Levamisole (Systemic)


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}.
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
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
  1. Ergamisol package insert (Janssen—US), Rev 6/90.
  1. 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.
  1. Levamisole with fluorouracil for colon cancer. Med Lett Drugs Ther.
  1. 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.
  1. Renoux G. The general immunopharmacology of levamisole. Drugs 1980; 19: 89-99.
  1. Spreafico F. Use of levamisole in cancer patients. Drugs 1980; 19: 105-16.
  1. 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.
  1. 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.
  1. 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.
  1. 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.
  1. 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.
  1. 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.
  1. 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.
  1. 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.
  1. Ergamisol package insert (Janssen—US), Rev 11/90.
  1. 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.
  1. 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.
  1. Reviewer comment, 3/1/90.
  1. Reviewer comment, 1/15/91.
  1. Reviewers" responses to panel question #3a, 1/91.
  1. Reviewers" responses to panel question #5, 1/91.
  1. Beart RW, O"Connell MJ. Postoperative follow-up of patients with carcinoma of the colon. Mayo Clin Proc 1983; 58: 361-3.
  1. 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.
  1. 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.
  1. Grem JL. Levamisole as a therapeutic agent for colorectal carcinoma. Cancer Cells 1990: 131-7.
  1. Dear Doctor Letter: Notice of Discontinuation, Ergamasol®, levamisole HCL. Janssen Pharmaceutica Inc., October 5, 2000. Reviewed 02/2001.
Hide
(web4)