Adverse Drug Reaction Classification System

Pharmaceutical Information
Drug Name Levoleucovorin
Drug ID BADD_D01276
Description Levoleucovorin is the enantiomerically active form of Folinic Acid (also known as 5-formyl tetrahydrofolic acid or leucovorin). Commercially available leucovorin is composed of a 1:1 racemic mixture of the dextrorotary and levorotary isomers, while levoleucovorin contains only the pharmacologically active levo-isomer. In vitro, the levo-isomer has been shown to be rapidly converted to the biologically available methyl-tetrahydrofolate form while the dextro form is slowly excreted by the kidneys. Despite this difference in activity, the two commercially available forms have been shown to be pharmacokinetically identical and may be used interchangeably with limited differences in efficacy or side effects (Kovoor et al, 2009). As folate analogs, levoleucovorin and leucovorin are both used to counteract the toxic effects of folic acid antagonists, such as methotrexate, which act by inhibiting the enzyme dihydrofolate reductase (DHFR). They are indicated for use as rescue therapy following use of high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Levoleucovorin, as the product Fusilev (FDA), has an additional indication for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Folic acid is an essential B vitamin required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. However, in order to function in this role, it must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted when high-dose methotrexate is used for cancer therapy. As methotrexate functions as a DHFR inhibitor to prevent DNA synthesis in rapidly dividing cells, it also prevents the formation of DHF and THF. This results in a deficiency of coenzymes and a resultant buildup of toxic substances that are responsible for numerous adverse side effects of methotrexate therapy. As levoleucovorin and leucovorin are analogs of tetrahydrofolate (THF), they are able to bypass DHFR reduction and act as a cellular replacement for the co-factor THF, thereby preventing these toxic side effects.
Indications and Usage Levoleucovorin is indicated for use as rescue therapy following high-dose methotrexate in the treatment of osteosarcoma or for diminishing the toxicity associated with inadvertent overdosage of folic acid antagonists. Levoleucovorin, as the product Fusilev (FDA, dosed at one-half the usual dose of racemic d,l-leucovorin), has an additional indication for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer (although they should not be mixed in the same infusion as a precipitate may form).
Marketing Status approved; investigational
ATC Code Not Available
DrugBank ID DB11596
KEGG ID D04715
MeSH ID D058766
PubChem ID 135398559
TTD Drug ID D0Q6LA
NDC Product Code 72266-121; 70121-1099; 70121-1572; 72893-004; 72893-009; 0143-9558; 68083-278; 72266-120; 43598-771; 43598-773; 68083-279; 72893-006
UNII 990S25980Y
Synonyms Levoleucovorin | (6S)-leucovorin | 6-S-leucovorin | 6 S leucovorin | S-leucovorin | S leucovorin | levo-leucovorin | levo leucovorin | Leucovorin, (S)-Isomer | 6S-leucovorin | 6S leucovorin | Leucovorin, Monosodium Salt, (S)-Isomer | Leucovorin, Monopotassium Salt, (S)-Isomer | Fusilev | Leucovorin, Calcium (1:1) Salt, (S)-Isomer
Chemical Information
Molecular Formula C20H23N7O7
CAS Registry Number 68538-85-2
SMILES C1C(N(C2=C(N1)N=C(NC2=O)N)C=O)CNC3=CC=C(C=C3)C(=O)NC(CCC(=O)O)C(=O)O
Chemical Structure
ADRs Induced by Drug
*The priority for ADR severity classification is based on FAERS assessment, followed by the most severe level in CTCAE rating. If neither is available, it will be displayed as 'Not available'.
**The 'Not Available' level is hidden by default and can be restored by clicking on the legend twice..
ADR Term ADReCS ID ADR Frequency (FAERS) ADR Severity Grade (FAERS) ADR Severity Grade (CTCAE)
Decreased appetite08.01.09.028; 14.03.01.005--
Feeling of body temperature change08.01.09.012--Not Available
Ill-defined disorder08.01.03.049--Not Available
Disease progression08.01.03.038--
Renal impairment20.01.03.010--Not Available
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