation is unavoidable. Animal studies show an increased risk of mortality with use of bleomycin and oxygen, although data in humans are lacking. The need for oxygen restriction in bleomycin-treated patients has, however, been questioned.
Bleomycin is thought to be poorly absorbed from the gastrointestinal tract. Absorption is rapid after parenteral, intraperitoneal, or intrapleural use. Bioavailability is 100% and 70% after intramuscular and subcutaneous dosage, respectively. A bioavailability of 45% has been reported after intraperitoneal or intrapleural use. Plasma protein binding is low. Enzymic degradation of bleomycin occurs, primarily in plasma, the liver and other organs, and to a much lesser extent in skin and lungs. Elimination is biphasic: mean initial and terminal half-lives of 0.5 and 4 hours respectively have been reported after an intravenous bolus. Elimination may be more prolonged after continuous intravenous infusion and mean half-lives of 1.3 and 9 hours respectively have been reported. About two-thirds of a dose is excreted unchanged in the urine; the rate of excretion is determined by renal function. Drug concentrations in the CSF are low. Bleomycin crosses the placenta.
Uses and Administration
Bleomycin is an antineoplastic antibiotic that binds to DNA and causes strand scissions, and is probably most effective in the G2 and M phases of the cell cycle. It is widely used to treat malignant disease; particularly squamous cell carcinomas, including those of the cervix and external genitalia, oesophagus, skin, and head and neck; Hodgkin’s disease and other lymphomas; malignant neoplasms of the testis, and malignant effusions. It has also been tried in other malignancies, including carcinoma of the bladder, lung, and thyroid, and some sarcomas, including Kaposi’s sarcoma. Bleomycin is often used with other antineoplastics, notably with doxorubicin, vinblastine, and dacarbazine (ABVD) for Hodgkin’s disease, and with etoposide and cisplatin (BEP) in testicular tumours. Bleomycin is given as the sulfate by either the intramuscular, intravenous, or subcutaneous route. It may also be given intra-arterially or instilled intrapleurally or intraperitoneally If intramuscular injections are painful they may be given in a 1% solution of lidocaine.
Doses are calculated in terms of the base, and are given in units, but the units used for preparations in the UK, which were formerly equivalent to those of the USP, are now international units equivalent to those of the Ph. Europe (see Units, above). Since 1000 international units is equivalent to 1 USP unit, UK doses now appear to be 1000 times greater than those previously in use, or than those in use in the USA, and care is recommended in evaluating the literature.
In the UK the licensed dose as a single agent for squamous cell or testicular tumours is 15 000 international units (15 USP units) three times a week, or 30 000 international units twice a week, by intramuscular or intravenous injection, although in practice treatment of malignancy will generally be with combination regimens. This may be repeated, at usual intervals of 3 to 4 weeks, up to a total cumulative dose of 500 000 international units. The dose and total cumulative dose should be reduced in those over 60 years of age (see below). Doses should be adjusted according to tolerance, and may need to be adjusted as part of combination chemotherapy. Continuous intravenous infusion at a rate of 15 000 international units per 24 hours for up to 10 days or 30 000 international units per 24 hours for up to 5 days may also be used. In patients with lymphoma a dose of 15 000 international units once or twice weekly by intramuscular injection has been suggested, to a total dose of 225 000 international units. Again, dosage should be reduced in older patients and in combination regimens if necessary. In the treatment of malignant effusions a solution of 60 000 international units in 100 mL of sodium chloride 0.9% may be instilled into the affected serous cavity. Treatment may be repeated as necessary up to a total cumulative dose of 500 000 international units depending on the patient’s age. Local anaesthetics or analgesics are given con-comitantly
In the United States of America licensed doses for lymphomas as well as squamous cell and testicular neoplasms are 250 to 500 international units/kg (0.25 to 0.5 USP units/kg), or 10 000 to 20 000 international units/m (10 to 20 USP units/m), given once or twice weekly. In view of the risk of an anaphylactoid reaction it has been suggested that patients with lymphomas should receive two test doses of 2000 international units (2 USP units) or less initially (but see Administration, below). In patients with Hodgkin’s disease, once a 50% response has been achieved it may be maintained with 1000 international units (1 USP unit) of bleomycin daily, or 5000 international units (5 USP units) weekly. In the UK, licensed product information suggests that a total dose of 500 000 international units (500 USP units) should not be exceeded. Total cumulative dose should not exceed 300 000 international units in those aged 60 to 69 years, 200 000 international units in those 70 to 79, and 100 000 international units in those 80 and over; the weekly dose should be no more than 60 000, 30 000 and 15 000 international units respectively. In the USA the recommended maximum total dose is 400 000 international units (400 USP units); it is generally agreed that patients receiving 400 000 international units or more are at increased risk of pulmonary toxicity (see Adverse Effects, above).
Dosage should be reduced in patients with renal impairment (see below).
Bleomycin hydrochloride has also been given parenterally for malignant neoplasms, and bleomycin sulfate has been applied topically for the local treatment of skin tumours.
Administration. Although test doses have been suggested as a way of avoiding anaphylactoid reactions in patients with lymphoma being treated with bleomycin, a review of the literature concluded that the evidence did not support such a strategy, since the onset of the reaction was unpredictable, and not associated with any particular dose. It had also been suggested that reactions were less frequent with intramuscular rather than intravenous dosage, but evidence for this was conflicting. There is some suggestion that giving bleomycin by intravenous infusion rather than bolus injection in combination regimens may result in reduced pulmonary toxicity.
Administration in renal impairment. A significant portion of a dose of bleomycin is excreted largely unchanged in the urine, and dose reduction should be considered in patients with renal impairment. UK licensed product information suggests a 50% dose reduction when the serum creatinine concentration is between 20 and 40 micrograms/mL and further reduction for serum creatinine above this. US licensed product information gives the following proposed percentages of the initial dose, based on creatinine clearance (CC): • CC 5 to 10 mL/mmute: 40%
• CC 10 to 20 mL/mmute: 45%
• CC 20 to 30 mL/mmute: 55%
• CC 30 to 40 mL/mmute: 60%
• CC 40 to 50 mL/mmute: 70%
• CC 50 mL/mrnute and above: 100%)
Leucoplakia. Leucoplakia is used to describe a white patch or plaque in the mouth which cannot be otherwise characterised. Such lesions are of concern because they may be pre-malignant, and patients with evidence of dysplasia may be at higher risk of transformation (see also Malignant Neoplasms of the Head and Neck). Leucoplakia must be distinguished from other conditions such as candidiasis, lichen planus, and oral hairy leucoplakia which is associated with HIV infection. Leucoplakia is often associated with tobacco smoking, and smoking cessation can result in regression. Where active treatment is desirable, small and easily accessible lesions can be removed surgically or by laser therapy, although they may recur. For extensive patches or those in which surgery would be difficult, the treatments described include topical bleomycin 1 %, dissolved in dimethyl sulfoxide and applied for 5 minutes daily for 14 consecutive days. In a group of 19 patients with dysplastic leucoplakia, improvement in the appearance of lesions and histo-logical evidence of remission of the dysplasia occurred in the majority of patients. Sustained effects were also found on long-term follow-up for up to 10 years.
There have been reports of partial or complete remission of leu-coplakia in studies of vitamin A or betacarotene given orally long-term, but lesions have recurred when supplementation was stopped. Topical treatment with retinoids such as tretinoin or isotretinoin has also been tried, with similar results to those of oral vitamin A and retinoid treatments. A small open study has also suggested that topical calcipotriol may be effective. A systematic review of treatments for leucoplakia found that there were few controlled trials reported, and that although these treatments might be effective in the resolution of lesions, the rate of relapse was high, and there was no evidence that they prevent malignant transformation.
Malignant effusions. Bleomycin is used for the sclerotherapy of malignant pleural and pericardial effusions.
Malignant neoplasms. Bleomycin is used in regimens for the management of Hodgkin’s disease, non-Hodgkin’s lymphomas, including AIDS-related lymphomas, and for germ-cell tumours of the ovary and testis, as well as for some other malignancies including those ofthe head and neck, and Kaposi’s sarcoma.
Pneumothorax. In a patient with AIDS and pneumocystis pneumonia who developed pneumothorax, instillation of bleomycin into each pleural cavity was successful in resolving the pneumothorax after tetracycline sclerotherapy failed to do so.
Warts. A number of studies have examined the local use of bleomycin sulfate to treat severe or resistant warts ofthe common, plane, plantar, eponychial, and mosaic types, usually by intralesional injection. At the doses used, adverse effects, other than pain at the inj ection site, do not seem to be common; however, nail dystrophy and Raynaud’s phenomenon have been reported (see under Effects on the Nails and Effects on the Vascular System, under Adverse Effects, above). Bleomycin has also been applied as a pressure-sensitive adhesive tape, and various techniques for better intralesional use have been investigated.
British Pharmacopoeia 2008: Bleomycin Injection;
The United States Pharmacopeia 31, 2008: Bleomycin for Injection.
Argentina: Bileco; Bleocris; Blocamicina; Cytorich;
Australia: Blenamax; Blenoxane;
Brazil: Blenoxane; Bonar; Tecnomicina;
Chile: Blexit; Nikableomicina; Oncobleocin;
Czech Republic: Bleocin;
Germany: Bleo-cell; Bleomedac;
Hong Kong: Bleocin;
India: Bleochem; Bleocin; Bleocip;
Indonesia: Blenamax; Bleocin;
Japan: Bleo-S Bleocin;
Malaysia: Blenamax; Bleocin;
Mexico: Blanoxan; Bleolem;
New Zealand: Blenoxane;
Philippines: Blenoxane; Bloicin-S;
Portugal: Blio ;
South Africa: Blenoxane; Bleolem;
Thailand: Bleo-S; Bleocin; Bleolem;
Turkey: Bleocin; Bleolem;
United Kingdom (UK): Bleo;
United States of America (US and USA): Blenoxane