ERGAMISOL® 50 mg film-coated tablets

INDICATIONS CONTRA-INDICATIONS DOSAGE SIDE-EFFECTS PREGNANCY OVERDOSE IDENTIFICATION PATIENT INFORMATION

ERGAMISOL® 50 mg film-coated tablets

SCHEDULING STATUS:
Schedule 4

PROPRIETARY NAME
(and dosage form):

ERGAMISOL^® 50 mg film-coated tablets

COMPOSITION
Each tablet contains 59 mg levamisole hydrochloride equivalent to 50 mg levamisole base.

PHARMACOLOGICAL CLASSIFICATION
A.20.2 Antimicrobial (Chemotherapeutic) agents other than antibiotics.

PHARMACOLOGICAL ACTION
Levamisole is an immunomodulator which restores depressed immune function. Levamisole is also an immunoadjuvant since its effect on the immune system depends in part on the presence of antigenic stimulation.
Levamisole can stimulate antibody formation to various antigens, enhance T-cell responses by stimulating T-cell activation and proliferation, potentiate monocyte and macrophage functions including phagocytosis, chemotaxis and increases motility, adherence and chemotaxis.
The exact mechanism of action of levamisole hydrochloride in combination with 5-fluorouracil (5-FU) is unknown.
Levamisole inhibits alkaline phosphatase and possesses cholinergic activity. Levamisole is rapidly absorbed from the gastro-intestinal tract following a single oral dose of 50 mg. Mean peak plasma concentrations of 0,13 µg/mL are reached within 1,5 to 2 hours. The plasma elimination half-life is 3 to 6 hours. Less than 5% of the dose is excreted unchanged in the urine and less than 0,2% in the faeces. Levamisole is extensively metabolised in the liver to many metabolites which are excreted predominantly by the kidneys (about 70% over 3 days) and to a lesser extent in the faeces (5%). A major metabolite recovered from urine is p-hydroxylevamisole and its glucuronide conjugate (12% of the dose).

INDICATIONS
In combination with 5-fluorouracil as adjuvant treatment after surgical resection in patients with Dukes' Stage C colon cancer.

CONTRA-INDICATIONS
Known hypersensitivity to any ingredients.
Safety in pregnancy and lactation has not been established.

WARNINGS
ERGAMISOL has been associated with agranulocytosis. Some fatalities have been reported. 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 haematological monitoring be done routinely during therapy with ERGAMISOL and 5-fluorouracil. Neutropaenia is usually reversible following discontinuation of therapy. Leucopaenia (total WBC below 3000 mm³) is not necessarily a sign of impending agranulocytosis; recovery is possible without withdrawal of the drug. However, a significantly reduced neutrophil count is reason for discontinuation of the medicine. Patients should be instructed to report immediately any flu-like symptoms.
There is some evidence that higher than recommended doses of ERGAMISOL may be associated with an increased incidence of agranulocytosis so that the recommended dose should not be exceeded.

DOSAGE AND DIRECTIONS FOR USE
The combination of ERGAMISOL and 5-fluorouracil is administered according to the following dosage schedule:
Initial Therapy

Week of therapy	5-fluorouracil 450 mg/m² i.v. push	ERGAMISOL 50 mg orally t.i.d
Week 1 (3rd to 4th week post surgery)	Days 1 –5	Days 1 –3
Week 2
Week 3		Days 1 –3
Week 4

Therapy should commence 3 –4 weeks post surgery.
5-Fluorouracil (450 mg/m²) is administered by rapid i.v. injection for the first 5 days of Week 1.
ERGAMISOL 50 mg tablet is administered orally three times a day for the first 3 days of Week 1, and again on the first 3 days of Week 3.

Maintenance Therapy

Week of therapy	5-fluorouracil 450 mg/m² i.v. push	ERGAMISOL 50 mg orally t.i.d.
Week 5	Day 1	Days 1 –3	Repeat cycle up to
Week 6	Day 1		Week 52

5-Fluorouracil therapy (450 mg/m²) is administered by rapid i.v. injection on the first day of each week.
ERGAMISOL 50 mg tablet is administered orally three times a day for the first three days of every alternate week.
This maintenance cycle is repeated up to Week 52.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The following side-effects have been reported with ERGAMISOL: headache, confusion, dizziness, excitation, convulsions, nervousness, insomnia, depression, nausea, vomiting, anorexia, diarrhoea, constipation, stomatitis, altered sense of taste, and/or smell, flu-like syndrome (fever, fatigue), cutaneous vasculitis, agranulocytosis (see "WARNINGS"), thrombocytopaenia, leucopaenia, skin rash, including fixed drug eruption, dermatitis, myalgia, arthralgia.
An encephalopathy-like syndrome has been reported. World-wide postmarketing experience with the combination therapy of ERGAMISOL and fluorouracil has also included several reports of neurological changes associated with demyelination. The onset of symptoms and clinical presentation in these cases are quite varied. Symptoms may include: memory loss, confusion, paraesthesia, lethargy, muscle weakness, speech disturbances, coma and seizures. Examination of cerebrospinal fluid may reveal a mild pleocytosis and CT and MRI scans often disclose lesions in the white matter suggestive of demyelination. This picture is known in the literature as MILE (multifocal inflammatory leukoencephalophathy). The occurrence of this syndrome necessitates the discontinuation of treatment. As a rule, the condition is at least partially reversible upon discontinuation and treatment with a corticosteroid.
Occasional cases of acute pancreatitis have been reported, not uncommonly in association with hypertriglyceridaemia.
The side-effects with the combination of ERGAMISOL and 5-fluorouracil are essentially similar to the side-effects of 5-fluorouracil alone ie. bone marrow suppression, leucopaenia, stomatitis, gastro-intestinal ulceration and bleeding, anaemia, thrombocytopaenia, nausea, vomiting, skin rashes, hyperpigmentation, alopecia, central neurotoxicity, myocardial ischaemia. Seizures may occur.
Mild and asymptomatic abnormalities (e.g. a doubling) in the results of liver-function tests (transaminase, alkaline phosphatase and/or bilirubinaemia) have been reported more frequently with Ergamisol alone than with untreated controls (11,2% versus 4,0% and 2,8%, respectively). In some instances hepatosteatosis was found. These liver abnormalities may be reversible upon discontinuation.
Due to the intermittent nature of the dosage schedule, drug discontinuation may not be necessary for successful resolution
Prior to beginning this adjuvant treatment, the physician should be familiar with the prescribing information relating to 5-fluorouracil.
An increase in serum triglyceride levels, sometimes associated with a rise in cholesterol, may occur. These increases reverse after ERGAMISOL therapy is discontinued.

Interactions
Caution is necessary when levamisole is used in combination with other drugs potentially affecting haemopoiesis.
ERGAMISOL may enhance the anticoagulant effect of coumarin-like drugs. The anticoagulant effect should be carefully titrated and monitored. Levamisole has been reported to produce disulfiram-like side-effects when given concomitantly with alcohol.
ERGAMISOL may increase the blood level of phenytoin. Blood levels of phenytoin should be monitored when both drugs are given concomitantly.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms of overdosage may include emesis, nausea, lethargy, cramps, diarrhoea, headache, dizziness and confusion. According to animal data, levamisole may have minor anticholinesterase activity and, on intravenous administration, some positive chronotropic and inotropic cardiac effects.
In cases of overdosage, gastric lavage together with monitoring of vital signs and general supportive measures are recommended.

IDENTIFICATION
White circular, normally arched, film-coated tablets with "L" above "50" inscribed on one side and "Janssen" inscribed on the other.

PRESENTATION
Cartons containing blister strips with 6, 9, 12 or 18 tablets

STORAGE INSTRUCTIONS
Store below 25°C.
Keep out of reach of children.

REGISTRATION NUMBER
Y/20.2/293

NAME AND BUSINESS ADDRESS OF THE APPLICANT
JANSSEN-CILAG
Janssen Pharmaceutica (Pty) Ltd., (Reg. No. 80/11122/07)
15th Road, HALFWAY HOUSE, 1685
© JPH (Pty) Ltd. SA 1991

DATE OF PUBLICATION OF THIS PACKAGE INSERT

9 October 1991.

Code No.. 023175
96D