Bleomycin

Bleomycin is a cytostatic antineoplastic of the antibiotic family, produced by a strain of Streptomyces verticillus (ATC L01DC01, cytotoxic antibiotics). The SmPC states that its mechanism of action is still not clearly elucidated; it acts essentially by causing single-strand breaks in double-stranded DNA.

Mechanism of Action

• DNA strand breaks: the main mode of action is cleavage of DNA. In laboratory studies this depends on oxygen and metal ions: bleomycin is believed to bind iron, forming a complex that reacts with oxygen to produce free radicals that cut the DNA.
• Synthesis inhibition: DNA synthesis is the process mainly inhibited; at high concentrations RNA and protein synthesis are suppressed as well (DrugBank).
• Cell cycle: most antibiotic-type antitumour drugs act in any phase of the cell cycle, whereas bleomycin has its main effects in the G2 and M phases (DrugBank).
• Marrow and immune effects: the SmPC notes that the medicine has little myelosuppressive or immunosuppressive effect.

Pharmacokinetics

• Distribution: bleomycin spreads rapidly into all tissues, where it is degraded more or less quickly depending on the tissue. The distribution half-life is about 25 minutes and the volume of distribution about 17.5 L/m². DrugBank gives plasma protein binding of about 1%.
• Intramuscular injection: the plasma peak is somewhat lower and occurs about 3 hours after the injection; the elimination parameters are the same as after intravenous administration.
• Elimination: the elimination half-life is about 4 hours. The kidneys eliminate most of the dose (renal clearance about 23 mL/min/m²), and 50–70% appears in the urine.
• Renal impairment: in patients with moderately severe renal failure, less than 20% of a dose was reported in the urine (DrugBank). The SmPC recommends reduced doses when creatinine clearance is below 50 mL/min.

Bleomycin is indicated for the following, which the SmPC lists without further qualification:

• Squamous cell carcinomas.
• Hodgkin and non-Hodgkin lymphomas.
• Testicular carcinomas.

The dose, route and schedule follow the protocol decided for the tumour concerned.

• Hypersensitivity to bleomycin (the active substance) or to any of the excipients.
• Severe respiratory failure.
• Pregnancy or breastfeeding.
• Combination with a live attenuated vaccine, during treatment and for at least six months after chemotherapy stops.
• Combination with brentuximab.

Pulmonary toxicity is the most important side effect of bleomycin. The SmPC lists most other reactions with a frequency that cannot be estimated from the available data.

Very common (≥1/10): pulmonary toxicity, including interstitial lung disease and pulmonary fibrosis (each also classed as common), which can be potentially fatal.

Common (≥1/100 to <1/10): hypersensitivity reactions (such as rashes); nausea; vomiting; mucositis.

Not known: potentially fatal anaphylaxis or anaphylactic shock, anaphylactoid and idiosyncratic reactions; mucocutaneous lesions that regress spontaneously when treatment stops, skin pigmentation (flagellate erythema), reversible hair loss (in 10–15% of cases), toxic skin rashes; scleroderma; amenorrhoea and azoospermia; arterial thromboembolic events (such as myocardial infarction and ischaemic stroke) and venous thromboembolic events (deep vein thrombosis, pulmonary embolism), sometimes fatal; Raynaud’s syndrome that can progress to necrosis; diarrhoea, paralytic ileus, gastrointestinal ulcers (duodenal, large bowel or rectal, gastric), dysphagia, anorexia, abdominal or epigastric pain, stomatitis; potentially fatal thrombotic microangiopathy (including haemolytic uraemic syndrome) and bone marrow toxicity; injection-site necrosis and fever reactions that antihistamines attenuate.

Pulmonary fibrosis is the most important reaction. It is cumulative and usually appears after a total dose of 300 mg or more, or earlier in patients at risk: those over 70 years, with previous lung radiotherapy, impaired kidney function, pre-existing lung disease, or exposure to a high oxygen concentration (for example during anaesthesia). The toxicity causes symptoms in 10% of cases and is fatal in 1%. It is less marked when bleomycin is given as a continuous intravenous infusion, and some combinations raise the risk (the M-BACOD protocol, in which vincristine seems to increase the toxicity). Regular clinical and lung-function monitoring is needed, since fibrosis can exceptionally occur at low cumulative doses.

Bleomycin shares the interactions that the SmPC lists for cytotoxic medicines in general, and has some of its own.

• Live attenuated vaccines (contraindicated): risk of fatal generalised vaccine disease, during treatment and for at least six months after chemotherapy stops.
• Brentuximab (contraindicated): increased pulmonary toxicity.
• Phenytoin and fosphenytoin (not recommended): the cytotoxic can reduce the absorption of phenytoin and so risk convulsions, or phenytoin can speed up the hepatic metabolism of the cytotoxic, increasing its toxicity or reducing its effect.
• Olaparib: with other antitumour agents such as bleomycin it may increase the risk of myelosuppression; use with precaution.
• Vincristine: strengthens the activity of bleomycin.
• Other antitumour agents and oxygen: cisplatin, cyclophosphamide, carmustine, gemcitabine and taxanes, and/or the administration of oxygen, are important factors that can increase the incidence and severity of pulmonary toxicity such as interstitial pneumonia or pulmonary fibrosis.
• Flucytosine: increased risk of haematological toxicity.
• Vitamin K antagonists: the thrombotic and haemorrhagic risk is higher in tumour disease and an interaction with chemotherapy is possible; check the INR more often.
• Immunosuppressants (such as ciclosporin, everolimus, tacrolimus, temsirolimus, sirolimus): excessive immunosuppression with a risk of lymphoproliferative syndrome; to be taken into account.
• Nephrotoxic agents such as cisplatin: impair the elimination of bleomycin.

Bleomycin is a cytotoxic medicine given by parenteral injection or infusion in hospital, following the protocol decided for the tumour concerned. 15 mg of bleomycin activity corresponds to 15,000 international units (IU). The SmPC gives separate instructions for preparing the solution for intravenous use.

Recommended Dose

• Usual dose: generally 10–20 mg/m² once or twice a week, by direct intravenous injection or continuous intravenous infusion, or by intramuscular or even subcutaneous injection.
• Cumulative limit: up to a total cumulative dose of 300 mg, which it is advisable not to exceed.
• Adaptation: the dose, route and frequency of injections may be changed according to the protocol decided for the tumour. Pulmonary toxicity is lower with continuous infusion.

Renal Impairment

Data are limited. In patients with a creatinine clearance below 50 mL/min the SmPC recommends reducing the dose to the following percentage of the usual dose:

• 50 mL/min or more: 100%
• 40 to 50 mL/min: 70%
• 30 to 40 mL/min: 60%
• 20 to 30 mL/min: 55%
• 10 to 20 mL/min: 45%
• 5 to 10 mL/min: 40%

Other Special Populations

• Elderly: no separate dose is given, but patients over 70 years have a higher risk of fatal pulmonary toxicity (see Special Instructions).
• Hepatic impairment and children: the SmPC sections reviewed give no specific recommendation; refer to the full SmPC.

Pulmonary Toxicity

Pulmonary toxicity is the dose-limiting toxicity of bleomycin and is dose-dependent. The SmPC gives these warnings:

• Use with caution in patients with a lung infection or pre-existing impaired lung function, and in patients who have had radiotherapy, particularly to the chest.
• The risk of fatal pulmonary toxicity is increased in elderly patients (over 70 years), in patients with renal impairment, and in those receiving doses higher than recommended, concomitant or previous lung irradiation, concomitant oxygen, or concomitant chemotherapy.
• Close monitoring of lung function is required. If pulmonary complications occur (dyspnoea, shortness of breath, dry cough), bleomycin must be interrupted and appropriate treatment given.
• The state of the lung tissue should be checked regularly to detect any risk of fibrosis. Prevention needs regular clinical and respiratory-function monitoring, and fibrosis can exceptionally occur at low cumulative doses.
• If anaesthesia needs ventilatory support, avoid ventilation with pure oxygen, which increases the risk of pulmonary toxicity (fibrosis in particular).

Thromboembolic Events

Arterial thromboembolic events (such as myocardial infarction and ischaemic stroke) and venous events (such as deep vein thrombosis and pulmonary embolism), sometimes fatal, have been reported, generally when bleomycin was combined with other anticancer drugs. Patients should contact their doctor immediately if they notice symptoms.

Blood Disorders, Allergy and Gastrointestinal Toxicity

• Acute myeloid leukaemia and myelodysplastic syndrome have been reported in patients given bleomycin with other anticancer agents.
• In thrombotic microangiopathy (including haemolytic uraemic syndrome), stop bleomycin immediately and start treatment promptly.
• In serious allergic, anaphylactoid or idiosyncratic reactions, stop bleomycin immediately, as they can be fatal.
• Gastrointestinal symptoms can be early signs of serious gastrointestinal toxicity.

Renal Impairment

Use with caution when creatinine clearance is below 50 mL/min. Monitor renal function closely and adjust the dose if appropriate.

Live Vaccines

Live attenuated vaccines are contraindicated during treatment with bleomycin. They should be given at least 4 weeks before immunosuppressive therapy, and vaccination after bleomycin must not begin until at least 6 months after the immunosuppressive therapy has stopped.

Pregnancy, Breastfeeding and Fertility

• Contraception: because bleomycin is genotoxic, women of childbearing potential must use effective contraception and avoid pregnancy during treatment and for 6 months after it stops. Men must use effective contraception and not father a child during treatment and for 3 months after it stops.
• Pregnancy: contraindicated. There are no meaningful data in pregnant women, and animal studies show reproductive toxicity.
• Breastfeeding: contraindicated. Passage into breast milk is unknown and a risk to the infant cannot be excluded.
• Fertility: data are limited, and cases of azoospermia have been reported in men. Patients of either sex who intend to have a child should seek advice on sperm preservation and/or genetic counselling before treatment.

Excipients

No excipients are listed in the SmPC (section 6.1: not applicable).

Effect on Driving

Some side effects may indirectly affect the ability to drive or use machines.

Store the powder at 2–8 °C before reconstitution. After reconstitution the solution can be kept for 24 hours at 2–8 °C. As a refrigerated product, it must stay in the cold chain during transport and storage. The vials are colourless type I glass (6 mL or 10 mL) with a grey butyl stopper and an aluminium cap with a polypropylene overseal, in boxes of 1 or 10 vials.

3 years before reconstitution. After reconstitution: 24 hours at 2–8 °C.

Prescription only (Rx). Bleomycin is a cytotoxic injection given in hospital within a treatment protocol, so it is supplied to the hospital or clinic that administers it. It must be kept at 2–8 °C, so it travels under cold-chain conditions.