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Daunorubicin Hydrochloride

(British Approved Name Modified, US Adopted Name, rINNM)

Drug Nomenclature

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

Daunorubicin HydrochlorideSynonyms: Cloridrato de Daunorrubicina; Daunomycin Hydrochloride; Daunorubicin hydrochlorid; Daunorubicin-hidroklorid; Daunorubicina, hidrocloruro de; Daunorubicinhydroklorid; Daunorubicini Hydrochloridum; Daunorubicino hidrochloridas; Daunorubisiinihydrokloridi; FI-6339 (daunorubicin); NDC-0082-4155; NSC-82151; RP-13057 (daunorubicin); Rubidomycin Hydrochloride
BAN: Daunorubicin Hydrochloride [BANM]
USAN: Daunorubicin Hydrochloride
INN: Daunorubicin Hydrochloride [rINNM (en)]
INN: Hidrocloruro de daunorubicina [rINNM (es)]
INN: Daunorubicine, Chlorhydrate de [rINNM (fr)]
INN: Daunorubicini Hydrochloridum [rINNM (la)]
INN: Даунорубицина Гидрохлорид [rINNM (ru)]
Chemical name: (1S,3S)-3-Acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxonaphthacen-1-yl 3-amino-2,3,6-trideoxy-αl-lyxo-pyranoside hydrochloride; (8Scis)-8-Acetyl-10-[(3-amino-2,3,6-trideoxy-αl-lyxo-hexopyranosyl)]oxy-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride
Molecular formula: C27H29NO10,HCl =564.0
CAS: 20830-81-3 (daunorubicin); 23541-50-6 (daunorubicin hydrochloride)
ATC code: L01DB02

Note. Daunorubicin citrate is used in the preparation of liposomal preparations (see Uses and Administration, below).

Pharmacopoeias. In China, Europe, Japan, and US. European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Daunorubicin Hydrochloride). The hydrochloride of a substance produced by certain strains of Streptomyces coeruleorubidus or S. peucetius or obtained by any other means. It is manufactured by methods designed to minimise or eliminate the presence of histamine. An orange-red, hygroscopic, crystalline powder. It contains between 95 and 102% of the hydrochloride (anhydrous and solvent-free basis). Freely soluble in water and in methyl alcohol; slightly soluble in alcohol; practically insoluble in acetone. A 0.5% solution in water has a pH of 4.5 to 6.5. Store in airtight containers. Protect from light.

The United States Pharmacopeia 31, 2008 (Daunorubicin Hydrochloride). An orange-red, hygroscopic, crystalline powder. It has a potency equivalent to not less than 842 and not more than 1030 micrograms of the base per mg. Freely soluble in water and in methyl alcohol; slightly soluble in alcohol; practically insoluble in acetone; very slightly soluble in chloroform. A 0.5% solution in water has a pH of 4.5 to 6.5. Store at a temperature not exceeding 40° in airtight containers. Protect from light.

Incompatibility. Daunorubicin is incompatible with heparin sodium, and has also been reported to be incompatible with a solution of dexamethasone sodium phosphate.

Stability. In a study of the stability of anthracycline antineoplastic agents in 4 infusion fluids (glucose 5%, sodium chloride 0.9%, lactated Ringer’s injection, and a commercial infusion fluid) daunorubicin hydrochloride was stable in all 4, the percentage remaining after 24 hours being 98.5%, 97.4%, 94.7%, and 95.4% respectively. Stability appeared to be partly related to pH; daunorubicin was more stable as the pH of the mixture became more acidic, with the best stability in glucose 5% with a pH of 4.5. Although daunorubicin solutions are degraded by light, the effect is reported not to be significant at concentrations of 500 micrograms/mL or above; however, below this concentration precautions should be taken to protect solutions from light, and storage should be in polyethylene or polypropylene containers to minimise adsorptive losses. It has been suggested that formulation with the food colouring Scarlet GN, which absorbs light over the same spectral region as daunorubicin, would stabilise daunorubicin solutions to light.

Liposomal daunorubicin should be diluted with glucose 5% solution as aggregation of the liposomes may result with sodium chloride. In addition, licensed product information advises that liposomal daunorubicin should not be mixed with substances containing benzyl alcohol or other detergent-like molecules, which can lead to premature rupture of the liposomes.

Adverse Effects, Treatment, and Precautions

As for Doxorubicin.

Cardiotoxicity is more likely when the total cumulative dose of daunorubicin exceeds 550 to 600 mg/m in adults, 300 mg/m in children, or in children aged under 2 years, 10 mg/kg. The cumulative dose should be limited to 400 mg/m in patients who have had previous radiation therapy to the mediastinum. Product information for liposomal daunorubicin recommends determining ventricular ejection fraction after cumulative doses of 320 mg/m, and every 160 mg/m thereafter. Daunorubicin should be used in reduced doses in hepatic and renal impairment.

Liposomal formulations of daunorubicin may be associated with a reduced potential for local tissue necrosis although current clinical experience is limited and such toxicity remains a possibility. An acute syndrome of back pain, flushing, and chest tightness may occur during infusion, but generally resolves on slowing or temporarily stopping the infusion.

Effects on the heart. For a discussion of the cardiotoxicity of anthracyc lines, and its management, see Effects on the Heart, under Doxorubicin.

Effects on the skin and nails. For reports of hyperpigmentation in patients given daunorubicin, see under Doxorubicin.

Handling and disposal. Daunorubicin hydrochloride is irritant; avoid contact with skin and mucous membranes. For a method for the destruction of daunorubicin in wastes see under Doxorubicin.

Interactions

As for Doxorubicin.

Antineoplasties. Hepatic dysfunction was reported in 13 patients given daunorubicin 180 to 450 mg/m. Ten of them had also received tioguanine or cytarabine, or a combination of these. The authors also noted that other studies had suggested that the related drug doxorubicin might enhance the hepatotoxicity of mercaptopurine, and thought that a similar interaction could occur between daunorubicin and tioguanine.

Pharmacokinetics

After intravenous injection, daunorubicin is rapidly distributed into body tissues, particularly the liver, lungs, kidneys, spleen, and heart with an initial distribution half-life of about 45 minutes. It is rapidly metabolised in the liver, and is excreted in bile and urine as unchanged drug and metabolites. The major metabolite, daunorubicinol, has antineoplastic activity. Up to 25% of a dose is excreted in urine in an active form over several days (the terminal plasma elimination half-lives of daunorubicin and its major metabolite are reported to be 18.5 and 26.7 hours respectively); an estimated 40% is excreted in bile. Daunorubicin does not appear to cross the blood-brain barrier, but crosses the placenta.

The pharmacokinetics of liposomal doxorubicin are significantly different from those of the conventional drug formulation, with a decreased uptake by normal tissues (although tumour neovasculature is reported to have increased permeability to the liposomes), and a terminal half-life of 4 to 5 hours.

Uses and Administration

Daunorubicin is an antineoplastic anthracycline antibiotic with actions similar to those of doxorubicin, to which it is closely related. It is used with other antineoplastics to induce remissions in acute leukaemias. Daunorubicin is given in combination regimens for acute lymphoblastic leukaemia and acute myeloid leukaemias. It has also been tried in some other malignancies. A liposomal formulation of daunorubicin has been developed for use in the management of Kaposi’s sarcoma in patients with AIDS.

Daunorubicin is usually given as the hydrochloride, but doses are expressed in terms of the base. Daunorubicin hydrochloride 21.4 mg is equivalent to about 20 mg daunorubicin.

In combination treatment regimens for adult acute leukaemia, the usual dose is 30 to 45 mg/m daily on days 1 to 3 of the first course, and days 1 and 2 of subsequent courses. Daunorubicin is given as a solution in sodium chloride 0.9% into a fast-running infusion of sodium chloride or glucose. Courses may be repeated after 3 to 6 weeks. A dose of 25 mg/m has been given intravenously once a week, in combination regimens, to children with acute lymphoblastic leukaemia. For children less than 2 years of age, or less than 0.5 m, a dose of 1 mg/kg has been used instead.

The total cumulative dose in adults should not exceed 550 to 600 mg/m; in patients who have received radiotherapy to the chest it may be advisable to limit the total dose to about 400 mg/m. Lower limits apply in children: a total cumulative dose of no more than 300 mg/m, or in children aged under 2 years 10 mg/kg, is recommended. Dosage should be reduced in patients with impaired hepatic or renal function (see below), and elderly patients with inadequate bone marrow reserves.

In the treatment of Kaposi’s sarcoma, liposomal daunorubicin is given intravenously every 2 weeks starting with a dose of 40 mg/m, and continued for as long as disease control can be maintained. It is diluted with glucose 5% (sodium chloride 0.9% should not be used) to a concentration between 0.2 and 1 mg/mL, and given over 30 to 60 minutes.

Blood counts should be determined frequently during treatment as daunorubicin has a potent effect on bone-marrow function (see also Bone-marrow Depression). Cardiac function should be monitored at regular intervals to detect signs of cardiotoxicity.

Administration in hepatic impairment. Doses of daunorubicin should be reduced in hepatic impairment. Some licensed product information recommends that patients with serum-bilirubin concentrations of 12 to 30 micrograms/mL should receive 75% of the usual dose, and those with concentrations greater than 30 micrograms/mL should be given 50% of the usual dose.

Administration in renal impairment. Doses of daunorubicin should be reduced in renal impairment. Some licensed product information recommends that patients with serum-creatinine concentrations of 105 to 265 micromoles/litre should receive 75% of the usual dose, and those with concentrations greater than 265 micromoles/litre should be given 50% of the usual dose.

Preparations

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

Proprietary Preparations

Argentina: Daunoblastina; Maxidauno;

Australia: DaunoXome;

Austria; Daunoblastin; DaunoXome;

Belgium: Cerubidine;

Brazil: Daunoblastina; Daunocin ; DaunoXome ;

Canada: Cerubidine;

Chile: Cerubidine; Daurocina; Onco-daunotec;

Czech Republic: Cerubidine ;

Denmark: Cerubidin; DaunoXome;

Finland: DaunoXome;

France: Cerubidine; DaunoXome;

Germany; Daunoblastin; DaunoXome;

Greece: Cerubidine; DaunoXome;

Hong Kong; Daunoblastina ;

Hungary: Daunoblastina;

India: Daunotec; Norubin;

Ireland: Cerubidin; DaunoXome;

Israel: Cerubidine;

Italy: Daunoblastina; DaunoXome;

Mexico: Rubilem;

The Netherlands: Cerubidine; DaunoXome;

Norway: Cerubidin;

Portugal: Daunoblastina ; DaunoXome;

Russia: DaunoXome;

South Africa: Cerubidin ; Daunoblastin;

Singapore: Daunoblastina;

Spain: Daunoblastina; DaunoXome ;

Sweden: Cerubidin ; DaunoXome;

Switzerland: Cerubidine; DaunoXome ;

United Kingdom (UK): DaunoXome;

United States of America (US and USA): Cerubidine; DaunoXome;

Venezuela: Daunoblastina.

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