ERGAMISOL® (levamisole hydrochloride) is an immunomodulator available in tablets for oral administration containing the equivalent of 50 mg as levamisole base. Fifty-nine (59) mg of levamisole HCl is equivalent to 50 mg of levamisole base. Inactive ingredients are colloidal silicon dioxide, hydrogenated vegetable oil, hydroxypropyl methylcellulose, lactose, microcystalline cellulose, polyethylene glycol 6000, polysorbate 80, and talc.

Levamisole hydrochloride is (-)-(S)-2,3,5,6-tetrahydro-6-phenylimidazo [2,1-b] thiazole monohydrochloride.

Levamisole hydrochloride is a white to almost white crystalline powder which is almost odorless and is freely soluble in water. It is quite stable in acid aqueous media but hydrolyzes in alkaline or neutral solutions. It has a molecular weight of 240.75.

Two clinical trials having essentially the same design have demonstrated an increase in survival and a reduction in recurrence rate in the subset of patients with resected Dukes' C colon cancer treated with a regimen of ERGAMISOL® (levamisole hydrochloride) plus fluorouracil 1,2 . After surgery, patients were randomized to no further therapy, ERGAMISOL® alone, or ERGAMISOL® plus fluorouracil.

In one clinical trial in which 408 Dukes' B and C colorectal cancer patients were studied, 262 Dukes' C patients were evaluated for a minimum follow-up of five years 1 . A subset analysis of these Dukes' C patients showed the estimated reduction in death rate was 27% for ERGAMISOL® plus fluorouracil (p = 0.11) and 28% for ERGAMISOL® alone (p = 0.11) 3 . The estimated reduction in recurrence rate was 36% for ERGAMISOL® plus fluorouracil (p = 0.025) and 28% for ERGAMISOL® alone (p = 0.11) 3 . In another clinical trial designed to confirm the above results, 929 Dukes' C colon cancer patients were evaluated for a minimum follow-up of 2 years 2 . The estimated reduction in death rate was 33% for ERGAMISOL® plus fluorouracil (p = 0.006). The estimated reduction in recurrence rate was 41% for ERGAMISOL® plus fluorouracil (p<0.0001). The ERGAMISOL® alone group did not show advantage over no treatment on improving recurrence or survival rates. There are presently insufficient data to evaluate the effect of the combination of ERGAMISOL® plus fluorouracil in Dukes' B patients. There are also insufficient data to evaluate the effect of ERGAMISOL® plus fluorouracil in patients with rectal cancer because only 12 patients with rectal cancer were treated with the combination in the first study and none in the second study.

The mechanism of action of ERGAMISOL® in combination with fluorouracil is unknown. The effects of levamisole on the immune system are complex. The drug appears to restore depressed immune function rather than to stimulate response to above-normal levels. Levamisole can stimulate formation of antibodies to various antigens, enhance T-cell responses by stimulating T-cell activation and proliferation, potentiate monocyte and macrophage functions including phagocytosis and chemotaxis, and increase neutrophil mobility, adherence, and chemotaxis. Other drugs have similar short-term effects and the clinical relevance is unclear.

Besides its immunomodulatory function, levamisole has other mammalian pharmacologic activities, including inhibition of alkaline phosphatase, and cholinergic activity.

The pharmacokinetics of ERGAMISOL® have not been studied in the dosage regimen recommended with fluorouracil. After administration of a single oral dose of 50 mg of a research formulation of ERGAMISOL®, it appears that levamisole is rapidly absorbed from the gastrointestinal tract. Mean peak plasma concentrations of 0.13 mcg/ml are attained within 1.5 to 2 hours. The plasma elimination half-life of levamisole is between 3-4 hours. Following a 150-mg radio-labeled dose, levamisole is extensively metabolized by the liver in humans and the metabolites excreted mainly by the kidneys (70% over 3 days). The elimination half-life of metabolite excretion is 16 hours. Approximately 5% is excreted in the feces. Less than 5% is excreted unchanged in the urine and less than 0.2% in the feces. Approximately 12% is recovered in the urine as the glucuronide of p-hydroxy-levamisole. The clinical significance of these data are unknown since a 150-mg dose may not be proportional to a 50-mg dose. In the presence of cirrhosis in twelve patients with alcoholic cirrhosis and hepatitis, the Cmax of ERGAMISOL® was not clearly increased, but the AUC was 1 to 20-fold increased compared to normal volunteers.

ERGAMISOL® (levamisole hydrochloride) is only indicated as adjuvant treatment in combination with fluorouracil after surgical resection in patients with Dukes' stage C colon cancer.

CONTRAINDICATIONS

ERGAMISOL® (levamisole hydrochloride) is contraindicated in patients with a known hypersensitivity to the drug or its components.

Cases of an encephalopathy-like syndrome associated with demyelination have been reported in patients treated with ERGAMISOL® (levamisole hydrochloride). Worldwide postmarketing experience with the combination therapy of ERGAMISOL® and fluorouracil has also included reports of peripheral neuropathy and multifocal inflammatory leukoencephalopathy. The onset of symptoms and the clinical presentation in these cases are quite varied. Symptoms may include coma, confusion, lethargy, memory loss, muscle weakness, paresthesia, seizures, and speech disturbances. This condition has been associated with MRI and CT scan findings of demyelinating lesions in the white matter. If an acute neurological syndrome occurs, ERGAMISOL® and fluorouracil should be discontinued immediately. Patients have generally recovered/improved with drug discontinuation, but in some cases patients have not recovered/improved and deaths have been reported. Patients are generally treated with corticosteroids, but the efficacy of corticosteroids has not been proven.

ERGAMISOL® has been associated with agranulocytosis, sometimes fatal. The onset of agranulocytosis is frequently accompanied by a flu-like syndrome (fever, chills, etc.); however, in a small number of patients it is asymptomatic. A flu-like syndrome may also occur in the absence of agranulocytosis. It is essential that appropriate hematological monitoring be done routinely during therapy with ERGAMISOL® and fluorouracil. Neutropenia is usually reversible following discontinuation of therapy. Patients should be instructed to report immediately any flu-like symptoms.

Higher than recommended doses of ERGAMISOL® may be associated with an increased incidence of agranulocytosis, so the recommended dose should not be exceeded. The combination of ERGAMISOL® and fluorouracil has been associated with frequent neutropenia, anemia and thrombocytopenia.

In the presence of cirrhosis in twelve patients with alcoholic cirrhosis and hepatitis, the Cmax of ERGAMISOL® was not clearly increased, but the AUC was 1 to 20-fold increased compared to normal volunteers. Patients with hepatic impairment should be monitored for adverse events, including encephalopathy. Dose modification or discontinuation of ERGAMISOL® may be necessary if adverse experiences are observed.

PRECAUTIONS

Before beginning this combination adjuvant treatment, the physician should become familiar with the labeling for fluorouracil.

Information for Patients:   The patient should be informed that if flu-like symptoms or malaise occurs, the physician should be notified immediately.

Drug Interactions:   ERGAMISOL® (levamisole hydrochloride) has been reported to produce "ANTABUSE®"-like side effects when given concomitantly with alcohol. Concomitant administration of phenytoin and ERGAMISOL® plus fluorouracil has led to increased plasma levels of phenytoin. The physician is advised to monitor plasma levels of phenytoin and to decrease the dose if necessary.

Because of reports of prolongation of the prothrombin time beyond the therapeutic range in patients taking concurrent levamisole and warfarin sodium, it is suggested that the prothrombin time be monitored carefully, and the dose of warfarin sodium or other coumarin-like drugs should be adjusted accordingly, in patients taking both drugs.

Laboratory Tests:   On the first day of therapy with ERGAMISOL®/fluorouracil, patients should have a CBC with differential and platelets, electrolytes and liver function tests performed. Thereafter, a CBC with differential and platelets should be performed weekly prior to each treatment with fluorouracil with electrolytes and liver function tests peformed every 3 months for a total of one year. Dosage modifications should be instituted as follows: If WBC is 2500-3500/mm 3 defer the fluorouracil dose until WBC is >3500/mm 3 . If WBC is < 2500/mm 3 , defer the fluorouracil dose until WBC is > 3500/mm 3 ; then resume the fluorouracil dose reduced by 20%. If WBC remains < 2500/mm 3 for over 10 days despite deferring fluorouracil, discontinue administration of ERGAMISOL®. Both drugs should be deferred unless enough platelets are present (>/= 100,000/mm 3 ).

Carcinogenesis, Mutagenesis, Impairment of Fertility: Adequate animal carcinogenicity studies have not been conducted with levamisole. Studies of levamisole administered in drinking water at 5, 20, and 80 mg/kg/day to mice for up to 18 months or adminstered to rats in the diet at 5, 20, and 80 mg/kg/day for 24 months showed no evidence of neoplastic effects. These studies were not conducted at the maximum tolerated dose, therefore the animals may not have been exposed to a reasonable drug challenge. No mutagenic effects were demonstrated 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.

Adverse effects were not observed on male or female fertility when levamisole was administered to rats in the diet at doses of 2.5, 10, 40, and 160 mg/kg. 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 60 mg/kg. No negative reproductive effects were present when the offspring were allowed to mate and litter.

Pregnancy:   Pregnancy Category C: Teratogenicity studies have been performed in rats and rabbits at oral doses up to 180 mg/kg. Fetal malformations were not observed. In rats, embryotoxicity was present at 160 mg/kg and in rabbits, significant embryotoxicity was observed at 180 mg/kg. There are no adequate and well-controlled studies in pregnant women and ERGAMISOL® should not be administered unless the potential benefits outweigh the risks. Women taking the combination of ERGAMISOL® and fluorouracil should be advised not to become pregnant.

Nursing Mothers:   It is not known whether ERGAMISOL® is excreted in human milk; it is excreted in cows' milk. Because of the potential for serious adverse reactions in nursing infants from ERGAMISOL®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:   Safety and effectiveness of ERGAMISOL® in children have not been established.

ADVERSE REACTIONS

Almost all patients receiving ERGAMISOL® (levamisole hydrochloride) and fluorouracil reported adverse experiences. Tabulated below is the incidence of adverse experiences that occurred in at least 1% of patients enrolled in two clinical trials who were adjuvantly treated with either ERGAMISOL® or ERGAMISOL® plus fluorouracil following colon surgery. In the larger clinical trial, 66 of 463 patients (14%) discontinued the combination of ERGAMISOL® plus fluorouracil because of adverse reactions. Forty-three of these patients (9%) developed isolated or a combination of gastrointestinal toxicities. (e.g., nausea, vomiting, diarrhea, stomatitis and anorexia). Ten patients developed rash and/or pruritus. Five patients discontinued therapy because of flu-like symptoms or fever with chills; ten patients developed central nervous system symptoms such as dizziness, ataxia, depression, confusion, memory loss, weakness, inability to concentrate, and headache; two patients developed reversible neutropenia and sepsis; one patient because of thrombocytopenia; one patient because of hyperbilirubinemia. One patient in the ERGAMISOL® plus fluorouracil group developed agranulocytosis and sepsis and died.

In the ERGAMISOL® alone arm of the trial, 15 of 310 patients (4.8%) discontinued therapy because of adverse experiences. Six of these (2%) discontinued because of rash, six because of arthralgia/myalgia, and one each for fever and neutropenia, urinary infection, and cough.

Adverse experience
ERGAMISOL®
  
N = 440
%
ERGAMISOL®
plus fluorouracil
N = 599
%
22 65
13 52
3 39
6 20
2 6
2 5
2 3
<1 2
<1 1
Hematological
   
  <2000/mm 3
<1 1
  >/=2000 to <4000/mm 3
4 19
  >/=4000/mm 3
2 33
  unscored category
0 <1
   
  <50,000/mm 3
0 0
  >/=50,000 to <130,000/mm 3
1 8
  >/=130,000/mm 3
1 10
0 6
<1 2
0 1
Skin and Appendages
8 23
3 22
1 2
Skin discoloration
0 2
<1 0
Body as a Whole
6 11
3 5
Rigors
3 5
<1 1
1 1
Resistance Mechanisms
5 12
Special Senses
   
8 8
Altered sense of smell
1 1
5 4
3 2
Central and peripheral nervous system
3 4
3 4
2 3
0 2
3 2
1 2
1 2
1 1
1 1
Forgetfulness
0 1
0 4
Blurred vision
1 2
<1 2
<1 1

In worldwide experience with ERGAMISOL®, less frequent adverse experiences included exfoliative dermatitis, fixed drug eruptions, periorbital edema, vaginal bleeding, anaphylaxis, confusion, convulsions, hallucinations, impaired concentration, renal failure, pancreatitis, elevated serum creatinine, and increased alkaline phosphatase.

Reports of hyperlipidemia have been observed in patients receiving combination therapy of ERGAMISOL® and fluorouracil; elevations in triglyceride levels have been greater than increases in cholesterol levels. In worldwide postmarketing experience with the combination therapy, there have been rare cases of elevated hepatic enzymes and hepatosteatosis in patients. Isolated cases of Stevens-Johnson syndrome have also been reported.

The following additional adverse experiences have been reported for fluorouracil alone: esophagopharyngitis, pancytopenia, myocardial ischemia, angina, gastrointestinal ulceration and bleeding, anaphylaxis and generalized allergic reactions, acute cerebellar syndrome, nystagmus, dry skin, fissuring, photosensitivity, lacrimal duct stenosis, photophobia, euphoria, thrombophlebitis, and nail changes.

OVERDOSAGE

Fatalities have been reported in a three-year-old child who ingested 15 mg/kg and in an adult who ingested 32 mg/kg. No further clinical information is available. In cases of overdosage, gastric lavage is recommended together with symptomatic and supportive measures.

DOSAGE AND ADMINISTRATION

The adjuvant use of ERGAMISOL® (levamisole hydrochloride) and fluorouracil is limited to the following dosage schedule:

Initial Therapy:
ERGAMISOL®: 50 mg p.o.
  q8h for 3 days
(starting 7-30 days
post-surgery)
fluorouracil: 450 mg/m 2 /day
  IV for 5 days
(starting 21-34 days
post-surgery)
  concomitant with a 3-day course
  of ERGAMISOL®

Maintenance:

ERGAMISOL®: 50 mg p.o. q8h for 3 days every 2 weeks.

fluorouracil: 450 mg/m 2 /day IV once a week beginning 28 days after the initiation of the 5-day course.

Treatment:   ERGAMISOL®, administered orally, should be initiated no earlier than 7 and no later than 30 days post-surgery at a dose of 50 mg q8h × 3 days repeated every 14 days for 1 year. Fluorouracil therapy should be initiated no earlier than 21 days and no later than 35 days after surgery providing the patient is out of the hospital, ambulatory, maintaining normal oral nutrition, has well-healed wounds, and is fully recovered from any postoperative complications. If ERGAMISOL® has been initiated from 7 to 20 days after surgery, initiation of fluorouracil therapy should be coincident with the second course of ERGAMISOL®, i.e., at 21 to 34 days. If ERGAMISOL® is initiated from 21 to 30 days after surgery, fluorouracil should be initiated simultaneously with the first course of ERGAMISOL®. Since the AUC of ERGAMISOL® is markedly increased in cirrhotic patients, such patients should be observed closely for adverse effects. Dose reduction or discontinuation of ERGAMISOL® may be warranted if adverse experiences are noted.

Fluorouracil should be administered by rapid IV push at a dosage of 450 mg/m 2 /day for 5 consecutive days. Dosage calculation is based on actual weight (estimated dry weight if there is evidence of fluid retention). This course should be discontinued before the full 5 doses are administered if the patient develops any stomatitis or diarrhea (5 or more loose stools). Twenty-eight days after initiation of this course, weekly fluorouracil should be instituted at a dosage of 450 mg/m 2 /week and continued for a total treatment time of 1 year. If stomatitis or diarrhea develop during weekly therapy, the next dose of fluorouracil should be deferred until these side effects have subsided. If these side effects are moderate to severe, the fluorouracil dose should be reduced 20% when it is resumed.

Dosage modifications should be instituted as follows: If WBC is 2500-3500/mm 3 defer the fluorouracil dose until WBC is >3500/mm 3 . If WBC is <2500/mm 3 , defer the fluorouracil dose until WBC is >3500/mm 3 ; then resume the fluorouracil dose reduced by 20%. If WBC remains <2500/mm 3 for over 10 days despite deferring fluorouracil, discontinue administration of ERGAMISOL®. Both drugs should be deferred unless platelets are adequate (>/=100,000/mm 3 ).

ERGAMISOL® should not be used at doses exceeding the recommended dose or frequency. Clinical studies suggest a relationship between ERGAMISOL® adverse experiences and increasing dose, and since some of these, e.g. agranulocytosis, may be life-threatening, the recommended dosage regimen should not be exceeded (see " " ).

Before beginning this combination adjuvant treatment, the physician should become familiar with the labeling for fluorouracil.

HOW SUPPLIED

ERGAMISOL® (levamisole hydrochloride) is available in white, coated tablets containing the equivalent of 50 mg of levamisole base, debossed "JANSSEN"and "L"/"50".

They are supplied in blister packages of 36 tablets (NDC 50458-270-36).

Store at controlled room temperature, (59°-77°F/15°-25°C).

Protect from moisture.

REFERENCES

  1. Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large-bowel carcinoma: An evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol. 1989; 7:1447-1456.
  2. Moertel CG, Fleming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl J Med. 1990; 322:352-358.
  3. Data on file, Janssen Pharmaceutica Inc.

Manufactured by:

Janssen Pharmaceutica, nv

Beerse, Belgium

Distributed by:

Janssen Pharmaceutica Inc.

Titusville, NJ 08560

Edition October 1998, August 1999

U.S. Patent Number 4,584,305

©Janssen Pharmaceutica Products, L.P. 1999

                                                             7500112

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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