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mundipharma Oncology

EC Safety Data Sheet

in accordance with 91/155/EEC

Ribomustin®

Bendamustin

The hybrid alkylating agent

Trade name: Ribomustin® Active substance: Bendamustin hydrochloride

Date: 03.07.1998, Revised on: 01.03.2007

1.

1.1 1.2

Identification of the substance/preparation and of the company/undertaking:

Trade name Ribomustin® Particulars of the pharmaceutical company and manufacturer Pharmaceutical Company: Mundipharma GmbH Mundipharma Strasse 2 65549 Limburg (Lahn) Telephone: 0 64 31/701-0 Fax: 0 64 31/7 42 72 Information Line: 0800/8 55 11 1 Email: [email protected] Marketing Authorisation Holder: Astellas Pharma GmbH Manufacturer: Temmler Werke GmbH Weihenstephaner Strasse 28 81673 München 24-hour emergency hotline Giftinformationszentrum Nürnberg [Poisons Information Centre Nuremberg] Telephone: 09 11/3 98 24 51

2.

2.1

Composition/Information on ingredients

Chemical characterisation Description: Medicinal product ready for use Active substance: Bendamustin hydrochloride CAS No.: 3543-75-7 Chemical designation: 4-[1-methyl-5-bis(2-chloroethyl)amino-benzimidazolyl(2)] butanic acid hydrochloride Hazardous constituents: Not applicable Symbol(s): T Risk phrases: R23/24/25/39/48, R36, R45, R46, R47, R61

2.2 2.3 2.4

3.

3.1

Possible risks

Hazards identification For the finished medicinal product Ribomustin®: Cytostatic Classification system: Medicinal products subject to a licensing or registration procedure under the terms of the Medicines Act are excluded from the rules of the Chemicals Act.

3.2

Information: To meet customers' wishes, the risk phrases are nevertheless listed for the active substance bendamustin hydrochloride. 3.3 Description of hazard Carcinogenic according to EC Category Mutagenic according to EC Category Embryotoxic according to EC Category Toxic to reproduction according to EC Category 2 2 2 2

T Toxic Toxic by inhalation, if swallowed and in contact with skin. Irritating to eyes. Danger of very serious irreversible effects. May cause cancer. May cause heritable genetic damage. May cause birth defects. Danger of serious damage to health by prolonged exposure. May cause harm to the unborn child.

4.

First aid measures

Take off contaminated clothing. Those assisting should take measures for their own protection. After inhalation: Rest, fresh air. In case of breathing difficulties, seek medical advice. After contact with skin: Thoroughly wash any contamination from skin immediately with plenty of warm water and soap. Seek medical advice. After contact with eyes: Thoroughly flush eyes immediately and copiously (15 minutes) under running water with the lids held apart (protect unaffected eye, take out contact lenses), if necessary, use an eyewash solution. Seek ophthalmic advice. After swallowing: Rinse mouth immediately (only if victim is conscious) and drink plenty of water in small mouthfuls (to dilute the substance), induce vomiting. Do not leave victim unattended. Keep warm and in a quiet place. If unconscious, place the victim in a stable recovery position. Seek medical advice immediately (gastric lavage). Advice to doctors: Bendamustin hydrochloride is an alkylating substance of the nitrogen mustard type with structural similarity to melphalan and chlorambucil. There is no specific antidote. Bendamustin hydrochloride is used as the active substance in the medicinal product Ribomustin®. There is no extensive experience of the symptoms which Ribomustin® causes in case of overdose. In case of overdose, the following sideeffects in particular should be watched for: myelosuppression such as leucopenia, thrombocytopenia and anaemia, vomiting, nausea, diarrhoea, cardiac arrhythmias, skin changes, stomatitis, neuropathy, central nervous phenomena, rise in liver and kidney values, lung function disturbance, alopecia, signs of local irritation and thrombophlebitis. Bone marrow transplantation and transfusions (thrombocytes, blood) can be carried out or haematological growth factors may be administered as effective countermeasures to control haematological sideeffects. Further information may be found in the Summary of Product Characteristics and Instructions for Use of Ribomustin®. General advice:

5.

5.1

Fire-fighting measures

Suitable extinguishing media: Water, powder or foam. Acid fumes and corrosive decomposition products may be formed. Prevent the product from entering the drainage system. Extinguishing media which must not be used for safety reasons: Not known Fumes posing a hazard which may arise in the event of fire: Carbon monoxide Hydrogen chloride Nitric oxides (NOx) Special protective equipment: Emergency services must be equipped with self-contained breathing apparatus and light chemical protective suits. Respiratory protection and light chemical protective suits must be worn when carrying out disposal tasks.

5.2

5.3

5.4

6.

6.1

Accidental release measures

Personal precautions: Personal protective clothing must be worn. Unauthorised persons must be kept out of the area. Environmental precautions: Do not allow to enter drains / surface waters / ground water / soil. Methods for cleaning up/collection: Air: Suppress product dust or decomposition products using a finely dispersed water spray. Water: Prevent the product or contaminated extinguishing water from entering drains. Observe rules for the prevention of water pollution. Soil: Collect carefully and place in sealable containers. Dispose of as special waste. Wear respiratory protection to carry out disposal work.

6.2 6.3

7.

7.1

Handling and storage (applicable to the finished medicinal product Ribomustin®)

Handling Advice on safe handling The product should be handled only by trained personnel. Ensure adequate extraction/ventilation in the workplace. Use only tightly sealed installations, apparatus or containers. Strictly avoid generating dust and aerosols. Wear safety glasses and protective gloves. Use a particle filter in any breathing apparatus. Advice on fire and explosion prevention: None Dust explosion class: Not determined

7.2

Storage Requirements for storage rooms and containers S7 Store in a dry place at room temperature with protection from light in tightly sealed shockproof containers. Advice on combined storage S13 Keep away from food and drink. Storage class: 11 (flammable solids; VCI Concept)

8.

8.1

Exposure control and personal protection

Additional advice on the design of technical installations Suitable extractors, e.g. safety workbenches complying with Class I according to DIN 12980, must be used when preparing Ribomustin® presentations. Ensure suitable extraction / ventilation in the workplace. Prevent dust generation. Ingredients with workplace-related limits to be monitored None Personal protection Wear eye protection ­ wear protective gloves ­ wear respiratory protection ­ wear protective overalls Respiratory protection Filter Type P3S (EN 149) Physical and chemical properties Appearance Form: Active substance: microcrystalline powder; finished medicinal product Ribomustin®: lyophilisate Colour: white Odour: odourless Important safety parameters Changes of state (active substance) Melting temperature: pH of substance in solution at 20°C Further information Solubility in water at 20°C Density of the reconstituted solution at 20°C (25mg/10mL or 100mg/40 mL) Solubility in organic solvents:

8.2 8.3

9. 9.1

9.2

Value 152-156 3-4

Units °C

Method 2.5 g/L

9.3

12.5

g/L

0.998 g/mL very readily soluble in ethanol

10.

10.1 10.2 10.3

Stability and reactivity

(applicable to the active substance bendamustin hydrochloride) Thermal decomposition/conditions to be avoided At approx. 240°C. Dangerous reactions/materials to be avoided: None Hazardous decomposition products: Hydrogen chloride gas, vapours and fumes; formation of nitrose gases, carbon monoxide and carbon dioxide possible.

11.

Toxicological information

Acute toxicity: Active substance: Bendamustin hydrochloride Animal species Administration LD50 Rat i.v. 40 mg/kg BW* Mouse i.v.; i.p. 80 mg/kg BW *BW = bodyweight Embryotoxic, teratogenic and mutagenic effects occurred in animal experiments. The substance was unequivocally carcinogenic in animal experiments. Experience in humans: In case of overdose, the following side-effects should be watched for: With high dosages, general cell damage can occur to the bone marrow, the lymphatic system, the gonads, buccal, intestinal and bladder mucosa and to the skin and adnexa. Kidney and liver damage, immune system depression and neurotoxic damage may also occur.

12.

Ecological information

(applicable to the finished medicinal product Ribomustin®) Extracted air must be ducted and cleaned so that the substance does not enter the environment. The substance is a potential pollutant of water and must not be disposed of undiluted into the sewerage system.

13.

Disposal considerations

(applicable to the finished medicinal product Ribomustin®) Disposal after de-activation with dilute ammonia solution (10%). Take precautions for personal protection. Flush away with water. Alternatively: Dispose of without prior treatment in medicinal waste. (Waste Code 20 0118)

14.

Transport information

Advice: Finished medicinal products are not dangerous goods within the meaning of national and international transport regulations. Information pertaining to transport is therefore not applicable.

15.

15.1

Regulatory information

Labelling according to EC Directives Finished medicinal product: not subject to labelling regulations. The following information relates to the active substance bendamustin hydrochloride: Hazard identification: T Toxic Product contains: Risk phrases 23/24/25/39/48 36 45 46 47 61 Safety phrases 22 24/25 27 28

Toxic: Danger of very serious irreversible effects and danger of serious damage to health by prolonged exposure through inhalation, swallowing and contact with skin. Irritating to eyes. May cause cancer. May cause heritable genetic damage. May cause birth defects. May cause harm to the unborn child. Do not breathe dust. Avoid contact with skin and eyes. Take off immediately all contaminated clothing. After contact with skin, wash immediately with plenty of water.

36/37/39 45 53

Wear suitable protective clothing, protective gloves and eye/face protection. In case of accident or if you feel unwell, seek medical advice immediately. Avoid exposure ­ obtain special instructions before use.

Further information Store under lock and key with access granted only to technically competent persons or their deputies. Transport and store only in containers of up to 1 kg. 15.2 National regulations Advice on limiting hours of work: Restrictions under the law for the protection of expectant and nursing mothers and the law for the protection of youth employed, and under the hazardous substances ordinance, must be complied with. Women of childbearing age must be informed about the possible dangers to expectant mothers and about limitations on hours of work. Classification of the finished medicinal product according to the Flammable Liquids Ordinance [VbF]: Not applicable. Other regulations: Notice M620 of the Professional Association for Health and Welfare Comply with rules for the "Safe Handling of Cytostatics". Other information Please observe the Summary of Product Characteristics and Instructions for Use, and the Standard Information for Hospital Pharmacists, which will be sent on request.

16.

Note: This information describes exclusively the safety requirements relating to the product and is based on the latest knowledge and experience in our possession. It offers no guarantee of the properties and quality descriptions of the product described within the meaning of the statutory product liability regulations. The safety data sheet is intended to describe the product in respect of its handling and safety requirements. Unless otherwise stated, the information relates to the pharmaceutical active substance as a bulk substance (chemical).

Ribomustin®. Active substance: Bendamustin hydrochloride. Prescription-only medicine. Composition: Pharmaceutically active ingredient: 1 injection vial of 55/220 mg of powder for the preparation of an infusion solution contains 25/100 mg of bendamustin hydrochloride. Other ingredients: Mannitol. Indications: Primary therapy of advanced indolent non-Hodgkin lymphomas as part of a combined therapeutic regimen. Advanced multiple myeloma Stage II with progression or Stage III (in Salmon and Durie's classification) as part of a combined protocol with prednisone. Chronic lymphatic leukaemia. Contraindications: Known hypersensitivity to bendamustin hydrochloride and/or mannitol. Pregnancy, suspected pregnancy, lactation, severe liver parenchyma damage, jaundice, existing severe bone marrow depression and severe changes in blood picture, previous major surgical operations less than 30 days before starting therapy, infections, especially if associated with leucopenia (danger of generalisation of the infection). Particular caution required in cases of pre-existing heart diseases. Side-effects: Infections and parasitic diseases: Very common: infections. Rare: sepsis. Very rare: lung function disturbance. Diseases of the blood and of the lymphatic system: Very common: leucopenia (lymphocytopenia and granulocytopenia), decrease in haemoglobin, thrombocytopenia. Common: haemorrhage, anaemia. Very rare: haemolytic anaemia. The dose-limiting side-effect is usually reversible impairment of bone marrow function. In immunosuppressed patients the risk of infection (e.g. with herpes zoster) may be increased. Diseases of the immune system: Common: hypersensitivity reaction (such as allergic dermatitis, urticaria). Rare: anaphylactic reaction, anaphylactoid reaction. Very rare: anaphylactic shock. Metabolic and nutritional disturbance: Common: rise in GOT/GPT, rise in alkaline phosphatase, rise in bilirubin. Diseases of the nervous system: Rare: Drowsiness, aphonia. Very rare: dysgeusia, paraesthesia, peripheral neuropathy, anticholinergic syndrome, neurological disorder, ataxia, encephalitis, tumour lysis syndrome. Cardiac diseases: Common: cardiac dysfunction, arrhythmia, hypotension. Uncommon: Pericardial effusion. Very rare: tachycardia, myocardial infarct, cardiopulmonary failure. Vascular diseases: Rate: acute circulatory collapse. Very rare: phlebitis. Local irritation phenomena and thrombophlebitis have occurred uncommonly, especially after administration as an i.v. bolus injection. Necrosis following accidental perivascular administration has been reported very rarely. Diseases of the airways, of the thoracic cavity and mediastinum: Common: lung function disturbance. Very rare: pulmonary fibrosis, primary atypical pneumonia. Diseases of the gastrointestinal tract: Very common: nausea/vomiting. Common: diarrhoea, constipation. Very rare: ulcerative-haemorrhagic oesophagitis, gastrointestinal bleeding. Diseases of the skin and hypodermis: Very common: alopecia (WHO Grade I, II). Common: alopecia (WHO Grade III), skin changes. Rare: erythema, dermatitis, pruritus, maculopapular exanthema, hyperhidrosis. Diseases of the sexual organs and mammary gland: Common: amenorrhoea. Very rare: infertility. General diseases: Very common: inflammation of the mucosa. Common: fever, pain. Very rare: multiple organ failure. Note: Reactions may be impaired. Mundipharma GmbH, 65549 Limburg (Lahn). Date of Information: March 2007 Mundipharma GmbH Mundipharma Strasse 2 65549 Limburg/Lahn Tel: 06431/701 - 0 Internet: www.mundipharma.de

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