Sanbelat

Bleomycin.

Each vial contains: Bleomycin Sulfate equivalent to 15.00 U of Bleomycin.

Pharmacology: Pharmacodynamics: Bleomycin belongs to cytostatic antibiotics: It is a mixture of structurally related, alkaline, water-soluble, glycopeptide antibiotics with a cytostatic effect. The activity of Bleomycin is based on intercalation with single-helix and double-helix DNA, resulting in single-helix and double-helix breaks, which inhibit cell division, growth and DNA synthesis.
To a lesser extent bleomycin influences the RNA and protein synthesis. The main factor in the tissue selectivity of Bleomycin is the difference in intracellular inactivation. Cells at the G2 and M stage of the cell cycle are the most sensitive. Squamous cells, with their small percentage of bleomycin hydrolase, have an increased sensitivity to Bleomycin. In sensitive tissues, both normal and neoplastic, chromosomal disorders such as fragmentation, chromatid breaks and translocations will often be produced.
Contrary to the most other cytostatics, bleomycin is hardly toxic to the bone marrow, causes no immunosuppression and is not neurotoxic or cardiotoxic. In patients suffering from testicular tumours who were treated with bleomycin, a disorder of the coronary arteries has been described.
The above toxicity profile makes bleomycin suitable foradministration in combination with other cytostatics.
Pharmacokinetics: Bleomycin is administered parenterally.
After intravenous administration of 15 U/m² body surface via a bolus injection, maximum plasma concentrations are obtained of 1 to 10 x 10^-3 U per mL. After intramuscular injection of 15 U bleomycin, maximum plasma concentrations of 1 x 10^-3 U per mL are obtained after 30 minutes.
Continuous infusion of 30 U bleomycin daily for 4 to 5 days results in an average steady state plasma concentration of 100 to 300 x 10^-6 U per mL.
Distribution: Bleomycin is rapidly distributed over the body tissues, with the highest concentration in the skin, the lungs, the peritoneum and the lymph. Low concentrations are only found on the bone marrow. Bleomycin has not been detected in the cerebrospinal fluid after intravenous injection.
The distribution volume in humans (about 22 L) is larger than the volume of extracellular water.
In the plasma, bleomycin is bound to plasma proteins only to a small extent.
Biotransformation: The biotransformation is not entirely known.
Inactivation of bleomycin takes place by enzymatic decomposition by bleomycin hydrolase, particularly in plasma, liver and other organs, and to a lesser extent in skin and lungs.
Elimination: After intravenous administration of a bolus dose, bleomycin is rapidly cleared and two phases of elimination are apparent. A short initial phase (t_½α: 10-25 min.) is followed by a longer terminal phase (t_½β: 2-6 h). After continuous intravenous infusion, the elimination half life can increase to about 9 hours.
Approximately 2/3 of the quantity of bleomycin administered is excreted unchanged in the urine, probably by glomerular filtration. The greater part of the dose is excreted within 8-12 hours.
This indicates that the excretion rate is largely influenced by the renal function. Plasma concentrations are sharply increased if usual doses are given to patients with renal function disorders. Observations show that it is difficult to eliminate Bleomycin by dialysis.
Toxicology: Preclinical safety data: Animal tests have shown that bleomycin is teratogenic and carcinogenic (see Use in Pregnancy and Lactation under Precautions).

SANBELAT is usually applied in combination with other cytostatics and/or radiotherapy.
SANBELAT is intended for: Squamous cell carcinoma of head and neck area.
Hodgkin's disease and non-Hodgkin lymphoma.
Testis carcinoma.

Bleomycin is administered parenterally by intramuscular injection and intravenous injection/infusion in a dose of 5-15 U/m² once or twice a week. Application and dosage only with knowledge of the specialist literature. Dosage and intervals between injection vary dependin gon area and type of application, age and condition of the patient.
It is recommended to adjust the dose to the patient's body surface.
1. In squamous cell carcinomas: Intramuscular or intravenous injection of 10-15 U/m² once a week.
Intravenous infusion during 6-24 hours of 10-15 U/m² daily in 4 to 7 consecutive days every 3 to 4 weeks.
2. In Hodgkin's disease and non-Hodgkin lymphoma: Intramuscular or intravenous injection of 5-10 U/m² once a week.
Due to the risk of an anaphylactic reaction, the initial dose in lymphoma patients may be lower (2-3 U, for example).
If no acute reaction occurs, the normal dosage regimen can be applied.
3. In testis carcinomas: Intramuscular or intravenous injection of 10-15 U/m² once or twice a week.
Intravenous infusion during 6-24 hours of 10-15 U/m² daily in 5 to 6 consecutive days every 3 to 4 weeks.
The total dose of Bleomycin should not exceed 400 U (225 U/m² body surface), unless lung function examination justifies continuation of the administration. In elderly the dose is adjusted as follows: See table.


Click on icon to see table/diagram/image


Until more information is available, the administration of Bleomycin to children should only take place in special cases; adjustment of the dose preferably on the basis of the child's body surface.
In radiotherapy or if Bleomycin is used in combination therapies, increased toxicity can appear and the dose of bleomycin should be lowered.
Changes of the dose in impaired renal function as follows:
1. In serum creatinine of 177-354 micromol/L (2-4 mg%) the dose should be reduced by 50%.
2. In serum creatinine over 354 micromol/L (4 mg%) the dose should be reduced by more than 50%.
Intramuscular injection: The contents of the bottle of Bleomycin should be dissolved in 1-5 mL saline. Inject with the local anaesthetic, if necessary.
Repeated intramuscular injection at the same site may cause local reactions: it is therefore recommended to alter injection sites.
Intravenous injection: The contents of the bottle of Bleomycin should be dissolved in 5-10 mL saline and slowly injected during 5 -10 minutes.
Avoid a shorter injection time, as this will cause a high bleomycin concentration in the blood and will increase the risk of damage to the lungs when passing through.
Intravenous infusion: Bleomycin should be dissolved in 200-1000 mL saline.
The infusion can be administered as a short infusion for about 30 minutes or for a number of days.

Symptoms of an overdosage will rarely occur, in view of the mode of administration and precautions to be taken.
The acute reactions in case of an overdosage are hypotension, fever, rapid pulse and general symptoms of shock. The treatment is symptomatic with careful monitoring of pulmonary function and haematological parameters.
In respiratory complications the patient should be treated with corticosteroids and broad spectrum antibiotics. Usually the pulmonary reactions to an overdose (fibrosis) are not reversible unless they are identified early.

Prior hypersensitivity or idiosyncratic reaction to Bleomycin.
Obstructive or restrictive pulmonary disorders.
Ataxia telangiectasia.
Pregnancy and lactation.

Bleomycin should only be used under strict supervision of a physician who has specialized in the use of oncolytics, preferably in institution experienced in this kind of therapy.
In patients treated with Bleomycin, lung function examination as well as thorax X-rays should be performed on a regular basis, for the entire duration of the treatment up to 8 weeks after completion of the treatment. In the event of simultaneous radiotherapy of the thorax, the lungs should be X-rayed more often. Examination of pulmonary function, in particular measuring carbon monoxide diffusion and vital capacity, often allow early diagnosis of pulmonary toxicity.
If unaccountable coughing, dyspnoea, basal crepitations or a diffuse reticular image on the thorax X-ray is observed, each of these phenomena in itself is a motive to discontinue the administration of Bleomycin, until bleomycin toxicity as a possible cause has been ruled out. Administration of antibiotics and, if necessary, corticosteroid is advised. In the event of lung damage as a result of Bleomycin, no further Bleomycin should be administered.
Although the pulmonary toxicity of Bleomycin clearly increases in a cumulative dose of 400 U (225 U/m²), this can also occur in considerably lower doses, particularly in older patients (see Dosage and Administration), patients with a hepatic or renal insufficiency, pre-existent lung disease, previous radiation of the lungs and in patients on oxygen.
Bleomycin sensitivity increases in the elderly.
As 2/3 the administered quantity of Bleomycin is excreted unchanged in the urine, the excretion rate is greatly influenced by the renal function. Plasma concentrations are sharply increased if usual doses are given to patients with renal function disorders. Due to the potential teratogenicity and mutagenicity of Bleomycin with respect to male and female reproductive cells, adequate contraception measures should be taken care of until three months after the end of therapy for male as well as female patients.
Extravasation: Extravasation usually does not require specific precaution. In case of doubt (concentrated solution or sclerotic tissue), perfusion with saline should be administered.
The usual caution in the preparation and administration of cytostatics is called for (see Safe handling under Cautions for Usage).
Effects on ability to drive and use machines: No influence on the ability to drive by bleomycin is to be expected on the basis of the pharmacological activity.
Bleomycin may impair the ability to drive or operate machines due to nausea and vomiting.
Use in Pregnancy and lactation: Insufficient information is available about the use of this drug in human pregnancy assess any harmfulness. Bleomycin will pass the placenta. Animal tests have shown this medication to the harmful.
On the basis of the pharmacological activity, harmfulness is possible if used in pregnancy.
The use of Bleomycin in pregnancy should be avoided, particularly during the first trimester.
During the treatment with Bleomycin no breast-feeding should take place.

Use in Pregnancy and lactation: Insufficient information is available about the use of this drug in human pregnancy assess any harmfulness. Bleomycin will pass the placenta. Animal tests have shown this medication to the harmful.
On the basis of the pharmacological activity, harmfulness is possible if used in pregnancy.
The use of Bleomycin in pregnancy should be avoided, particularly during the first trimester.
During the treatment with Bleomycin no breast-feeding should take place.

As applies to most cytostatics, Bleomycin can have both an acute and a delayed toxic effect.
Acute symptoms may be: Anorexia, fatigue. Pain at the injection site or in the tumour region may occur, as well as arterial hypotension and venous occlusion in case of intravenous administration.
Lungs: The most severe side effect (in 2-10% patients) which may occur during or after the discontinuation of Bleomycin treatment is interstitial pneumonia. If not immediately identified and treated, this may lead to irreversible lung fibrosis. The risk of pulmonary toxicity increases with cumulative dose. Pulmonary toxicity may occur even in very low cumulative dosages in older patients, patients who underwent radiation therapy of the thorax or those who received oxygen.
Vascular changes occurs in the lung, which partly affect the elasticity of the vascular wall.
If unaccountable coughing, dyspnoea, basal crepitations or a diffuse reticular image on the thorax X-ray develops, each of these phenomena in itself is a reason to discontinue the administration of Bleomycin, until bleomycin toxicity as a cause has been ruled out. There is no specific therapy for Bleomycin-related lung toxicity. In some cases a favourable effect was described after treatment with corticosteroids.
Fever: Fever may occur 2 to 6 hours after the first injection (see also Hypersensitivity reactions as follows). If the fever persists, administration of antipyretics may be necessary. The incidence of the development of a fever decreases after subsequent injections.
Skin and mucous membrane: Skin and mucous membrane changes are the most common symptoms (up to 50 % of the patients). Skin problems usually occur in the area of the hands and feet. Thickening, hyperkeratosis, redness, swelling of the fingertips, discolouration of the nails, swelling of the skin in places subject to pressure such as elbows, loss of hair and stomatitis may occur. These side effects are rarely severe and will usually disappear after completion of the therapy. Also paraesthesia and hyperaesthesia of the fingers is possible, but reversible. Ulceration of the mucous membranes can exacerbate if Bleomycin is combined with radiation therapy or other drugs that are toxic to the mucous membranes.
Stomach/intestines: Gastrointestinal side effects such as nausea, vomiting, loss of appetite, weight loss and inflammation of the mucous membrane may occur, particularly in high dosages. Antiemetics may be useful.
Hypersensitivity reactions: Severe idiosyncratic reactions were observed in approximately 1% of the patients, predominantly lymphoma patients. These severe, partially delayed, anaphylactic reactions cause fever attacks and may be fatal. This reaction may occur immediately, or after a delayed period of several hours after the first or second dose.
Circulation: Hypotensive episodes have been described in patients with Hodgkin's disease who were treated with high initial dose. Damage to blood vessels (eg. cardiac infarction, coronary heart disease, circulatory disorders in the brain, inflammation of the cranial arteries, so-called haemolytic uraemic syndrome) rarely occurs.
Bone marrow: Bleomycin causes only a minor bone marrow suppresion. Slight thrombopenia may occur, which is quickly reversed when therapy is completed. This is a result of increased use of platelets and is not attributable to reduction of new thrombocyte formation.
Other adverse reactions: Pain in the muscles, limbs and at the site of injection.

An increased risk of pulmonary toxicity has been described in simultaneous administration of BCNU, mitomycin-C, cyclophosphamide and Methotrexate.
An increase in toxicity of Bleomycin can result from comedication with nephrotoxic substances such as cytostatics (eg. Cisplatin) due to delayed elimination.
There have been reports of a reduced effect of digoxin as a result of diminished oral bioavailibility and a reduction in phenytoin levels in the blood when combined with bleomycin.
Previous or current radiotherapy of the thorax is an important factor to increase the incidence and severity of pulmonary toxicity.
Patients treated with bleomycin are at larger risk of pulmonary toxicity if pure oxygen is administered during an operation. A reduction in the oxygen concentration during and after surgery is recommended.
In patients with a testis carcinoma who are treated with a combination of Bleomycin and vinca-alkaloids, a syndrome has been described which corresponds with Reynaud's disease: Ischemia of the peripheral parts of the body, which may lead to necrosis of these parts (fingers, toes and nose).

Safe handling: The usual caution is called for in preparing and administering cytostatics. For waste-disposal and safety information, guidelines on safe-handling of antineoplastic drugs should be followed. Preparation must be carried out by specially trained personnel. During preparation an aseptic wording technique should be used; protective measures should include the use of gloves, mask, safety goggles and protective clothing. Use of a laminar airflow (LAF) hood is recommended. Gloves should be worn during administration. Waste disposal procedures should take into account the cytotoxic nature of this substance. Direct contact with skin, eyes and mucous membranes should be avoided. If direct contact has taken place, immediately wash thoroughly with water. Soap may be used for skin cleaning.
Stability: After reconstitution, chemical and physical in-use stability has been demonstrated for 24 hours at 15-25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C or 12 hours at 15-25°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Store below 25°C, away from light.

Cytotoxic Chemotherapy

L01DC01 - bleomycin ; Belongs to the class of other cytotoxic antibiotics. Used in the treatment of cancer.

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