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Chlormethine Hydrochloride

(British Approved Name Modified, rINNM)

Drug Nomenclature

INNs in main languages (French, Latin, Russian, and Spanish):

Chlormethine HydrochlorideSynonyms: Chlorethazine Hydrochloride; Clormetina, hidrocloruro de; HN2 (chlormethine); Mechlorethamine Hydrochloride; Mustine Hydrochloride; NSC-762; Nitrogen Mustard (chlormethine); WR-147650
BAN: Chlormethine Hydrochloride [BANM]
INN: Chlormethine Hydrochloride [rINNM (en)]
INN: Hidrocloruro de clormetina [rINNM (es)]
INN: Chlorméthine, Chlorhydrate de [rINNM (fr)]
INN: Chlormethini Hydrochloridum [rINNM (la)]
INN: Хлорметина Гидрохлорид [rINNM (ru)]
Chemical name: Bis(2-chloroethyl)methylamine hydrochloride; 2,2´-Dichloro-N-methyldiethylamine hydrochloride
Molecular formula: C5H11Cl2N,HCl =192.5
CAS: 51-75-2 (chlormethine); 55-86-7 (chlormethine hydrochloride)
ATC code: L01AA05
Read code: y02jy

Pharmacopoeias. In British, China, International, and US.

British Pharmacopoeia 2008 (Chlormethine Hydrochloride). A white or almost white, hygroscopic, vesicant, crystalline powder or mass. Very soluble in water. Store at a temperature of 8° to 15°.

The United States Pharmacopeia 31, 2008 (Mechlorethamine Hydrochlonde). A white, hygroscopic, crystalline powder. A 0.2% solution in water has a pH of 3.0 to 5.0. Store in airtight containers. Protect from light.

Stability

Solutions of chlormethine hydrochloride lose their activity very rapidly, particularly at neutral or alkaline pH. A study using an assay specific for chlormethine found that a 0.1% solution in Water for Injections or sodium chloride 0.9% inj ection underwent a loss of about 10% when stored for 6 hours at room temperature, and of about 4 to 6% when stored for the same period at 4°; similar results were obtained whether the solution was stored in glass vials or plastic syringes.

Solutions in 500 mL of sodium chloride or glucose 5% injection and stored in PVC infusion bags were still less stable, with 15% and 10% degradation respectively after 6 hours at room temperature. Chlormethine hydrochloride has been used in extemporaneous ointment preparations in the treatment of mycosis fungoides. One formulation of chlormethine hydrochloride, dissolved in acetone and worked into white soft paraffin, was reported to be stable for at least 84 days when stored at 4°, and for at least 40 days at 37°.

Adverse Effects, Treatment, and Precautions

For general discussions see Antineoplastics.

Chlorethazine HydrochlorideChlormethine hydrochloride is extremely toxic and its use is invariably accompanied by adverse effects. Severe nausea and vomiting may begin within an hour of inj ection of the drug and last for some hours; antiemetics should be given before treatment. It causes varying degrees of bone-marrow depression depending on the dose. In heavily pretreated patients, or when the total dose for a single course exceeds 400 micrograms/kg, there is a risk of severe and possibly fatal depression with anaemia, lymphocytopenia, granulocytopenia, and thrombocytopenia with consequent haemorrhage.

Depression of lymphocytes may be apparent within 24 hours of a dose and maximum suppression of granulocytes and platelets occurs within 7 to 21 days; haematological recovery may be adequate after 4 weeks.

Tinnitus, vertigo, deafness, headache, drowsiness, and other neurological symptoms have been reported, as have episodes of jaundice. Skin reactions to chlormethine hydrochloride include maculopapular rashes. Hypersensitivity is frequent when topical preparations are used.

Chlormethine hydrochloride has a powerful vesicant action on the skin and mucous membranes and great care must be taken to avoid contact with the eyes. Thrombophlebitis is a potential hazard of chlormethine particularly if it is not sufficiently diluted. Extravasation of the injection causes severe irritation and even sloughing. If extravasation occurs during injection, it has been suggested that the involved area should be infiltrated with an isotonic 4% solution of sodium thiosulfate, followed by the application of an ice compress intermittently for 6 to 12 hours, although the role of specific antidotes in antineoplastic extravasation is somewhat contentious.

Chlormethine hydrochloride may produce temporary or permanent inhibition of fertility. There is some evidence of mutagenicity, teratogenicity, and carcinogenicity.

Effects on the nervous system

Severe immediate neurotoxcity developed in 14 of 21 evaluable patients who underwent bone marrow transplantation after preparation with cytotoxic regimens including chlormethine 0.3 to 2 mg/kg. Symptoms developed a median of 4 days after treatment and included headache, hallucinations, confusion, convulsions, paraplegia, and tremor. Symptoms resolved in most, although in some they had not done so before their death.

Six of the patients who recovered from acute toxicity developed a delayedneurotoxicity, beginning a median of 169 days after the first chlormethine injection and characterised by symptoms including confusion, somnolence, personality change, dementia, focal motor seizures, and hydro-cephalus. Patients older than 21 years, those who had received CNS irradiation, and those treated concomitantly with other cytotoxic agents were at increased risk of neurotoxicity.

Handling and disposal

Chlormethine hydrochloride is a strong vesicant; avoid contact with skin and mucous membranes. The manufacturers state that unused injection solutions of chlormethine hydrochloride may be neutralised by mixing with an equal volume of a solution containing sodium thiosulfate 5% and sodium bicarbonate 5% and allowing to stand for 45 minutes. Equipment used in the preparation and administration of such solutions may be treated similarly. Alternatively a solution containing sodium carbonate 2.5% or sodium hydroxide in a mixture of industrial methylated spirit and water has been suggested for the decontamination of equipment.

Urine produced for up to 48 hours after a dose of chlormethine should be handled wearing protective clothing.

Pharmacokinetics

On intravenous injection, chlormethine is rapidly converted to a reactive ethyleneimmonium ion. It usually disappears from the blood in a few minutes. A very small proportion is excreted unchanged in the urine.

Uses and Administration

Chlormethine belongs to the group of antineoplastic drugs described as alkylating agents. It also possesses weak immunosuppressant properties.

Chlormethine hydrochloride has been used in the treatment of advanced Hodgkin’s disease, historically with a vinca alkaloid, procarbazine, and prednisone or prednisolone (the MOPP regimen). Chlormethine has also been tried in non-Hodgkin’s lymphomas, notably mycosis fungoides, and some other malignancies including chronic leukaemias, tumours of the breast, ovary, and lung, and in polycythaemia vera. Chlormethine has been used in the management of malignant effusions but is not the agent of choice.

In the MOPP regimen chlormethine hydrochloride has been given in doses of 6 mg/m However, when licensed for use as a single agent, the usual dose of chlormethine hydrochloride is 400 micrograms/kg, preferably as a single dose, although it may be divided into 2 or 4 equal doses on successive days. It is given by intravenous injection in a strength of 1 mg/mL in Water for Injections or sodium chloride 0.9%. Injection over 2 minutes into the tubing of a fast running intravenous infusion of sodium chloride 0.9% or glucose 5% may reduce the incidence of thrombophlebitis and the risk of extravasation. The response should be assessed by the trend of the blood counts. Treatment with chlormethine may be repeated when the bone-marrow function has recovered.

Intracavitary injections of 200 to 400 micrograms/kg have been given in the treatment of malignant, especially pleural, effusions. In mycosis fungoides with extensive skin involvement, very dilute solutions of chlormethine (e.g. 200 micrograms/mL) have been applied topically.

Histiocytic syndromes

Dilute solutions of chlormethine (200 micrograms/mL) have been applied topically for the cutaneous symptoms of Langerhans-cell histiocytosis. Such therapy was reported to effectively clear skin lesions in most patients, and be well tolerated. However, although no malignant skin disease developed during the follow-up of one group of children, the long-term effects of topical chlormethine are of concern in young patients.

Mycosis fungoides

Chlormethine is used topically in the management of mycosis fungoides. A retrospective cohort analysis of 203 patients treated with chlormethine found a partial response rate of 33% and a complete response rate of 50%. The median time to achieve complete response was 12 months and the time to relapse was also 12 months. Mild disease of limited skin involvement responded better than generalised patch/plaque disease, and more patients with mild disease obtained long-term remission.

Maintenance therapy was used in some patients, but on cessation the relapse rate was similar to patients who did not receive maintenance therapy. Treatment had usually been applied as either an aqueous solution or an ointment containing chlormethine 100 to 200 micrograms/mL.

Preparations

British Pharmacopoeia 2008: Chlormethine Injection;

The United States Pharmacopeia 31, 2008: Mechlorethamine Hydrochloride for Injection.

Proprietary Preparations

Canada: Mustargen;

France: Caryolysine;

Greece: Caryolysine;

Israel: Mustargen;

Switzerland: Mustargen;

United States of America (US and USA): Mustargen.

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