Bleocin

Bleocin

bleomycin

Manufacturer:

Nippon Kayaku

Distributor:

Four Star
/
Main Life
Full Prescribing Info
Contents
Bleomycin hydrochloride.
Description
Each vial contains Bleomycin hydrochloride 15 mg.
Physicochemistry: Nonproprietary name: bleomycin hydrochloride (JAN); bleomycin (INN).
Abbreviation: BLM.
Bleomycin hydrochloride occurs as a white to yellowish white powder. It is freely soluble in water and slightly soluble in ethanol (95). It has hygroscopic property.
Bleocin is a white to yellowish white lyophilized product for injection.

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pH: The pH value of a solution prepared by reconstituting the contents with water for injection at 5 mg (potency)/mL.
Osmotic pressure ratio: Ratio to physiological saline solution when the vial contents are reconstituted with 5 mL of physiological saline solution.
Action
Pharmacology: Pharmacodynamics: Antineoplastic activity: In vitro: In HeLaS3 cells, Ehrlich ascites liver carcinoma and Yoshida sarcoma cells, etc., inhibition of DNA and protein syntheses and growth inhibition of the cells were observed.
In vivo: Disappearance of spontaneous lympho-sarcoma in dogs was observed.
Mechanism of Action: The mechanism of action of bleomycin is the inhibitory effect on DNA synthesis and the DNA strand splitting.
Clinical Studies: Results of Domestic Clinical Studies: The response rates for each disease are summarized as follows: (See Table 2.)

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Results of Reevaluation (1989): Response rates by diseases are shown as follows. For skin cancer, the response rate is higher than the rate at the time of approval, since Bleocin has mainly been used concomitantly with other drugs. Evaluation of efficacy for thyroid cancer was performed in only 3 patients. For other diseases, the results of reassessment were almost the same as those at the time of approval. (See Table 3.)

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Pharmacokinetics: Pharmacokinetics and metabolism: Pharmacokinetics of Bleocin is characteristic and shows the main component, bleomycin A2, is highly distributed to the skin. Assays for the biological activity of bleomycin distributed to each tissue show that Bleocin is active form in the skin, lung, kidney, and bladder, while inactive form in other tissues including liver, spleen, etc. These findings demonstrate that Bleocin has effects particularly on skin cancer and head and neck cancer, without causing hematopoietic disorder.
When bleocin is administered intravenously at 15 mg (potency) in adults, the blood concentration reaches 3 μg/mL immediately after administration and < 0.5 μg/mL by 1 hour later. When Bleocin is administered intramuscularly, the blood concentration reaches a peak value by approximately one third of the value for intravenous administration, and then gradually decreases. The urinary excretion rate was 38.3% for intravenous administration and 19.2% for intramuscular administration up to 24 hours after administration. When surgery was performed 30-37 minutes after intravenous administration of Bleocin at 15 mg (potency) in 3 patients with penile cancer or penis carcinoma, the blood concentration was 0.69-0.94 μg/mL and intratumoral concentration was 0.08-0.49 μg/g. When surgery was performed 7 days after intravenous administration of Bleocin at a total dose of 300 mg (potency) in a patient with orchioncus, the concentration was 430 μg/g in the skin and 4 μg/g in the tumor. The urinary excretion rate of the unchanged drug was 68%. Systemic clearance was 1.1 mL/min/kg, distribution volume was 0.27 L/kg, and half-life in blood was 3.1 hours.
Blood concentration: The figure as follows shows the blood concentration when bleomycin is administered intravenously or intramuscularly at a dose of 15 mg (potency) in 4 cancer patients. (See Figure.)

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Indications/Uses
Skin cancer, head and neck cancer (maxillary cancer, tongue cancer, lip cancer, pharyngeal cancer, laryngeal cancer, mouth cancer, etc.), lung cancer (particularly, primary or metastatic squamous cell carcinoma), esophageal carcinoma, malignant lymphoma, uterine cervical cancer, neuroglioma, thyroid cancer.
Dosage/Direction for Use
Intravenous Injection: The usual adult dosage is 15-30 mg (potency) of bleomycin hydrochloride dissolved in a suitable injection solution of approximately 5-20 mL such as physiological saline solution or dextrose solution and administered slowly by the intravenous route. When severe fever is noted, Bleocin should be administered at 5 mg (potency) or lower per dose.
Intramuscular and Subcutaneous Injection: The usual adult dosage is 15-30 mg (potency) of bleomycin hydrochloride dissolved in suitable solution of approximately 5 mL such as physiological saline solution and administered intramuscularly or subcutaneously.
When Bleocin is administered subcutaneously around the affected area, the concentration of bleomycin hydrochloride should be 1 mg (potency)/1 mL or less.
Intraarterial Injection: The usual adult dosage is 5-15 mg (potency) of bleomycin hydrochloride dissolved in suitable injection solution such as physiological saline solution or dextrose solution and injected in a single dose or continuously.
Frequency of Injection: Bleocin is administered twice a week, as a rule. This dose frequency may be increased to once daily (every day) or decreased to once a week depending on symptoms.
Total Dose: The total administered dose of bleomycin hydrochloride should be 300 mg (potency) or less to achieve tumor clearance.
Precautions concerning Dosage and Administration: Even with a comparatively low dose of Bleocin, adverse reactions may occur because adverse reactions are highly variable among individuals. Careful attention should be paid to the Precautions.
When administered, Bleocin should be started at a low dose depending on the symptoms and conditions of the patient.
A total dose should not exceed 300 mg (potency). The fact should be kept in mind that administration via multiple routes may lead to increase in the total dose.
[Results at the time of reevaluation showed incidences of pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis were 6.5% for a total dose of ≤150 mg (potency), 10.2% for 151-300 mg (potency), and 18.8% for ≥301 mg (potency), indicating increased incidences along with increases in total dose.]
The total dose of bleomycin administered in patients receiving peplomycin should be expressed as the sum of the administered amount of peplomycin and bleomycin, as a rule.
Contraindications
(Bleocin is contraindicated in the following patients.)
(1) Patients with serious pulmonary function impairment or with chest X-ray finding suggesting diffuse fibrotic changes or any other remarkable changes. [Pulmonary function impairment, fibrotic lesions, etc. may be aggravated.]
(2) Patients with a history of hypersensitivity to the ingredient of Bleocin or a similar drug (peplomycin).
(3) Patients with serious renal function disorder. [Since excretion function may be deteriorated, serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis may occur.]
(4) Patients with serious heart disease. [Since cardio-vascular function may be deteriorated, serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis may occur.]
(5) Patients receiving radiation therapy to the chest and surrounding area. [See Interactions.]
Warnings
(1) Serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis may occur due to administration of Bleocin, with occasional fatal outcome. Therefore, Bleocin must be administered only to patients who are considered appropriate for treatment of Bleocin. In addition, patients should be monitored by a physician during treatment with Bleocin and for a certain period (approximately 2 months) after the completion of administration. Particularly, administration of Bleocin to the elderly of age of 60 or over or patients with underlying diseases in the lung should only be performed after full consideration of "Precautions". When early symptoms such as exertional dyspnea, fever, cough, crepitations (rales), abnormal chest radiographs, and abnormality of alveolar-arterial oxygen difference (A-aDO2), partial pressure of arterial oxygen (PaO2), or diffusing capacity for carbon monoxide (DLCO) are identified, Bleocin should be immediately discontinued and appropriate measures should be taken.
(2) Cancer combination chemotherapy including Bleocin should be performed only in patients who are considered appropriate for the therapy under the supervision of a physician with adequate experience in cancer chemotherapy at a medical facility fully equipped for emergency treatment. Furthermore, much attention should be paid to select appropriate patients by referring the package inserts of each combined drug.
Special Precautions
After dissolution, use as promptly as possible.
Careful Administration (The following patients should be carefully observed and Bleocin should be administered with care by reducing the dose, prolonging the dose interval, etc.): Patients with a history or complication of lung disorder: [Serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis may occur.]
Patients aged 60 years or older: [Serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis may occur.]
Patients with renal disorder: [Adverse reactions may occur strongly.]
Patients with heart disorder: [Adverse reactions may occur strongly.]
Patients who have received radiation therapy to the chest: [Serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis may occur.]
Patients with liver disorder: [Adverse reactions may occur strongly.]
Patients with chickenpox: [Fatal general system disorders may occur.]
Important Precautions: (1) Interstitial pneumonia or pulmonary fibrosis: The condition of the patient should be sufficiently monitored [Refer to text as follows], and careful attention should be paid to the onset of crepitations (rales), because crepitations (rales), because crepitations may offer an early sign of interstitial pneumonia or pulmonary fibrosis. If any abnormality is noted, administration of Bleocin should be immediately discontinued. In accordance with treatment and procedures for idiopathic pulmonary fibrosis, adrenal cortical hormones should be administered and appropriate antibiotics should be administered to prevent secondary infection.
The frequency of interstitial pneumonia or pulmonary fibrosis is high even with a total dose of ≤150 mg (potency) in patients with underlying pulmonary diseases and aged 60 years or older, thus great care is required.
Patients receiving Bleocin should be maintained under sufficient observation of clinical symptoms including fever, cough, exertional dyspnea, etc. and should also be followed up to detect any abnormality on chest radiogram and the crepitation (rale). Also, alveolar-arterial oxygen tension difference (A-aDO2), arterial oxygen tension (PaO2), carbon monoxide diffusing capacity (DLCO), etc. should be examined, where such examinations are available. These observations and examinations should be performed on a regular basis during treatment and until approximately 2 months after the completion of administration.
Examination for A-aDO2, PaO2, etc. should be performed once a week if possible, and if there is an increase in A-aDO2 or decrease in PaO2 during 2 consecutive weeks, administration of Bleocin should be discontinued. More specifically, if A-aDO2 and PaO2 worsen by ≥ 10 Torr compared with the values prior to Bleocin treatment, the condition of the patient should be carefully monitored along with other clinical symptoms. When an adverse reaction is suspected, Bleocin should be immediately discontinued and medications such as steroids should be commenced. Also, the measures should be taken in a small manner if DLCO decreases by ≥15% compared with that prior to Bleocin treatment.
If Bleocin has to be administered in a patient in whom decreased pulmonary function parameters are noted before treatment, the clinical course of the patient should be carefully monitored, and Bleocin should be immediately discontinued if any decrease in the parameters is noted.
(2) With long-term administration, adverse reactions may appear strongly and become prolonged, thus administration must be performed with care.
(3) When Bleocin is administered in patients receiving peplomycin or other bleomycin products, toxicity is thought to be additive, thus administration must be performed with care.
(4) Careful attention should be paid to the onset or exacerbation of infection and any bleeding tendency.
(5) If Bleocin has to be administered in pediatric patients or patients of reproductive age, effects on the gonads should be taken into account.
Precautions concerning Use: Intravenous administration: Since intravascular administration may cause vascular pain, due care should be paid to concentration and administration speed. Give intravenously as slowly as possible.
Intramuscular administration: To avoid affecting tissue, nerves, etc., the following points must be considered. 1) Intramuscular administration may cause induration at the injection site. Particularly, repeated injection at the same site should be avoided. Special care is required when Bleocin is administered in neonates, low birth weight babies, infants or children.
2) Pay due attention to avoid injecting at innervated sites.
3) If a patient complains of severe pain or back flow of blood into syringe is identified when a needle is inserted, the needle should be immediately pulled out and inserted into a different site.
Other Precautions: Myocardial infarction, cerebral infarction, etc. due to the concomitant use of Bleocin and other anti-cancer agents have been reported in overseas countries.
Bleocin has been reported to cause fibrosarcoma and renal carcinoma in laboratory animals (rats) administered subcutaneously.
Use during Pregnancy, Delivery or Lactation: The administration of Bleocin is not recommended for pregnant women or women who may possibly be pregnant. [Bleocin has been reported to have teratogenic effects in laboratory animals (mice and rats).]
Administration of Bleocin should be avoided in nursing mothers. If administration of Bleocin is unavoidable, instruct the patient to discontinue breast feeding.
[The safety of Bleocin in nursing mothers has not been established.]
Use in Children: particular care is required concerning the appearance of adverse reactions when administering this drug to children.
[The safety of this drug in children has not been established.]
Use in the Elderly: Since patients aged 60 years or older are more likely to experience interstitial pneumonia or pulmonary fibrosis, Bleocin should be administered with care.
[The incidence of serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis was 5.9% for patients aged <50 years, 8.1% for patients in their 50s, 10.9% for patients in their 60s, and 15.5% for patients ≥70 years, showing an increase with age.]
Use In Pregnancy & Lactation
Use during Pregnancy, Delivery or Lactation: The administration of Bleocin is not recommended for pregnant women or women who may possibly be pregnant. [Bleocin has been reported to have teratogenic effects in laboratory animals (mice and rats).]
Administration of Bleocin should be avoided in nursing mothers. If administration of Bleocin is unavoidable, instruct the patient to discontinue breast feeding.
[The safety of Bleocin in nursing mothers has not been established.]
Adverse Reactions
The frequently observed adverse reactions to Bleocin in total 1,613 patients (374 patients at the time of approval and 1,239 patients from post-marketing surveillance) were serious pulmonary manifestation such as interstitial pneumonia and pulmonary fibrosis (10.2%), dermal sclerosis and pigmentation (40.6%), fever and chills (39.8%), alopecia (29.5%), anorexia and weight decreased (28.7%), general malaise (16.0%), nausea and vomiting (14.6%), stomatitis (13.3%), nail changes (11.2%), etc.
Clinically significant adverse reactions: Interstitial pneumonia, pulmonary fibrosis (10%): Since serious interstitial pneumonia and pulmonary fibrosis may occur, sufficient observation is necessary, and if any abnormality is noted by examination for A-aDO2, PaO2, and DLCO or on chest radiography [see Important Precautions under Precautions], or if pulmonary manifestations including cough, exertional dyspnea or crepitation (rale) develops, administration of Bleocin should be immediately discontinued and administration of adrenal cortical hormones and treatment with appropriate antibiotics, etc. should be implemented.
Shock (<0.1%): Since treatment with Bleocin may cause shock, sufficient observation is necessary. In case of any abnormality, administration of Bleocin should be discontinued and appropriate measures should be taken. (Shock often develops in patients with malignant lymphoma at the first or second administration. Therefore, treatment with Bleocin should be started at the initial and second doses of ≤5 mg (potency). The dose is then increased to the normal dose after confirming that no acute reactions have been caused.)
Hemorrhage (2%): Careful attention should be paid, because a focus of the cancer may rapidly necrotize, resulting in bleeding.
Other adverse reactions: (See Table 4.)

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Drug Interactions

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Storage
Store at 2-8°C.
Expiration date: Three years.
ATC Classification
L01DC01 - bleomycin ; Belongs to the class of other cytotoxic antibiotics. Used in the treatment of cancer.
Presentation/Packing
Inj (amp) (white to yellowish white lyophilized product for injection) 15 mg x 1's.
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