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Clinical data | |
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Trade names | Ergamisol |
AHFS/Drugs.com | Micromedex Detailed Consumer Information |
MedlinePlus | a697011 |
Routes of administration | By mouth |
ATC code | |
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Pharmacokinetic data | |
Metabolism | Liver |
Elimination half-life | 3–4 hours |
Excretion | Urine (70%) |
Identifiers | |
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CAS Number |
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PubChemCID | |
IUPHAR/BPS | |
DrugBank | |
ChemSpider |
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UNII | |
KEGG |
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ChEBI | |
ChEMBL |
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CompTox Dashboard(EPA) | |
ECHA InfoCard | |
Chemical and physical data | |
Formula | C11H12N2S |
Molar mass | 204.292 g/mol g·mol−1 |
3D model (JSmol) | |
Density | 1.31 g/cm3 |
Melting point | 60 °C (140 °F) |
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(what is this?)(verify) |
• Levamisole is a bulking agent for crack. The process of making crack involves 'washing' cocaine and filtering out impurities and cutting agents. Levamisole slips through this process, meaning you can produce more volume of crack with less pure cocaine.
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Levamisole, sold under the trade name Ergamisol among others, is a medication used to treat parasitic worm infections.[1] Specifically it is used for ascariasis and hookworm infections.[2] It is taken by mouth.[2]
Side effects may include abdominal pain, vomiting, headache, and dizziness.[2] Use is not recommended during breastfeeding or the third trimester of pregnancy.[2] Serious side effects may include an increased risk of infection.[3] It belongs to the antihelmintic class of medications.[3]
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Levamisole was discovered in 1966.[4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] The wholesale cost in the developing world is about US$0.18 to US$0.33 for a course of treatment.[6] It is not commercially available in the United States.[3] Levamisole is also used as a dewormer for livestock.[7]
- 1Medical uses
Medical uses[edit]
Worms[edit]
Levamisole was originally used as an anthelmintic to treat worm infestations in both humans and animals. Levamisole works as a nicotinic acetylcholine receptoragonist that causes continued stimulation of the parasitic worm muscles, leading to paralysis. In countries that still permit the use of levamisole, the recommended dose for anthelmintic therapy is a single dose, with a repeated dose 7 days later if needed for a severe hookworm infection.[8] Most current commercial preparations are intended for veterinary use as a dewormer in cattle, pigs, and sheep. However, levamisole has also recently gained prominence among aquarists as an effective treatment for Camallanusroundworm infestations in freshwatertropical fish.[9]
Cancer[edit]
After being pulled from the market in the U.S. and Canada in 1999 and 2003, respectively, levamisole has been tested in combination with fluorouracil to treat colon cancer. Evidence from clinical trials support its addition to fluorouracil therapy to benefit patients with colon cancer. https://simpmusmari.tistory.com/7. In some of the leukemic cell line studies, both levamisole and tetramisole showed similar effect.[10]
Other[edit]
Levamisole has been used to treat a variety of dermatologic conditions, including skin infections, leprosy, warts, lichen planus, and aphthous ulcers.[11]
An interesting adverse side effect these reviewers reported in passing was 'neurologic excitement'. Later papers, from the Janssen group and others, indicate levamisole and its enantiomer, dexamisole, have some mood-elevating or antidepressant properties, although this was never a marketed use of the drug.[12][13]
Adverse effects[edit]
One of the more serious side effects of levamisole is agranulocytosis, or the depletion of the white blood cells. In particular, neutrophils appear to be affected the most. This occurs in 0.08–5% of the studied populations.[14] There have also been reports of levamisole induced necrosis syndrome in which erythematous painful papules can appear almost anywhere on skin.
It has been used as an adulterant in cocaine resulting in serious side effects.[15][16][17]
Metabolism[edit]
Levamisole is readily absorbed from the gastrointestinal tract and metabolized in the liver. Its time to peak plasma concentration is 1.5–2 hours. The plasma elimination half-life is fairly quick at 3–4 hours which can contribute to not detecting Levamisole intoxication. The metabolite half-life is 16 hours. Levamisole's excretion is primarily through the kidneys, with about 70% being excreted over 3 days. Only about 5% is excreted as unchanged levamisole.[18][19]
Drug testing of racehorse urine has led to the revelation that among levamisole equine metabolites are both pemoline and aminorex, stimulants that are forbidden by racing authorities.[20][21][22] Further testing confirmed aminorex in human and canine urine, meaning that both humans and dogs also metabolize levamisole into aminorex.,[23] though it is unclear whether plasma aminorex is present at any appreciable level. Blood samples following oral administration of levamisole out to 172 hr post-dose did not demonstrate any plasma aminorex levels above that of the limit of quantification (LoQ). Additionally, in cocaine-positive plasma samples, of which 42% contained levamisole, aminorex was never reported at concentrations higher than LoQ.[24]
Detection in body fluids[edit]
Levamisole may be quantified in blood, plasma, or urine as a diagnostic tool in clinical poisoning situations or to aid in the medicolegal investigation of suspicious deaths involving adulterated street drugs. About 3% of an oral dose is eliminated unchanged in the 24-hour urine of humans. A post mortem blood levamisole concentration of 2.2 mg/L was present in a woman who died of a cocaine overdose.[25][26]
Illicit use[edit]
Levamisole has increasingly been used as a cutting agent in cocaine sold around the globe with the highest incidence being in the USA. In 2008–2009, levamisole was found in 69% of cocaine samples seized by the Drug Enforcement Administration (DEA).[15] By April 2011, the DEA reported the adulterant was found in 82% of seizures.[27]
Levamisole adds bulk and weight to powdered cocaine (whereas other adulterants produce smaller 'rocks' of cocaine) and makes the drug appear purer.[28] In a series of investigative articles for The Stranger, Brendan Kiley details other rationales for levamisole's rise as an adulterant: possible stimulant effects, a similar appearance to cocaine, and an ability to pass street purity tests.[29]
Levamisole suppresses the production of white blood cells, resulting in neutropenia and agranulocytosis. With the increasing use of levamisole as an adulterant, a number of these complications have been reported among cocaine users.[15][30][31] Levamisole has also been linked to a risk of vasculitis,[32] and two cases of vasculitic skin necrosis have been reported in users of cocaine adulterated with levamisole.[33]
Levamisole-tainted cocaine was linked to several high-profile deaths. Toxicology reports showed levamisole, along with cocaine, was present in DJ AM's body at the time of his death.[34] Andrew Koppel, son of newsman Ted Koppel, was also found with levamisole in his body after his death was ruled a drug overdose.[35] In 2014 it was suspected to be involved in the death of a Sydney teenager.[36]
In response to the dangers, The Stranger, People's Harm-Reduction Alliance, and DanceSafe began producing tests to identify levamisole's presence in cocaine. The kits include a survey postcard, and one revealed its presence in a 1/4-kg block of cocaine, indicating both users and dealers were using the kits.[37] https://simpmusmari.tistory.com/2.
Chemistry[edit]
Mac zip file download while mac is asleep. The original synthesis at Janssen Pharmaceutica resulted in the preparation of a racemic mixture of two enantiomers, whose hydrochloride salt was reported to have a melting point of 264–265 °C; the free base of the racemate has a melting point of 87–89 °C. The racemic mixture is referred to as 'tetramisole' - levamisole refers only to the levorotatory enantiomer of tetramisole.
Toxicity[edit]
The LD50 (intravenous, mouse) is 22 mg/kg.[38] I forsee the dark ahead if i stay.
Laboratory use[edit]
Levamisole reversibly and noncompetitively inhibits most isoforms of alkaline phosphatase (e.g., human liver, bone, kidney, and spleen) except the intestinal and placental isoform.[39] It is thus used as an inhibitor along with substrate to reduce background alkaline phosphatase activity in biomedical assays involving detection signal amplification by intestinal alkaline phosphatase, for example in in situ hybridization or Western blot protocols.
It is used to immobilize the nematode C. elegans on glass slides for imaging and dissection.[40]
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In a C. elegans behavioral assay, analyzing the time course of paralysis provides information about the neuromuscular junction. Levamisole acts as an acetylcholine receptor agonist, which leads to muscle contraction. Continuing activation leads to paralysis. The time course of paralysis provides information about the acetylcholine receptors on the muscle. For example, mutants with fewer acetylcholine receptors may paralyze slower than wild type.[41]
Research[edit]
It has also been studied as a method to stimulate the immune system as part of the treatment of cancer.[42] It has also shown some efficacy in the treatment of nephrotic syndrome in children.[43]
References[edit]
- ^Keiser J, Utzinger J (April 2008). 'Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis'. JAMA. 299 (16): 1937–48. doi:10.1001/jama.299.16.1937. PMID18430913.
- ^ abcdWHO Model Formulary 2008(PDF). World Health Organization. 2009. pp. 86, 590. ISBN9789241547659. Archived(PDF) from the original on 2016-12-13.
- ^ abc'Levamisole Advanced Patient Information - Drugs.com'. www.drugs.com. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
- ^Prevenier, Martha Howelland Walter (2001). From reliable sources : an introduction to historical methods (1. publ. ed.). Ithaca: Cornell university press. p. 77. ISBN9780801485602. Archived from the original on 2017-09-10.
- ^'WHO Model List of Essential Medicines (19th List)'(PDF). World Health Organization. April 2015. Archived(PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- ^'Levamisole'. International Drug Price Indicator Guide. Retrieved 1 December 2016.
- ^Taylor, M. A.; Coop, R. L.; Wall, R. L. (2015). Veterinary Parasitology. John Wiley & Sons. p. 329. ISBN9781119073673. Archived from the original on 2017-09-10.
- ^'Levamisole (Martindale: The Complete Drug Reference)'. Lexicomp. Archived from the original on 21 December 2016. Retrieved 21 April 2014.
- ^Sanford, Shari (2007). 'Levamisole Hydrochloride: Its application and usage in freshwater aquariums'. Loaches Online. Archived from the original on 2009-03-01. Retrieved 2009-02-27.
- ^(Chirigos et al. (1969, 1973, 1975)).
- ^Scheinfeld N, Rosenberg JD, Weinberg JM (2004). 'Levamisole in dermatology : a review'. American Journal of Clinical Dermatology. 5 (2): 97–104. doi:10.2165/00128071-200405020-00004. PMID15109274.
- ^Vanhoutte PM, Van Nueten JM, Verbeuren TJ, Laduron PM (January 1977). 'Differential effects of the isomers of tetramisole on adrenergic neurotransmission in cutaneous veins of dog'. The Journal of Pharmacology and Experimental Therapeutics. 200 (1): 127–40. PMID189006.
- ^Przegaliński E, Bigajska K, Siwanowicz J (1980). 'Psychopharmacological profile of dexamisole'. Polish Journal of Pharmacology and Pharmacy. 32 (1): 21–9. PMID7454609.
- ^'Levamisole'(PDF). DEA. Archived(PDF) from the original on 17 October 2013. Retrieved 21 April 2014.
- ^ abcCenters for Disease Control Prevention (CDC) (December 2009). 'Agranulocytosis associated with cocaine use - four States, March 2008-November 2009'. MMWR. Morbidity and Mortality Weekly Report. 58 (49): 1381–5. PMID20019655.
- ^Chang A, Osterloh J, Thomas J (September 2010). 'Levamisole: a dangerous new cocaine adulterant'. Clinical Pharmacology and Therapeutics. 88 (3): 408–11. doi:10.1038/clpt.2010.156. PMID20668440.
- ^'Cocaine powder: review of its prevalence, patterns of use and harm'. Advisory Council on the Misuse of Drugs. 12 March 2015.
- ^Kouassi E, Caillé G, Léry L, Larivière L, Vézina M (1986). 'Novel assay and pharmacokinetics of levamisole and p-hydroxylevamisole in human plasma and urine'. Biopharmaceutics & Drug Disposition. 7 (1): 71–89. doi:10.1002/bdd.2510070110. PMID3754161.
- ^Luyckx M, Rousseau F, Cazin M, Brunet C, Cazin JC, Haguenoer JM, Devulder B, Lesieur I, Lesieur D, Gosselin P, Adenis L, Cappelaere P, Demaille A (1982). 'Pharmacokinetics of levamisole in healthy subjects and cancer patients'. European Journal of Drug Metabolism and Pharmacokinetics. 7 (4): 247–54. doi:10.1007/bf03189626. PMID7166176.
- ^Gutierrez, J.; Eisenberg, R.L.; Koval, N.J.; Armstrong, E.R.; Tharappel, J.; Hughes, C.G.; Tobin, T. (August 2010). 'Pemoline and tetramisole 'positives' in English racehorses following levamisole administration'. Irish Veterinary Journal. 63 (8): 498. doi:10.1186/2046-0481-63-8-498. PMC4177197. PMID21777496.
- ^Ho EN, Leung DK, Leung GN, Wan TS, Wong AS, Wong CH, Soma LR, Rudy JA, Uboh C, Sams R (April 2009). 'Aminorex and rexamino as metabolites of levamisole in the horse'. Analytica Chimica Acta. 638 (1): 58–68. doi:10.1016/j.aca.2009.02.033. PMID19298880.
- ^J. Scarth et al. (2010) 'The use of in vitro drug metabolism studies to complement, reduce and refine in vivo administrations in medication and doping control.' Proceedings of the 18th International Conference of Racing Analyists and Veterinarians. pp 213-222
- ^Bertol E, Mari F, Milia MG, Politi L, Furlanetto S, Karch SB (July 2011). 'Determination of aminorex in human urine samples by GC-MS after use of levamisole'. Journal of Pharmaceutical and Biomedical Analysis. 55 (5): 1186–9. doi:10.1016/j.jpba.2011.03.039. PMID21531521.
- ^Hess C, Ritke N, Broecker S, Madea B, Musshoff F (May 2013). 'Metabolism of levamisole and kinetics of levamisole and aminorex in urine by means of LC-QTOF-HRMS and LC-QqQ-MS'. Analytical and Bioanalytical Chemistry. 405 (12): 4077–88. doi:10.1007/s00216-013-6829-x. PMID23436169.
- ^Vandamme TF, Demoustier M, Rollmann B (1995). 'Quantitation of levamisole in plasma using high performance liquid chromatography'. European Journal of Drug Metabolism and Pharmacokinetics. 20 (2): 145–9. doi:10.1007/bf03226369. PMID8582440.
- ^R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, 2011, pp.901-902. 'Archived copy'(PDF). Archived from the original(PDF) on 2011-09-10. Retrieved 2011-01-22.CS1 maint: Archived copy as title (link).
- ^Moisse, Katie (2011-06-23). 'Cocaine Laced With Veterinary Drug Levamisole Eats Away at Flesh'. ABC News. Archived from the original on 2011-06-25. Retrieved 2011-06-23.
- ^Doheny, Kathleen (Jun 1, 2010). 'Contaminated Cocaine Can Cause Flesh to Rot'. Yahoo!. Archived from the original on 7 June 2010. Retrieved 8 June 2010.
- ^Kiley, Brendan (August 17, 2010). 'The Mystery of the Tainted Cocaine'. The Stranger. Archived from the original on December 11, 2010. Retrieved December 21, 2010.
- ^Zhu NY, Legatt DF, Turner AR (February 2009). 'Agranulocytosis after consumption of cocaine adulterated with levamisole'. Annals of Internal Medicine. 150 (4): 287–9. doi:10.7326/0003-4819-150-4-200902170-00102. PMID19153405.
- ^Kinzie E (April 2009). 'Levamisole found in patients using cocaine'. Annals of Emergency Medicine. 53 (4): 546–7. doi:10.1016/j.annemergmed.2008.10.017. PMID19303517.
- ^Menni, Silvano; Pistritto, Grazia; Gianotti, Raffaele; Ghio, Luciana; Edefonti, Alberto (1997). 'Ear Lobe Bilateral Necrosis by Levamisole-Induced Occlusive Vasculitis in a Pediatric Patient'. Pediatric Dermatology. 14 (6): 477–479. doi:10.1111/j.1525-1470.1997.tb00695.x.
- ^Bradford M, Rosenberg B, Moreno J, Dumyati G (June 2010). 'Bilateral necrosis of earlobes and cheeks: another complication of cocaine contaminated with levamisole'. Annals of Internal Medicine. 152 (11): 758–9. doi:10.7326/0003-4819-152-11-201006010-00026. PMID20513844.
- ^''Kate Plus Eight' is enough'. The San Francisco Chronicle. September 29, 2009. Archived from the original on February 2, 2014. Retrieved January 21, 2014.
- ^Parascandola, Rocco (2010-06-18). 'Ted Koppel's son, Andrew Koppel, overdosed on cocktail containing booze, heroin, cocaine and Valium'. Daily News. New York. Archived from the original on 2010-06-22.
- ^Olding, Rachel (2014-01-12). 'Young man's death highlights the tragic reality of online illegal drug stores'. Sydney Morning Herald. Sydney. Archived from the original on 2014-01-13.
- ^Brendan Kiley (September 11, 2012). 'Now Drug Dealers (Not Just Users) Are Testing Their Cocaine for Levamisole'. The Stranger. Archived from the original on September 28, 2012. Retrieved September 14, 2012.
- ^J. Symoens et al. (1979). In Pharmacological and Biochemical Properties of Drug Substances, Vol. 2, (M. E. Goldberg, Ed.), pp. 407-464, Washington: American Pharmaceutical Association.
- ^Van Belle H (July 1976). 'Alkaline phosphatase. I. Kinetics and inhibition by levamisole of purified isoenzymes from humans'. Clinical Chemistry. 22 (7): 972–6. PMID6169.
- ^'Gonad Dissections | Schedl Lab'. Archived from the original on 2014-05-17. Retrieved 2014-05-15. Schedl Lab Protocol for gonad dissections
- ^Rand JB (January 2007). 'Acetylcholine'. WormBook: 1–21. doi:10.1895/wormbook.1.131.1. PMC4781110. PMID18050502.
- ^Dillman RO (February 2011). 'Cancer immunotherapy'. Cancer Biotherapy & Radiopharmaceuticals. 26 (1): 1–64. doi:10.1089/cbr.2010.0902. PMID21355777.
- ^Couderc A, Bérard E, Guigonis V, Vrillon I, Hogan J, Audard V, Baudouin V, Dossier C, Boyer O (December 2017). '[Treatments of steroid-dependent nephrotic syndrome in children]'. Archives de Pediatrie. 24 (12): 1312–1320. doi:10.1016/j.arcped.2017.09.002. PMID29146214.
VA CLASSIFICATION
Primary: IM700
Secondary: AN400
Commonly used brand name(s): Ergamisol.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
*Not commercially available in the U.S.
Category:
Biological response modifier—
antineoplastic adjunct—
Indications
Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.
Accepted
[Carcinoma, colorectal (treatment adjunct)]{26}—Levamisole is indicated, in combination with fluorouracil, for treatment of Dukes C adenocarcinoma of the colon (i.e., with regional lymph node involvement {14}{16}) after complete resection of primary tumor {01}{02}{06}{07}{08}{09}{10}{12}{13}{14}{17}, with no gross or microscopic evidence of residual disease and no evidence of distant metastases or remaining local metastases that could not be removed en bloc with the primary resection {02}{06}{07}{08}{09}{10}{12}{13}{14}{16}. It is not useful for therapy of advanced and metastatic disease {19}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
240.75
Mechanism of action/Effect:
Not precisely known. Levamisole appears to act as an immunorestorative agent in the presence of immunosuppression resulting from recent surgery and chemotherapy {02}{06}{08}{10}, but does not stimulate the immune response to above normal levels {01}. May be related to T-cell activation and proliferation, augmentation of monocyte and macrophage activity (including phagocytosis and chemotaxis), and an increase in neutrophil mobility, adherence, and chemotaxis {01}{02}. Does not have cytotoxic effects {05}{06}.
Other actions/effects:
Anthelmintic {02}{07}{16}. Also has cholinergic {01}{02}{05}, mood-elevating, and, at high doses, convulsant effects {02}{05}. Inhibits alkaline phosphatase in animals {01}{17}.
Absorption:
Rapidly absorbed from gastrointestinal tract {01}{03}{05}.
Biotransformation:
Hepatic, extensive {01}{03}{05}.
Half-life:
Levamisole—3 to 4 hours {01}{05}.
Metabolites—16 hours {01}.
Time to peak plasma concentration
1.5 to 2 hours {01}.
Elimination:
Renal {01}{03}{05}{14}, 70% over 3 days {01} (less than 5% unchanged {01}{05}{14}); fecal {01}{03}{05}{14}, 5% (less than 0.2% unchanged) {01}.
Precautions to Consider
Carcinogenicity
Adequate studies in animals have not been done {16}. Studies at doses of 5, 20, and 80 mg per kg of body weight (mg/kg) per day for up to 18 months in mice and up to 24 months in rats found no evidence of carcinogenicity; however, these studies were not conducted at the maximum tolerated dose, and there is a possibility that the animals may not have been exposed to a reasonable drug challenge {01}. Chronic administration of high doses (25 mg/kg) in New Zealand Black mice increased the rate and intensity of spontaneous lymphomas {05}. No carcinogenic effect was found in 12- to 18-month studies in dogs.
Mutagenicity
Levamisole was not found to be mutagenic in dominant lethal studies in male and female mice, in an Ames test, and in a study to detect chromosomal aberrations in cultured peripheral human lymphocytes {01}.
Pregnancy/Reproduction
Fertility—
Administration through 3 generations of rats and rabbits did not affect fertility {05}. No adverse effects on male or female fertility were noted in rats given oral doses of 2.5, 10, 40, and 160 mg/kg {01}. In a rat gavage study at doses of 20, 60, and 180 mg/kg, the copulation period was increased, the duration of pregnancy was slightly increased, and fertility, pup viability and weight, lactation index, and number of fetuses were decreased at a dose of 60 mg/kg {01}. No adverse reproductive effects occurred when the offspring were allowed to mate and litter {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done.
Studies in rats and rabbits at oral doses up to 180 mg/kg found no evidence of fetal malformations {01}. Embryotoxicity occurred at doses of 160 mg/kg in rats and was significant in rabbits at doses of 180 mg/kg {01}.
FDA Pregnancy Category C.
Breast-feeding
It is not known whether levamisole is distributed into human breast milk; however, it is distributed into cows' milk {01}.
Pediatrics
No information is available on the relationship of age to the effects of levamisole in pediatric patients. Safety and efficacy have not been established {01}.
Geriatrics
Appropriate studies on the relationship of age to the effects of levamisole have not been performed in the geriatric population. However, clinical trials were conducted in older patients and geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected {08}{10}{12}{14}.
Dental
The leukopenic effects of levamisole may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia occurs, dental work should be deferred until blood counts have returned to normal and patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.
Levamisole may also cause mild stomatitis associated with discomfort (severe stomatitis may occur during combination therapy with fluorouracil).
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Anticoagulants, coumarin (there have been reports of prolongation of the prothrombin time beyond the therapeutic range with concurrent use {01}; monitoring of prothrombin time and adjustment of anticoagulant dose, if necessary, are recommended {15})
Bone marrow depressants (see Appendix II ) or
Radiation therapy (leukopenic and/or thrombocytopenic effects of bone marrow depressants or radiation may be increased with concurrent or recent therapy if levamisole causes the same effects; dosage adjustment of the bone marrow depressant, if necessary, should be based on blood counts)
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Risk-benefit should be considered when the following medical problems exist
» Bone marrow depression{13}{14} (may be increased)
» Infection{14} (may be worsened because of bone marrow depression)
Seizure disorder (incidence of seizures associated with levamisole therapy may be increased {24})
» Sensitivity to levamisole{16}
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Alanine aminotransferase (ALT [SGPT]) values, serum and
Alkaline phosphatase values, serum, and
Aspartate aminotransferase (AST [SGOT]) values, serum and
Bilirubin values, serum (recommended prior to initiation of therapy and at 3, 6, 9, and 12 months after initiation of therapy {01}{16})
» Complete blood counts, including differential and platelets{01} (recommended prior to initiation of therapy and before each dose of fluorouracil {01}; although leukopenia is not an indication for withdrawal of levamisole, it is an indication for delaying administration of fluorouracil {16})
Electrolyte concentrations, serum{01}{16} (recommended prior to initiation of therapy and 3, 6, 9, and 12 months after initiation of therapy {01}{16})
Monitoring for tumor recurrence or second primary, which may include{20}{22}{23} :
Carcinoembryonic antigen (CEA)
Chest x-ray
Computed tomographic (CT) scan of abdomen and pelvis
» Colonoscopy or double contrast barium enema x-ray
» History and physical examination
Proctosigmoidoscopy (prior to initiation of therapy and at periodic intervals during therapy)
Side/Adverse Effects
Note: Frequency of side effects listed is for levamisole alone. Side effects are usually mild. Incidence of most side effects, especially hematological and gastrointestinal effects, is more frequent with combination treatment with fluorouracil {01}{02}{03}, although not more frequent than would be expected with fluorouracil alone {02}{03}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Blood dyscrasias, including agranulocytosis{01}{06}{11}{13}{14} or leukopenia{01}{02}{06} (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination), or thrombocytopenia{01}{02} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic
flu-like syndrome{01}{06}{13}{14} (fever; chills; unusual feeling of discomfort or weakness)
mild stomatitis (sores in mouth and on lips)—more frequent with combination treatment with fluorouracil{01}{02}{06}{12}
Note:Agranulocytosis is an idiosyncratic-allergic effect {06}. Sudden onset {06}; commonly preceded by and associated with flu-like syndrome, but may be asymptomatic {01}{06}. Reversible, usually within 7 to 10 days {06}, after levamisole therapy is withdrawn {01}{06}. Sometimes fatal {01}
Levamisole For Horses
.Leukopenia is not associated with bone marrow function impairment {06}. Usually does not develop into agranulocytosis {06} and leukocyte counts usually recover even with continued levamisole therapy (does not apply to combination therapy with fluorouracil) {06}.
The flu-like syndrome is commonly associated with agranulocytosis and may be an early sign of agranulocytosis {06}, but may also occur in the absence of agranulocytosis {01}; also an allergic-type reaction; usually occurs within hours of a dose; may be mild and transient or severe and progressive {06}.
Incidence rare
Central nervous system toxicity, specifically{25} ataxia{24} (trouble in walking), blurred vision{24}
confusion{24}
paranoia{24}
paresthesias{24} (numbness, tingling, or pain in face, hands, or feet), seizures{24}
tardive dyskinesia{24} (lip smacking or puckering; puffing of cheeks; rapid or worm-like movements of tongue; uncontrolled movements of arms and legs), or tremors{25}
cerebrospinal fluid (CSF) pleiocytosis{24} (blurred vision; fever)
hepatotoxicity{01}{17} —not symptomatic
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Diarrhea{01}{02}{06}
metallic taste{01}{02}{03}{17}
nausea{01}{02}{06}{12}{13}{14}
Incidence less frequent
Arthralgia or myalgia{01}{17} (pain in joints or muscles)
central nervous system (CNS) effects, specifically anxiety or nervousness{01}{17}{24}
dizziness{01}
headache{01}{01}{06}{24}
insomnia{24}
mental depression{01}{17}
nightmares{24}
or unusual tiredness or sleepiness{01}{17}
dermatitis{02}{03}{06}{12}{13}{14} (skin rash or itching)
vomiting{02}{06}{13}{14}
Note: A life-threatening exfoliative dermatitis has been reported {17}.
Those not indicating need for medical attention
Incidence less frequent
Alopecia{01}{02}{17} (loss of hair)
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Treatment of overdose
Recommended treatment of overdose includes gastric lavage with symptomatic and supportive treatment {01}.
Patient Consultation
Levamisole Hcl For Fish
As an aid to patient consultation, refer to Advice for the Patient, Levamisole (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to levamisole
Other medical problems, especially infection
Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed
Checking with physician if vomiting occurs shortly after dose is taken
» Proper dosing
Missed dose: Not taking at all; not doubling doses; checking with physician
» Proper storage
Precautions while using this medication
» Importance of close monitoring by the physician
Side/adverse effects
Signs of potential side effects, especially leukopenia, agranulocytosis, flu-like syndrome, stomatitis, and thrombocytopenia
Physician or nurse can help in dealing with side effects
General Dosing Information
Patients receiving levamisole should be under supervision of a physician experienced in cancer therapy.
If agranulocytosis occurs in patients receiving levamisole alone, it is recommended that levamisole be discontinued {06}. However, if leukopenia (leukocyte count of 2500–3500) occurs, single-agent levamisole therapy may be continued {06}{21} with careful monitoring.
Patients who develop leukopenia should be observed carefully for signs of infection. Antibiotic support may be required. In neutropenic patients who develop fever, broad-spectrum antibiotic coverage should be initiated empirically, pending bacterial cultures and appropriate diagnostic tests.
Special precautions are recommended in patients who develop thrombocytopenia as a result of administration of levamisole. These may include extreme care in performing invasive procedures; regular inspection of intravenous sites, skin (including perirectal area), and mucous membrane surfaces for signs of bleeding or bruising; limiting frequency of venipuncture and avoiding intramuscular injections; testing urine, emesis, stool, and secretions for occult blood; care in use of regular toothbrushes, dental floss, toothpicks, safety razors, and fingernail and toenail cutters; avoiding constipation; and using caution to prevent falls and other injuries. Such patients should avoid alcohol and aspirin intake because of the risk of gastrointestinal bleeding. Platelet transfusions may be required.
For use in combination with fluorouracil for colorectal carcinoma
Fluorouracil therapy should be discontinued promptly if the patient develops stomatitis or diarrhea. If stomatitis or diarrhea develops during weekly therapy, the next dose of fluorouracil should be withheld until it has resolved. If these effects are moderate to severe, a 20% reduction in dosage is recommended when fluorouracil therapy is resumed {01}{17}.
If leukopenia occurs, the following adjustments in fluorouracil therapy are recommended: • If the leukocyte count is 2500–3500, the fluorouracil dose should be withheld until the count exceeds 3500.
• If the leukocyte count is less than 2500, the fluorouracil dose should be withheld until the count exceeds 3500, then resumed with a dosage reduction of 20%. If the leukocyte count remains below 2500 for over 10 days despite withholding of fluorouracil, administration of both levamisole and fluorouracil should be discontinued. {01}
If thrombocytopenia occurs, it is recommended that both levamisole and fluorouracil be withheld until platelet counts exceed 100,000 {01}.
Oral Dosage Forms
Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.
LEVAMISOLE HYDROCHLORIDE TABLETS
Note: The dosing and strengths are expressed in terms of levamisole base.
Usual adult dose
[Colorectal carcinoma]
Oral, beginning seven to thirty days after surgery, 50 mg (base) every eight hours for three days, repeated every two weeks for one year. It is given in combination with fluorouracil 450 mg per square meter of body surface by rapid intravenous push once a day for five days concomitant with a three-day course of levamisole, followed by 450 mg per square meter of body surface once a week beginning twenty-eight days after initiation of the five-day course and continued for a total treatment time of one year. Fluorouracil therapy should be initiated between twenty-one and thirty-five days after surgery. If levamisole treatment is initiated from seven to twenty days after surgery, fluorouracil should be initiated with the second course of levamisole (i.e., at twenty-one to thirty-four days). If levamisole is initiated from twenty-one to thirty days after surgery, fluorouracil should be initiated with the first course of levamisole. {01}{26}
Note: Although fluorouracil dosages are based on the patient's actual weight, use of estimated lean body mass (dry weight) is recommended in obese patients or those with weight gain due to edema, ascites, or other abnormal fluid retention {01}.
Usual pediatric dose
Safety and efficacy have not been established {01}.
Strength(s) usually available
U.S.—
Not commercially available in the United States.{26}
Canada—
50 mg (base) (Rx) [Ergamisol (lactose)]
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.
Revised: 02/20/2001
References
- Ergamisol package insert (Janssen—US), Rev 6/90.
- Laurie JA, Moertel C, Fleming TR. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol 1989 Oct; 7: 1447-56.
- Levamisole with fluorouracil for colon cancer. Med Lett Drugs Ther.
- Procedures for treatment use and sale of investigational drugs established. Food and Drug Administraton Order, published at 52 F.R. 19466, May 22, 1987; corrected, 52 F.R. 23628, June 23, 1987. Food Drug Cosmetic Law Reports 1987 Jul 7; Item 40,351; p. 40,769-88.
- Renoux G. The general immunopharmacology of levamisole. Drugs 1980; 19: 89-99.
- Spreafico F. Use of levamisole in cancer patients. Drugs 1980; 19: 105-16.
- Verhaegen H, De Cree J, De Cock W, et al. Levamisole therapy in patients with colorectal cancer. In Terry WD, Rosenberg SA, editors. Immunotherapy of human cancer. New York: Elsevier; 1982. p. 225-9.
- Borden ED, Davis TE, Crowley JJ, et al. Interim analysis of a trial of levamisole and 5-fluorouracil in metastatic colorectal carcinoma. In Terry WD, Rosenberg SA, editors. Immunotherapy of human cancer. New York: Elsevier; 1982. p. 225-9.
- Laurie J, Moertel C, Fleming T, et al. Surgical adjuvant therapy of poor prognosis colorectal cancer with levamisole alone or combined levamisole and 5-fluorouracil (5-FU). A North Central Cancer Treatment Group and Mayo Clinic study [abstract 316]. Proc Am Soc Clin Oncol 1986; 5: 81.
- Windle R, Bell PRF, Shaw D. Five year results of a randomized trial of adjuvant 5-fluorouracil and levamisole in colorectal cancer. Br J Surg 1987; 74: 569-72.
- Focan C, Schyns-Mosen J, Focan-Henrard D. Levamisole or placebo after effective chemotherapy for remission and survival prolongation in advanced human solid tumors—a double-blind randomized trial. Acta Oncol 1989; 28(1): 105-6.
- Chlebowski RT, Nystrom S, Reynolds R, et al. Long-term survival following levamisole or placebo adjuvant treatment of colorectal cancer: a Western Cancer Study Group trial. Oncology 1988; 45: 141-3.
- Arnaud JP, Buyse M, Adloff M, et al. Interim analysis of a double-blind phase-III clinical trial of adjuvant levamisole versus control in resectable Dukes-C colon cancer: a study of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Recent Results Cancer Res 1988; 110: 101-3.
- Arnaud JP, Buyse M, Nordlinger B, et al. Adjuvant therapy of poor prognosis colon cancer with levamisole: results of an EORTC double-blind randomized clinical trial. Br J Surg 1989 Mar; 76: 284-9.
- Ergamisol package insert (Janssen—US), Rev 11/90.
- Group C/Treatment Protocol. Levamisole plus 5-fluorouracil as an adjuvant to surgery for resectable adenocarcinoma of the colon. NCI Protocol #189-0017, 6/30/89.
- Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl J Med 1990; 322: 352-8.
- Reviewer comment, 3/1/90.
- Reviewer comment, 1/15/91.
- Reviewers' responses to panel question #3a, 1/91.
- Reviewers' responses to panel question #5, 1/91.
- Beart RW, O'Connell MJ. Postoperative follow-up of patients with carcinoma of the colon. Mayo Clin Proc 1983; 58: 361-3.
- Sugarbaker PH, Gianola FJ, Dwyer A, et al. A simplified plan for follow-up of patients with colon and rectal cancer supported by prospective studies of laboratory and radiologic test results. Surgery 1987; 102: 79-87.
- Dept. of Health and Human Services memorandum from Senior Investigator, BES, IDB, CTEP, DCT, NCI. To: All investigators using levamisole. Subject: The possible association of CNS syndromes (including seizures and CSF pleiocytosis) following levamisole administration. Dated: August 16, 1990.
- Grem JL. Levamisole as a therapeutic agent for colorectal carcinoma. Cancer Cells 1990: 131-7.
- Dear Doctor Letter: Notice of Discontinuation, Ergamasol®, levamisole HCL. Janssen Pharmaceutica Inc., October 5, 2000. Reviewed 02/2001.
Further information
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.